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1 pages, 127 KiB

Open AccessAbstract

Development of Thienopyridines as Potent Antiproliferative Agents

by David Barker, Lisa Ivy Pilkington, Natalie Haverkate, Euphemia Leung and Johannes Reynisson

Proceedings 2019, 22(1), 2; https://doi.org/10.3390/proceedings2019022002 - 6 Aug 2019

Viewed by 1519

Abstract

Virtual high throughput screening of a large compound library against the regulatory enzyme phospholipase C (PLC) led to the discovery of the thieno[2,3-b]pyridine-2-carboxamides as potential inhibitors. Subsequent biological testing verified the antiproliferative activity of this compound class. Morphology and motility assays, [...] Read more.

Virtual high throughput screening of a large compound library against the regulatory enzyme phospholipase C (PLC) led to the discovery of the thieno[2,3-b]pyridine-2-carboxamides as potential inhibitors. Subsequent biological testing verified the antiproliferative activity of this compound class. Morphology and motility assays, using a number of triple negative breast cancer cell lines, led to the conclusion that PLC is the most probable biomolecular target. Using a combination of computer-aided drug design and synthesis, further analogues have been prepared and tested for their antiproliferative activity, allowing a comprehensive SAR to be developed. Numerous analogues with low nano-molar growth inhibition against various cancers have been prepared. SAR studies suggest that the core structure can be fine-tuned to specific cancers, potentially due to enzyme/isoform specificity. Additionally, mouse xenograft assays showed significant reduction in tumour size after treatment, whilst showing no adverse effects to non-cancerous mice. Here, we report on our recent development of novel thienopyridines and derivatives, expanding the SAR against PLC, and our efforts to prepare potent, soluble, and bioavailable compounds. Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 128 KiB

Open AccessAbstract

The Indole Phytoalexin Derivatives Induced a Significant Inhibition on Src Kinase Activity of Human Cancer Cells

by Filiz Bakar-Ates

Proceedings 2019, 22(1), 3; https://doi.org/10.3390/proceedings2019022003 - 6 Aug 2019

Viewed by 1237

Abstract

The Src, a protein kinase, is a family of protein tyrosine kinases (SFKs), and this protein catalyses the phosphorylation of tyrosine. The studies have revealed its key roles in regulating signal transduction from cell surface receptors. The Src kinases act as cytoplasmic signalling [...] Read more.

The Src, a protein kinase, is a family of protein tyrosine kinases (SFKs), and this protein catalyses the phosphorylation of tyrosine. The studies have revealed its key roles in regulating signal transduction from cell surface receptors. The Src kinases act as cytoplasmic signalling machinery through regulating various cellular processes, such as cell growth, differentiation, migration, and survival. The pleiotropic functions of the Src family emphasise the importance of family members which have also been accepted as cellular oncogenes. Indole phytoalexins, which have been identified in various plants, have a structure with indole nucleus with the side chain or a heterocycle containing nitrogen and sulphur atoms. The antiproliferative effects of some phytoalexins have been demonstrated in various cancers. Among the members of phytoalexins, brassinin is known with a dithiocarbamate moiety and S-alkyl piece linked to indole core, and camalexin has an indole structure substituted at position 3 by the 1,3-thiazol-2-yl group. The inhibitory effects of these compounds on cancer cell proliferation have been reported. The aim of this study is to evaluate the effects of compounds on Src kinase activity. Human MCF-7 breast carcinoma and SW480 colorectal carcinoma cells were treated with compounds, and the effects of compounds on Src kinase activity were evaluated by Src-tyrosine kinase assay. The data were also compared with the growth inhibitory potential of compounds. The results have shown that both brassinin and camalexin have significantly inhibited the activity of Src kinase at 10 mM and higher concentrations in MCF-7 and SW480 cell lines (p < 0.05). In conclusion, this study is the first to evaluate the role of indole phytoalexins on the Src kinase activity of cancer cells. The data obtained have proven that the indole phytoalexin structure can show anticancer activity as Src mediated. It is thought that existing data will shed light on novel anticancer drug development studies. Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 157 KiB

Open AccessAbstract

A Lipoaminopeptaibol Secreted by Alkalophilic Fungus Emericellopsis alkalina Demonstrates a Strong Cytotoxic Effect against Tumor Cell Lines

by Eugene Rogozhin and Vera Sadykova

Proceedings 2019, 22(1), 4; https://doi.org/10.3390/proceedings2019022004 - 6 Aug 2019

Cited by 2 | Viewed by 1308

Abstract

Soil fungi are known to produce and secrete antibiotics with a strong antimicrobial effect towards eukaryotic organisms. In many occasions, these compounds belong to peptides that are products of non-ribosomal biosynthesis and are called peptaibols. Many peptaibols are cytotoxic and some of them [...] Read more.

Soil fungi are known to produce and secrete antibiotics with a strong antimicrobial effect towards eukaryotic organisms. In many occasions, these compounds belong to peptides that are products of non-ribosomal biosynthesis and are called peptaibols. Many peptaibols are cytotoxic and some of them suppress tumor cell lines much better than normal cells by inducing calcium-mediated apoptosis. The main antimicrobial lipoaminopeptaibol—emericellipsin A—isolated from the fungus Emericellopsis alkalina strain VKPM F-1428, which demonstrates promising antifungal activity against different fungal taxons,has been found to exhibit selective cytotoxic activity against HepG2 and Hela cell lines (EC₅₀ 2.8 and 0.5 μM, respectively) in MTT assays in vitro. This result corresponds to the standard antitumor antibiotic doxorubicin, which has an EC₅₀ value of 440 nM. In a fibroblast toxicity test, emericellipsin A exhibited less cytotoxic activity than doxorubicin (EC₅₀ 14 and 0.34 μM, respectively). Therefore, it is less toxic to normal cells than doxirubicin (~40 times), but it yields a more potent cytotoxic effect on tumor cell lines. That is why emericellipsin A can be considered for future more detailed investigations to be an effective antitumor substance. Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 149 KiB

Open AccessAbstract

Anticancer Activities and Underlying Molecular Mechanisms of Novel Mangostin Glycosides in Human Hepatocellular Carcinoma Hep3B Cells

by Sung Min Kim, Jang Mi Han and Hye Jin Jung

Proceedings 2019, 22(1), 5; https://doi.org/10.3390/proceedings2019022005 - 6 Aug 2019

Viewed by 1343

Abstract

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and is a leading cause of cancer-related death worldwide. Therefore, exploring effective anticancer agents and their modes of action is essential for the prevention and treatment of HCC. Glycosylation can significantly [...] Read more.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and is a leading cause of cancer-related death worldwide. Therefore, exploring effective anticancer agents and their modes of action is essential for the prevention and treatment of HCC. Glycosylation can significantly improve the physicochemical and biological properties of small molecules, such as high solubility, stability increase, and lower toxicity. In this study, for the first time, we evaluated the anticancer activities of mangostin-3-O-β-d-2-deoxyglucopyranoside (Man-3DG) and mangostin 6-O-β-d-2-deoxyglucopyranoside (Man-6DG), glycosides of mangostin, against human hepatoma Hep3B cells. Our results demonstrated that Man-3DG and Man-6DG significantly suppressed growth and migration of Hep3B cells. In addition, they induced apoptosis of Hep3B cells by regulating apoptosis-related proteins of mitochondria. Noticeably, Man-3DG and Man-6DG also caused autophage, while cotreatment of the mangostin glycosides with an autophage inhibitor 3MA enhanced the inhibitory effect on Hep3B cell growth, compared to single agent treatment. Moreover, Man-3DG and Man-6DG inhibited the c-Met signaling pathway, which plays a critical role in the pathogenesis of liver cancer. Furthermore, the mangostin glycosides decreased tumor cell-induced angiogenesis in vitro through downregulation of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF). These findings suggest that Man-3DG and Man-6DG might be promising anticancer agents for HCC treatment with superior pharmacological properties than parent molecule mangostin. Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 129 KiB

Open AccessAbstract

Bis-Pyridazine Derivatives with Anticancer Activity

by Amariucai-Mantu Dorina, Mangalagiu I. Ionel, Antoci Vasilichia and Mangalagiu Violeta

Proceedings 2019, 22(1), 6; https://doi.org/10.3390/proceedings2019022006 - 6 Aug 2019

Viewed by 1344

Abstract

Over the last decades, pyridazine derivatives are considered “privileged structures” in medicinal chemistry, with special attention being given to pyridazinones derivatives, which were found to have a large range of biological activities, including anticancer. On the other hand, because of the huge difficulties [...] Read more.

Over the last decades, pyridazine derivatives are considered “privileged structures” in medicinal chemistry, with special attention being given to pyridazinones derivatives, which were found to have a large range of biological activities, including anticancer. On the other hand, because of the huge difficulties in cancer treatment, there is an urgent need from the pharmaceutical industry for new anticancer drug candidates. As part of our ongoing efforts in searching for new biologically active entities with anticancer potential, we report here the design, synthesis, structure and in vitro anticancer activity of a new class of pyridazinones derivatives, namely bis-pyridazinones. The structures of the compounds were proven by elemental and spectral analysis: IR, LC-MS, 1H-NMR, 13C-NMR, two-dimensional experiments 2D-COSY, HMQC, and HMBC. A few of the compounds were accepted by the National Cancer Institute (USA) for anticancer screening and were evaluated for their in vitro cytotoxic activity against a panel of 60 human tumor cell lines, representing cancers of the brain, breast, colon, kidney, lung, ovary, prostate, as well as leukemia and melanoma. Three of the tested compounds have proven to be active against non-small cell lung cancer HOP 92 and NCI-H226, CNC cancer SNB-75, renal cancer A498 and UO-31, with a growth inhibition between 50–80 mM. Interestingly, one compound (unsubstituted bis-pyridazinones I) has a selective anticancer activity, being active only on non-small cell lung cancer HOP 92, with a growth inhibition of 51.45 mM. SAR correlation has been performed. Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 131 KiB

Open AccessAbstract

Repositioning of Dantrolene as a Multitarget Agent for Neurodegenerative Diseases

by Isabella Bolognino, Marco Catto, Leonardo Pisani, Saverio Cellamare, Cosimo D. Altomare and Nicola Giangregorio

Proceedings 2019, 22(1), 7; https://doi.org/10.3390/proceedings2019022007 - 7 Aug 2019

Viewed by 1213

Abstract

Dantrolene is an orphan drug representing the sole therapeutic treatment for malignant hyperthermia, a life-threatening pathology affecting 0.2 in every 10,000 people in the EU. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 143 KiB

Open AccessAbstract

Novel Antimalarial Inhibitors That Specifically Target the Invasion Motor Protein Myosin A in Malaria Parasites

by Janna Ehlert, Arne Alder, Viola Introini, Julia Weder, Pietro Cicuta, Tim W. Gilberger and Matthias Preller

Proceedings 2019, 22(1), 9; https://doi.org/10.3390/proceedings2019022009 - 7 Aug 2019

Viewed by 1893

Abstract

Malaria remains a devastating disease with nearly half a million deaths per year. The WHO reports a stagnating number of new infections every year without a significant decline, as a result of insufficient access to antimalarials in endemic regions as well as complex [...] Read more.

Malaria remains a devastating disease with nearly half a million deaths per year. The WHO reports a stagnating number of new infections every year without a significant decline, as a result of insufficient access to antimalarials in endemic regions as well as complex resistance mechanisms of the parasites against current treatments. Due to its critical role during the parasite’s life cycle, the invasion motor myosin A is a promising target, which has not yet been considered in drug discovery. Myosins appeared to be undruggable since they are ubiquitously expressed and involved in a wide range of cellular processes. In total, the protein superfamily of myosins comprises 35 known subclasses. However, recent studies highlighted the possibility to modulate the myosin motor activity of specific myosin isoforms and classes using small allosteric effector molecules. Exploiting the concept of reversible covalent binding, we show the development of highly potent and specific inhibitors of the key motor myosin A of the glideosome—a sophisticated motor machinery involved in parasite motility and host cell invasion. Combining chemical synthesis with biophysical in vitro analysis confirmed the preferential inhibition of the target protein in the submicromolar range. The developed compounds show significant antiparasitic activities and block efficiently glideosome-associated processes, parasite proliferation, and parasitemia of the malaria parasites. Our findings demonstrate the high potential of our approach using reversible covalent binding to develop new allosteric inhibitors, targeting specifically the key invasion motor as a novel drug target to treat infections caused by malaria parasites. Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 132 KiB

Open AccessAbstract

Use of a Zebrafish Model to Evaluate Toxicity of Schiff Base Complexes of Copper (II) and Zinc (II) as Possible Antineoplastic Agents

by Claudia Cardozo, Andreas Reiber and Veronica Akle

Proceedings 2019, 22(1), 11; https://doi.org/10.3390/proceedings2019022011 - 7 Aug 2019

Viewed by 1494

Abstract

Cancer continues to be one of the leading causes of death, according to the World Health Organization, and chemotherapy is its principal treatment. Organometallic complexes with copper (II) and zinc (II) with Schiff bases as ligand, capable of interacting with cancer cells’ DNA [...] Read more.

Cancer continues to be one of the leading causes of death, according to the World Health Organization, and chemotherapy is its principal treatment. Organometallic complexes with copper (II) and zinc (II) with Schiff bases as ligand, capable of interacting with cancer cells’ DNA under physiological conditions, may work as good chemotherapy agents because they are less toxic to healthy cells than to cancerous ones. In view of the above, this work focuses on obtaining new Schiff base ligands and their copper and zinc complexes and characterizing them by nuclear magnetic resonance, mass spectrometry, infrared spectroscopy, and other spectroscopic and spectrometric techniques. The objective is to evaluate the toxic activity of the new molecules using the fast proliferating cells of the zebrafish model during development. The toxicity test was performed in zebrafish embryos at 8, 24, 48 and 72 h post fertilization, and a survival and malformation index were registered. Preliminary results show a dose-related effect of the designed Schiff ligands and complexes on the toxicity of the zebrafish embryo and larvae. The survival and malformation index are more severe when exposure occurs during early developmental stages, when cell division is higher due to rapid organization and growth of the new organism. This is a promising result, as the molecules might be cytotoxic to highly proliferating cells, as it occurs in cancer cells. This work represents one of the very few examples that use the zebrafish model to evaluate the cytotoxic activity of Schiff base complexes. Developing the animal model to test the effect of Schiff ligands and their complexes is an important first step to assess the effectiveness of new molecules as antineoplastic agents. Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 153 KiB

Open AccessAbstract

Ferrocenes as Potential Anticancer Drugs: Determination of the Mechanism of Action

by Roman Hrstka, Hana Skoupilová, Martin Bartošík, Lucia Sommerová, Jindřich Karban and Jiří Pinkas

Proceedings 2019, 22(1), 16; https://doi.org/10.3390/proceedings2019022016 - 7 Aug 2019

Cited by 1 | Viewed by 1547

Abstract

Chemotherapy is an essential treatment that still plays a vital role in cancer treatment worldwide. The ferrocene derivatives of the general formula [Fe{(η⁵‑C₅H₄CH₂(p‑C₆H₄)CH₂(N‑het)}₂] bearing modified [...] Read more.

Chemotherapy is an essential treatment that still plays a vital role in cancer treatment worldwide. The ferrocene derivatives of the general formula [Fe{(η⁵‑C₅H₄CH₂(p‑C₆H₄)CH₂(N‑het)}₂] bearing modified six and five membered N-heterocycles were tested in vitro for their cytotoxic properties against ovarian cancer cell lines A2780 and SK-OV-3. These ferrocene complexes displayed cytotoxicity in low micromolar concentrations against both cell lines. To study cellular uptake of particular ferrocenes into tumor cells, we used differential pulse voltammetry and ICP-MS. We confirmed the crucial role of transferrin receptors in the process of intracellular accumulation of these ferrocenes. Interestingly, the rate of intracellular accumulation of particular ferrocenes clearly mirrored the cytotoxicity of these organometallic compounds. Deeper investigation of the mechanism by which ferrocenes kill tumor cells revealed induction of apoptosis associated with significant increase of reactive oxygen species. In conclusion, our screening identified several ferrocene derivatives exerting promising cytostatic activity in vitro. Further investigation led to the identification of the mechanism of action of these potential anticancer agents, which represents an important milestone in preclinical anticancer drug discovery programs. This work was supported by the project MEYS-NPS I-LO1413, MH CZ-DRO (MMCI, 00209805) and Czech Science Foundation project 17-05838S. Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 141 KiB

Open AccessAbstract

Design, Synthesis, and Anticancer Evaluation of Fused 1,2-diazine Derivatives

by Antoci Vasilichia, Amariucai-Mantu Dorina, Mangalagiu Violeta, Danac Ramona and Mangalagiu I. Ionel

Proceedings 2019, 22(1), 26; https://doi.org/10.3390/proceedings2019022026 - 7 Aug 2019

Viewed by 1376

Abstract

Cancer is one of the most serious and merciless health problems of humankind, and the number of new cases is expected to increase in the next decades. Despite extensive cancer research in order to find more effective drugs and treatments, cancer chemotherapy is [...] Read more.

Cancer is one of the most serious and merciless health problems of humankind, and the number of new cases is expected to increase in the next decades. Despite extensive cancer research in order to find more effective drugs and treatments, cancer chemotherapy is complex and complicated, because of the limited eﬃcacy of drugs, significant levels of toxicity, and lack of selectivity, and the emergence of drug resistance and multidrug resistance make the situation even worse. We report here the design, synthesis, structure, and in vitro anticancer activity of two series of compounds derived from pyridazine and phthalazine. The in vitro anticancer activity was tested on a panel of 60 human tumor cell lines representing cancers of the brain, breast, colon, kidney, lung, ovary, prostate, as well as leukemia and melanoma, to the National Cancer Institute (USA). The test was conducted on a single dose and five dose assay. Notably, from the tested compounds, five of them show very good anticancer activity (superior to Doxorubicin, the NCI standard drug for this type of analysis), with a growth inhibition in the area of nanomolar, between 20–100 nM, on several cancer cell lines: breast cancer MCF7, colon cancer HCT-15, KM12 and SW-620, leukemia K562 and SR, melanoma MDA-MB-435, SK-MEL-5, and UACC-62, and renal cancer A498. SAR correlation in the two series and in between the two series has been performed. One compound has an excellent anticancer activity against breast cancer MCF7 cell, leukemia SR cell, and melanoma MDA-MB-435 cell, in the area of 20 nM. Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 133 KiB

Open AccessAbstract

Design of Novel GPR6 Inverse Agonists Using a Fragment Replacement Scaffold Hopping Approach

by Israa Isawi, Paula Morales, Dow Hurst, Nadine Jagerovic and Patricia Reggio

Proceedings 2019, 22(1), 29; https://doi.org/10.3390/proceedings2019022029 - 7 Aug 2019

Viewed by 1688

Abstract

The orphan G protein coupled receptor 6 (GPR6) is a cannabinoid-related Class A GPCR. It is highly expressed in the central nervous system and exhibits high constitutive activation of adenylyl cyclase. Several research groups have demonstrated that GPR6 represents a possible target for [...] Read more.

The orphan G protein coupled receptor 6 (GPR6) is a cannabinoid-related Class A GPCR. It is highly expressed in the central nervous system and exhibits high constitutive activation of adenylyl cyclase. Several research groups have demonstrated that GPR6 represents a possible target for the treatment of neurodegenerative disorders such as Parkinson’s, Alzheimer’s, and Huntington’s diseases. Several patents claim the use of a wide range of pyrazine derivatives as GPR6 inverse agonists for the treatment of Parkinson’s disease and other dyskinesia syndromes. Using cyclic AMP accumulation assays in hGPR6-CHO cells as a readout, the most potent GPR6 pyridopyrazine inverse agonist compounds identified thus far have been found to display IC₅₀ values in the low nanomolar range. A subset of these compounds was used here as starting points for the design of novel potent GPR6 inverse agonists using a core hopping approach. In parallel with the core hopping studies, we employed a recently constructed homology model of the GPR6 inactive state. The X-ray crystal structure of the Sphingosine-1-phosphate receptor 1 (S1P1) receptor structure was used as the template and the conformational memories technique was used to explore the conformational consequences of sequence differences between S1P1 and GPR6. The most potent GPR6 pyridopyrazine inverse agonists were docked in the resultant GPR6 inactive state model, first as tests of the model. Once we had identified the binding site of each inverse agonist, we used this site to identify amino acid sites in proximity that we can use to build additional interactions for ligands output from core hopping studies above. ADME properties and the absence of PAINS will also be considered for the hit selection process. These potential GPR6 chemotypes may serve as research tools for further understanding the biological role of this orphan receptor. Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 142 KiB

Open AccessAbstract

New TRPV1 Antagonists as Candidates for Effective Anticonvulsant and Antinociceptive Agents

by Krzysztof Kamiński, Marcin Jakubiec, Mirosław Zagaja, Marta Andres-Mach, Szczepan Mogilski and Gniewomir Latacz

Proceedings 2019, 22(1), 30; https://doi.org/10.3390/proceedings2019022030 - 7 Aug 2019

Viewed by 1408

Abstract

Epilepsy is recognized as one of the most common neurological disorders with a high risk of drug resistance. Notably, about one-third of the patients with epilepsy are not responsive to pharmacological treatment. Thus, the search for new, more effective anticonvulsants with a novel [...] Read more.

Epilepsy is recognized as one of the most common neurological disorders with a high risk of drug resistance. Notably, about one-third of the patients with epilepsy are not responsive to pharmacological treatment. Thus, the search for new, more effective anticonvulsants with a novel mechanism of action is undoubtedly necessary. The most recent neurobiological studies implicate central TRPV1 receptors in the induction of epileptic seizures. Moreover, it is suggested that TRPV1 desensitization is one of the crucial mechanisms of action responsible for the anticonvulsant activity of cannabidiol (CBD), which was proven to be effective against drug-resistant epilepsy. Bearing in mind the aforementioned facts, we developed in our recent studies a series of chemically original TRPV1 antagonists. Their structures were designed as integrated hybrids that join on the common chemical template the structural fragments of anticonvulsants identified by our team in the previous studies and known TRPV1 antagonists (described in the literature). As a result, these compounds revealed potent anticonvulsant activity in the preclinical studies using the most widely employed animal seizure models, namely, the maximal electroshock (MES) test, and the psychomotor 6 Hz (32 mA and 44 mA) seizure model in mice. In addition, selected substances demonstrated potent effectiveness by decreasing pain responses in formalin-induced tonic pain, in capsaicin-induced neurogenic pain, as well as in oxaliplatin-induced neuropathic pain in mice. Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 141 KiB

Open AccessAbstract

CNS-Selective Estrogen Therapy

by Katalin Prokai-Tatrai and Laszlo Prokai

Proceedings 2019, 22(1), 31; https://doi.org/10.3390/proceedings2019022031 - 7 Aug 2019

Viewed by 1328

Abstract

17β-Estradiol (E2), the main human estrogen, has been known to exert multiple actions throughout the body, including in the central nervous system (CNS). In particular, it has been shown that E2 is gender-independently needed for brain and eye health. Lack of E2 due [...] Read more.

17β-Estradiol (E2), the main human estrogen, has been known to exert multiple actions throughout the body, including in the central nervous system (CNS). In particular, it has been shown that E2 is gender-independently needed for brain and eye health. Lack of E2 due to normal aging and/or pathological processes leads to neurological and psychiatric diseases as well as accelerated neurodegeneration. Current estrogen replacement therapies, however, cannot be used as therapeutic interventions to treat these maladies due to a profound, unwanted hormonal exposure to the rest of the body. In this presentation, we show that the small-molecule bioprecursor prodrug 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED) produces E2 only in the CNS but remains inert in the rest of the body, both upon chronic systemic and topical administrations, thereby avoiding the detrimental side-effects of the hormone, such as stimulation of the uterus and tumor growth. The highly localized production of E2 in the CNS will be shown through a series of bioanalytical assays and efficacy studies using animal models of estrogen-responsive maladies pertaining to the brain and the retina. Owing to DHED’s significantly more favorable physicochemical properties than the highly lipophilic parent E2 for transport through biological membranes such as the blood-brain barrier or the cornea, a highly effective E2 therapy can be achieved in rodents upon prodrug administration, which further enhances therapeutic safety. Altogether, our patented DHED approach shows unprecedented selectivity to deliver E2 into the CNS and, thus, promises a high translation value in terms of efficacious and safe treatment against neurodegeneration as well as neurological and psychiatric symptoms arising from estrogen deficiency. Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 132 KiB

Open AccessAbstract

Tools and Drugs for Purine-Binding Targets—Important Players in Inflammation and Cancer

by Christa E. Müller

Proceedings 2019, 22(1), 33; https://doi.org/10.3390/proceedings2019022033 - 7 Aug 2019

Viewed by 1279

Abstract

Despite decades of research, only few drugs have been approved that interact with purine receptors. Recently, new hypes and hopes have been created in the field, mainly due to the gold rush fever in immuno-oncology. Adenosine is one of the strongest immunosuppressant agents [...] Read more.

Despite decades of research, only few drugs have been approved that interact with purine receptors. Recently, new hypes and hopes have been created in the field, mainly due to the gold rush fever in immuno-oncology. Adenosine is one of the strongest immunosuppressant agents of the innate immune system. Cancer cells and tissues can release large amounts of ATP, which is immediately hydrolyzed by ectonucleotidases. These ecto-enzymes, including ectonucleotide pyrophosphatase/phosphodiesterase 1 (NPP1, CD203a), ectonucleoside diphosphohydrolase 1 (NTPDase1, CD39), and ecto-5′-nucleotidase (CD73), are upregulated on many cancer cells, leading to the production of adenosine. The cloud of adenosine formed around cancer tissues contributes to immune escape by interacting with adenosine A_2A and A_2B receptor subtypes (A_2AAR, A_2BAR) on immune cells. In addition, activation of A_2BARs by adenosine enhances cancer cell proliferation, metastasis, and angiogenesis. Blockade of A_2A and A_2B adenosine receptors and/or inhibition of adenosine formation by blocking ectonucleotidases are being pursued as novel principles that activate the immune system to defeat cancer. Recent progress in the development of adenosine receptor antagonists and ectonucleotidase inhibitors will be presented and discussed. Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 146 KiB

Open AccessAbstract

The Ameliorating Effect of Phenylsulfonamide Derivatives on Scopolamine-Induced Memory Impairment in Mice via Inhibition of mPGES-1

by Ki Deok Ryu, Yoon Hyoung Moon, Do Hyeong Ko, Kyung-Tae Lee and Jae Yeol Lee

Proceedings 2019, 22(1), 36; https://doi.org/10.3390/proceedings2019022036 - 7 Aug 2019

Viewed by 1252

Abstract

Our previous research showed that a novel series of phenylsulfonyl hydrazide derivatives reduced LPS-induced PGE₂ levels in RAW 264.7 macrophage cells via an inhibition of mPGES-1 enzyme. As a continuous work, new phenylsulfonamide derivatives (5a-5k) as methylene analogues [...] Read more.

Our previous research showed that a novel series of phenylsulfonyl hydrazide derivatives reduced LPS-induced PGE₂ levels in RAW 264.7 macrophage cells via an inhibition of mPGES-1 enzyme. As a continuous work, new phenylsulfonamide derivatives (5a-5k) as methylene analogues of phenylsulfonyl hydrazide derivatives, including MPO-0063, were synthesized and biologically evaluated in vitro. Among synthetic compounds, 5a (MPO-0112) showed decreased inhibitory activity against PGE₂ production (IC₅₀: 0.34 µM) compared to MPO-0063 (IC₅₀: 0.04 µM) but inhibited the mPGES-1 enzyme (IC₅₀: 7.37 µM) similar to MPO-0063 (IC₅₀: 0.10 µM) together with excellent selectivity over COX-enzymes (COX-1 and 2). According to recent studies on the close correlation between up-regulation of mPGES-1 and Alzheimer's disease, we investigated whether 5a could ameliorate scopolamine-induced memory impairment using the passive avoidance test. The memory impairment-ameliorating effect of 5a (1.0 mg/kg, p.o.) was found to be effective, comparable to that of donepezil (5 mg/kg, p.o.) as a positive control. On the other hand, 5a exhibited little or weak AChE and BuChE inhibitory activity, which implies that 5a could ameliorate scopolamine-induced memory impairment by inhibiting mPGES-1 enzyme instead of cholinesterase enzymes. In addition, MPO-0112 exhibited a favorable in vitro CYP profile, which is suggestive of no potential drug–drug interactions. Therefore, these overall results suggest that 5a as a selective mPGES-1 inhibitor may be a novel therapeutic agent for diseases associated with cognitive deficits, such as Alzheimer’s disease. Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 153 KiB

Open AccessAbstract

Inhibition of LPS-Induced PGE₂ Production by Arylsulfonamide Derivatives via the Selective Inhibition of mPGES-1 Enzyme

by Misong Kim, Changyoung Jang, Yunchan Nam, Kyung-Tae Lee and Jaeyeol Lee

Proceedings 2019, 22(1), 37; https://doi.org/10.3390/proceedings2019022037 - 7 Aug 2019

Viewed by 1243

Abstract

Microsomal prostaglandin E synthase-1 (mPGES-1) is responsible for the massive prostaglandin E₂ (PGE₂) formation during inflammation. Increasing evidence reveals mPGES-1 inhibitors as a safe alternative to nonsteroidal anti-inflammatory drugs. Recently, we reported that a novel series of phenylsulfonyl hydrazide derivatives [...] Read more.

Microsomal prostaglandin E synthase-1 (mPGES-1) is responsible for the massive prostaglandin E₂ (PGE₂) formation during inflammation. Increasing evidence reveals mPGES-1 inhibitors as a safe alternative to nonsteroidal anti-inflammatory drugs. Recently, we reported that a novel series of phenylsulfonyl hydrazide derivatives could reduce LPS-induced PGE₂ levels in RAW 264.7 macrophage cells via an inhibition of the mPGES-1 enzyme. However, a few of the phenylsulfonyl hydrazide derivatives showed poor metabolic stability in liver microsomes. In order to identify new mPGES-1 inhibitors with improved metabolic stability, therefore, a series of arylsulfonamide derivatives has been synthesized and biologically evaluated against PGE₂ production and the mPGES-1 enzyme. Among them, MPO-0186 inhibits the production of PGE₂ (IC₅₀ = 0.20 μM) in A549 cells via inhibition of mPGES-1 (IC₅₀ = 0.49 μM in a cell-free assay) together with high selectivity over both COX-1 and COX-2. A molecular docking study theoretically suggests that MPO-0186 could inhibit PGE₂ production by blocking the PGH₂ binding site of the mPGES-1 enzyme. Furthermore, MPO-0186 demonstrated good metabolic stability in human liver microsomes and no significant inhibition observed in clinically relevant CYP isoforms. Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 181 KiB

Open AccessAbstract

Why Does the Type of Halogen Atom Matter for Radiosensitizing Properties of 5-Substituted 4-Thio-2′-Deoxyuridines?

by Paulina Spisz, Magdalena Zdrowowicz, Samanta Makurat, Witold Kozak, Konrad Skotnicki, Krzysztof Bobrowski and Janusz Rak

Proceedings 2019, 22(1), 40; https://doi.org/10.3390/proceedings2019022040 - 8 Aug 2019

Viewed by 1139

Abstract

In order to explain the unexpected difference between radiosensitizing. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 127 KiB

Open AccessAbstract

Rhenium(I) Complexes with Pincer Ligands as a New Class of Potential Antitumor Agents

by Diana V. Aleksanyan, Svetlana G. Churusova, Ekaterina Yu. Rybalkina and Vladimir A. Kozlov

Proceedings 2019, 22(1), 43; https://doi.org/10.3390/proceedings2019022043 - 8 Aug 2019

Viewed by 1450

Abstract

Transition metal complexes attract continuous research interest as potential antitumor agents. The most popular compounds are ruthenium, gold, titanium, osmium, iridium, zinc, and palladium complexes, which have already displayed cytotoxic features that are not typical for classical platinum-containing chemotherapeutic agents. Substantially lower attention [...] Read more.

Transition metal complexes attract continuous research interest as potential antitumor agents. The most popular compounds are ruthenium, gold, titanium, osmium, iridium, zinc, and palladium complexes, which have already displayed cytotoxic features that are not typical for classical platinum-containing chemotherapeutic agents. Substantially lower attention is drawn to organometallic compounds of rhenium. However, the known examples of cytotoxic organometallic rhenium derivatives with bidentate heterocyclic, organophosphorus, labile alkoxide, and hydroxide ligands render further studies in this field very promising. As for their analogs with multidentate ligands, a literature survey has revealed only a few examples of cytotoxic rhenium complexes, whereas the antitumor activity of cyclometallated derivatives has not been studied at all. At the same time, it is known that the use of pincer-type ligands having specific tridentate monoanionic frameworks, which offer multiple options for directed structural modifications, allows one to finely tune the thermodynamic and kinetic stability of the resulting metal complexes. Therefore, we synthesized and studied the cytotoxic properties of a series of rhenium(I) complexes with tridentate pincer-type ligands based on functionalized carboxamides bearing ancillary donor groups both in the acid and amine components. It was shown that the target complexes can be obtained not only by the conventional solution-based method, but also under solvent-free conditions according to the solid-phase methodology recently developed in our group. The results obtained were used to define the main structure–activity relationships for a principally new class of potential antitumor agents and to choose the most promising compounds for further studies in order to create new pharmaceuticals. Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 165 KiB

Open AccessAbstract

Physicochemical and Pharmacokinetic Properties of New Dual-Acting Compounds for the Treatment of Mental Disorders

by Agnieszka Zagórska, Paweł Żmudzki, Paulina Janiszewska and Maria Walczak

Proceedings 2019, 22(1), 50; https://doi.org/10.3390/proceedings2019022050 - 8 Aug 2019

Viewed by 1285

Abstract

Abstract: Physicochemical and pharmacokinetic properties of compounds marked with acronyms PQA-AZ-4 and PQA-AZ-6 were studied using experimental methods. Selected compounds (dual-active effective inhibitors of phosphodiesterase (PDE) 10A and serotonin 5-HT_1A and 5-HT₇ receptor ligands) in prescreening pharmacological studies revealed [...] Read more.

Abstract: Physicochemical and pharmacokinetic properties of compounds marked with acronyms PQA-AZ-4 and PQA-AZ-6 were studied using experimental methods. Selected compounds (dual-active effective inhibitors of phosphodiesterase (PDE) 10A and serotonin 5-HT_1A and 5-HT₇ receptor ligands) in prescreening pharmacological studies revealed antipsychotic-like, antidepressant-like, and anxiolytic activities. The liquid chromatographic–tandem mass spectrometric method with electrospray ionization (LC/ESI-MS/MS) system was calibrated and validated for lipophilicity studies. Lipophilicity was assessed from the y axis intercept (y₀) of the linear regression line of ln((t − t₀)/t₀) against % concentration of organic eluent. Finally, lipophilicity was calculated using a linear regression equation of the logP value against y₀ values obtained for the reference compounds in the same experimental conditions. Next, the thermodynamic aqueous solubility of selected compounds was detected with UPLC detection. The LC/ESI-MS/MS system was used for the simultaneous determination of PQA-AZ-4 and PQA-AZ-6 in mouse plasma, hippocampus, striatum, and frontal cortex, developed and validated according to GLP procedures. Finally, drug-likeness properties of selected compounds were evaluated using a predictive bioavailability radar model from the SwissADME web tool. The descriptors of physicochemical properties (lipophilicity, size, polarity, solubility, flexibility, and saturation) for selected compounds were projected next on the optimal range for each property to be considered drug-like. Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 170 KiB

Open AccessAbstract

Inhibitors of the Inducible Nitric Oxide Synthase as Antiglioma Agents

by Cristina Maccallini, Marialucia Gallorini, Pasquale Amoia, Alessandra Ammazzalorso, Barbara De Filippis, Marialuigia Fantacuzzi, Letizia Giampietro, Amelia Cataldi and Rosa Amoroso

Proceedings 2019, 22(1), 52; https://doi.org/10.3390/proceedings2019022052 - 8 Aug 2019

Cited by 1 | Viewed by 1201

Abstract

Malignant gliomas are highly lethal brain tumors with poor prognosis for patients. The current [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 133 KiB

Open AccessAbstract

FOXM1 Inhibitors: Emergence of a Neglected Binding Force

by Seyed Amirhossein Tabatabaei Dakhili, David Javier Perez, Keshav Gopal, John Reyes Ussher and Carlos Alberto Velázquez Martínez

Proceedings 2019, 22(1), 58; https://doi.org/10.3390/proceedings2019022058 - 9 Aug 2019

Viewed by 1830

Abstract

The Forkhead boX M1 (FOXM1) is an essential transcription factor for normal activation of the cell cycle and cell replication. However, increasing evidence suggests that overexpression of this protein correlates with cancer development and poor patient prognosis, which makes FOXM1 a promising drug [...] Read more.

The Forkhead boX M1 (FOXM1) is an essential transcription factor for normal activation of the cell cycle and cell replication. However, increasing evidence suggests that overexpression of this protein correlates with cancer development and poor patient prognosis, which makes FOXM1 a promising drug target in medicinal chemistry. Based on a computer-based molecular modeling protocol reported by our group, we hypothesized that FOXM1 inhibitors bind to the FOXM1 DNA binding domain (DBD) by (i) a pi-sulfur interaction with His287, and (ii) a halogen bonding with Arg297 within the FOXM1 DNA binding domain. To test this hypothesis, we modified the chemical structure of a known “forkhead domain inhibitor” (FDI) to synthesize and screen a series of FDI-derivatives. In this regard, we removed or replaced two essential groups in FDI-6, namely (i) the 4-fluorophenyl position and (ii) the heterocyclic sulfur atoms. We determined the inhibitory effects of test molecules on the protein expression of FOXM1 using a triple negative breast cancer cell line (MDA-MB-231), and then we measured their binding affinity to DNA by electrophoretic mobility shift assay (EMSA). Next, using a site-directed mutagenesis technique, we confirmed specific binding interactions exerted by these molecules. These results validate the role of essential binding interactions (pi-sulfur binding) predicted by computer simulations and provide preliminary evidence to postulate a mechanism of action exerted by “direct” FOXM1 inhibitors. Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 136 KiB

Open AccessAbstract

Photoprotective and Therapeutic Potential in Skin Cancer of Amaryllidaceae Alkaloids

by Carol Castañeda, Karent Bravo, Natalie Cortés, Warley de S. Borges, Jaume Bastida and Edison Osorio

Proceedings 2019, 22(1), 59; https://doi.org/10.3390/proceedings2019022059 - 9 Aug 2019

Viewed by 1366

Abstract

Skin cancer has evolved as the most common malignant disease, accounting for 4.5% of all new cancer cases. Melanoma, the most aggressive skin cancer type, develops in melanocytes and has high mortality rates due to its biological features and frequent failures of therapeutic [...] Read more.

Skin cancer has evolved as the most common malignant disease, accounting for 4.5% of all new cancer cases. Melanoma, the most aggressive skin cancer type, develops in melanocytes and has high mortality rates due to its biological features and frequent failures of therapeutic alternatives. On the other hand, non-melanoma skin cancers (NMSC), the most common malignant tumors in humans, are developed in keratinocytes of the basal or spinous layer, and increased exposure to ultraviolet (UV) light remains the most important modifiable risk factor. To date, treatment alternatives for melanoma are limited to surgery, in cases of early diagnosis, and a few pharmacological options in inoperable tumors. These limitations for skin cancer management evidence the need to develop therapeutic options for prevention and treatment. The antiproliferative effects of Amaryllidaceae alkaloids have been tested for different types of cancer. However, their activity on skin models is not well-established. Pure alkaloids and alkaloidal fractions characterized by GC-MS of several Amaryllidaceae species from Crinum, Zephyranthes, Hippeastrum, and Eucharis genera were assayed by their effects on skin cancer. Photoprotective effects of the alkaloids and fractions were determined through cell viability assay, and the quantification of intracellular reactive oxygen species (ROS) and inflammation biomarker IL-6 in UVB-stimulated keratinocytes (HaCaT). Cytotoxicity were assessed in human metastatic melanoma cells (CRL-3229) to evaluate therapeutic potential, and chemometric techniques were used to analyze data. Most substances enhanced HaCaT proliferation at 5.0 µg/mL. E. caucana and Z. carinata bulbs alkaloidal fractions significantly reduced intracellular ROS and IL-6 production in UVB-stimulated HaCaT, respectively. Tazettine and lycoramine showed photoprotective effects. Additionally, E. caucana bulbs alkaloidal fraction was selectively cytotoxic in melanoma cells at 20.0 µg/mL. Collectively, these results demonstrate that Amaryllidaceae alkaloids could represent a new option in skin cancer management, acting as photoprotective agents in healthy UVB-exposed keratinocytes and therapeutic agents in melanoma. Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 159 KiB

Open AccessAbstract

Organometallic Nucleosides: Synthesis and Biological Evaluation of Substituted Dicobalt Hexacarbonyl Alkynyl Modified 2′-Deoxyuridines

by Roman Dembinski, Renata Kaczmarek, Dariusz Korczyński and Karolina Królewska-Golińska

Proceedings 2019, 22(1), 62; https://doi.org/10.3390/proceedings2019022062 - 12 Aug 2019

Viewed by 1407

Abstract

In continuation of synthetic pursuit of metallo-nucleosides, in particular dicobalt hexacarbonyl 5-alkynyl-2′-deoxyuridines, novel compounds with alkynyl groups were synthesized, starting from 5-iodo-2′-deoxyuridine. Reactions of dicobalt octacarbonyl [Co₂(CO)₈] with 2′-deoxy-5-oxopropynyluridines and related compounds gave dicobalt hexacarbonyl nucleoside complexes (83–31%). The [...] Read more.

In continuation of synthetic pursuit of metallo-nucleosides, in particular dicobalt hexacarbonyl 5-alkynyl-2′-deoxyuridines, novel compounds with alkynyl groups were synthesized, starting from 5-iodo-2′-deoxyuridine. Reactions of dicobalt octacarbonyl [Co₂(CO)₈] with 2′-deoxy-5-oxopropynyluridines and related compounds gave dicobalt hexacarbonyl nucleoside complexes (83–31%). The growth inhibition of HeLa and K562 cancer cell lines by organometallic nucleosides was examined and compared to that by alkynyl nucleoside precursors. Coordination of the dicobalt carbonyl moiety to the 2′-deoxy-5-alkynyluridines led to a significant increase in its cytotoxic potency. The cobalt compounds antiproliferative activities against the HeLa cell line and the K562 cell line will be described. Coordination of an acetyl-substituted cobalt nucleoside was expanded using the 1,1-bis(diphenylphosphino)methane (dppm) ligand, resulting in cytotoxicity at comparable levels. The formation of reactive oxygen species in the presence of cobalt compounds was determined in K562 cells. The results indicate that the mechanism of action for most antiproliferative cobalt compounds may be related to the induction of oxidative stress. Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 130 KiB

Open AccessAbstract

In Search of Selectivity: Design, Synthesis, and Biological Evaluation of New Classes of HDAC Inhibitors

by L. M. Viranga Tillekeratne, Ayad Ayad Al-Hamashi, Samkeliso Dlamini, William Taylor, Radhika Koranne, Mary Kay Pflum, Ahmed T. Negmeldin and Joseph Knoff

Proceedings 2019, 22(1), 63; https://doi.org/10.3390/proceedings2019022063 - 12 Aug 2019

Cited by 2 | Viewed by 1573

Abstract

Epigenetic regulation of gene expression without changing DNA sequences is a promising strategy in developing therapeutic agents for human diseases, especially cancer. Histone deacetylases (HDACs) are a family of enzymes involved in epigenetic modulation of gene expression by chromatin remodeling. Deacetylation of the [...] Read more.

Epigenetic regulation of gene expression without changing DNA sequences is a promising strategy in developing therapeutic agents for human diseases, especially cancer. Histone deacetylases (HDACs) are a family of enzymes involved in epigenetic modulation of gene expression by chromatin remodeling. Deacetylation of the lysine side chains of histones by HDAC proteins renders DNA transcriptionally inactive, resulting in the inhibition of expression of tumor suppressor genes, leading to tumorigenesis and tumor progression. Therefore, inhibiting HDAC enzymes has become an attractive strategy to modulate gene expression as a strategy for developing anticancer drugs. There are currently four FDA-approved cancer drugs in clinical use, and many more are in different stages of clinical trials. However, their clinical utility is limited due to undesirable side effects, mainly attributed to their lack of selectivity and the presence of a hydroxamic acid moiety as the metal-binding group. There are eighteen different isoforms of HDACs belonging to four classes that have been identified in humans. A major challenge in HDAC inhibitor development is how to make them selective for these HDAC isoforms and classes. We report the design and synthesis of new classes of HDAC inhibitors and the evaluation of their anticancer activity and selectivity. Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

2 pages, 185 KiB

Open AccessAbstract

Amaryllidaceae Alkaloids from Zephyrantes Carinata and Their Evaluation as Cholinesterases (AChE and BChE) Inhibitors

by Karina Sierra, Natalie Cortés, Luciana R. Tallini, Warley de S. Borges, Jean Paulo de Andrade, Jaume Bastida and Edison Osorio Durango

Proceedings 2019, 22(1), 66; https://doi.org/10.3390/proceedings2019022066 - 12 Aug 2019

Viewed by 1644

Abstract

The subfamily Amaryllidoideae within of the Amaryllidaceae family has an exclusive group of compounds called Amaryllidaceae alkaloids. Galanthamine, the most known Amaryllidaceae alkaloid, is approved by the FDA as an inhibitor of the enzyme acetylcholinesterase (AChE) for the palliative treatment of Alzheimer Disease [...] Read more.

The subfamily Amaryllidoideae within of the Amaryllidaceae family has an exclusive group of compounds called Amaryllidaceae alkaloids. Galanthamine, the most known Amaryllidaceae alkaloid, is approved by the FDA as an inhibitor of the enzyme acetylcholinesterase (AChE) for the palliative treatment of Alzheimer Disease (AD). However, butyrylcholinesterase (BChE) contributes critically to cholinergic dysfunction associated with AD. Thus, the development of novel therapeutics may involve the inhibition of both cholinesterase enzymes. Zephyranthes carinata, a species of the Amaryllidaceae family, has been reported to have inhibitory activity against cholinesterases. In order to determine the enzymatic inhibition potential, the major alkaloids of bulbs and leaves of Z. carinata were evaluated in both AChE and BChE. A purification and characterization process was made using different chromatographic and spectrometric techniques, and the inhibitory activity was evaluated with the Ellman method. Alkaloidal extracts of bulbs and leaves exhibited an inhibitory activity with IC₅₀ values of 5.8 ± 0.2 and 8.7 ± 0.3 μg/mL, respectively, against AChE. Further, bulb extract showed IC₅₀ values of 77.9 ± 3.4 μg/mL against BChE. Amaryllidaceae alkaloids hamayne, pseudolycorine, galanthine, criasbetaine, tazettine, lycoramine, hippeastidine, galanthamine, trisphaeridine, 3-epimacronine, haemanthamine, lycorine, and vittatine were purified and evaluated for their AChE and BChE inhibitory activities. Lycoramine (galanthamine type) presented the lowest IC₅₀ value in AChE (17 ± 0.7 μg/mL), and trisphaeridine (narciclasine type) showed the lowest IC₅₀ value in BChE (33.1 ± 3.6 μg/mL). Combined major alkaloids (>10%) were analyzed to observe synergistic behavior. The mixture alkaloids lycoramine and galanthine presented IC₅₀ values of 14.55 ± 1.0 μg/mL against AChE, and the lycoramine, trisphaeridine, and vittatine mix presented IC₅₀ values of 38.42 ± 3.4 μg/mL in BChE. These results showed prominent inhibitory activity against AChE and BChE enzymes, indicating their potential as agents for treating AD through a combined strategy. Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 129 KiB

Open AccessAbstract

Potent and Selective Estrogen Receptor-Beta Agonists Which Enhance Memory Consolidation in an Ovariectomized Mouse Model

by Alicia M. Hanson, Iresha Sampathi Perera, Jaekyoon Kim, Noreena Sweeney, Andrea Imhoff, Adam J. Wargolet, Rochelle M. Van Hart, Andrew Craig Mackinnon, Karyn M. Frick, Daniel S. Sem and William A. Donaldson

Proceedings 2019, 22(1), 73; https://doi.org/10.3390/proceedings2019022073 - 15 Aug 2019

Viewed by 1767

Abstract

Estrogen receptor-beta (ER-beta) is a drug target for memory consolidation in postmenopausal [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 158 KiB

Open AccessAbstract

Kinetic Characterization of Novel HIV-1 Entry Inhibitors: Discovery of a Relationship between Off-Rate and Potency

by Megan E. Meuser, Michael B. Murphy, Adel A. Rashad and Simon Cocklin

Proceedings 2019, 22(1), 77; https://doi.org/10.3390/proceedings2019022077 - 15 Aug 2019

Viewed by 1229

Abstract

The entry of HIV-1 into permissible cells remains an extremely attractive and underexploited therapeutic intervention point. We have previously demonstrated the ability to extend the chemotypes available for optimization in the entry inhibitor class using computational means. Here, we continue this effort, designing [...] Read more.

The entry of HIV-1 into permissible cells remains an extremely attractive and underexploited therapeutic intervention point. We have previously demonstrated the ability to extend the chemotypes available for optimization in the entry inhibitor class using computational means. Here, we continue this effort, designing and testing three novel compounds with the ability to inhibit HIV-1 entry. We demonstrate that alteration of the core moiety of these entry inhibitors directly influences the potency of the compounds, despite common proximal and distal groups. Moreover, by establishing for the first time a surface plasmon resonance (SPR)-based interaction assay with soluble recombinant SOSIP Env trimers, we demonstrate that the off-rate (kd) parameter shows the strongest correlation with potency in an antiviral assay. Finally, we establish an underappreciated relationship between the potency of a ligand and its degree of electrostatic complementarity (EC) with its target, the Env complex. These findings not only broaden the chemical space in this inhibitor class, but also establish a rapid and simple assay to evaluate future HIV-1 entry inhibitors. Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 125 KiB

Open AccessAbstract

Selective Activity-Based Probes Targeting Fibroblast Activation Protein (FAP)

by Johannes Vrijdag, Anvesh Jallapally, An De Decker, Koen Janssen, Filipe Elvas, Steven Staelens, Ingrid De Meester, Koen Augustyns, Anne-Marie Lambeir and Pieter Van der Veken

Proceedings 2019, 22(1), 84; https://doi.org/10.3390/proceedings2019022084 - 20 Aug 2019

Viewed by 1530

Abstract

Fibroblast activation protein (FAP) is a type II transmembrane serine protease that belongs to the dipeptidyl peptidase (DPP) family. Although FAP expression is practically non-existent in the majority of healthy adult tissues, it is clearly upregulated in tissue remodeling processes associated with several [...] Read more.

Fibroblast activation protein (FAP) is a type II transmembrane serine protease that belongs to the dipeptidyl peptidase (DPP) family. Although FAP expression is practically non-existent in the majority of healthy adult tissues, it is clearly upregulated in tissue remodeling processes associated with several diseases. These include cancer, atherosclerosis, arthritis, hepatic, and pulmonary fibrosis. This finding has recently sparked intensive research aiming at the clinical implementation of FAP as a diagnostic and/or prognostic biomarker for the aforementioned diseases. Several immunochemical approaches have been reported that can quantify FAP expression. The main drawback of these approaches, however, lies in the fact that some of the commercially available FAP antibodies have been reported to lack specificity. On the other hand, an orthogonal line of research focuses on the quantification of the enzymatically active fraction of FAP, generally relying on peptidic activity-based probes. Developing a selective activity-based assay for FAP has proven to be challenging, owing to the frequently encountered lack of probe selectivity towards prolyl oligopeptidase (PREP, PO). In response, we report a novel series of activity-based FAP probes, based on our potent and selective inhibitor UAMC-1110. Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 187 KiB

Open AccessAbstract

Toward an Innovative Treatment of Alzheimer’s Disease: Design of MTDLs Targeting Acetylcholinesterase and α-7 Nicotinic Receptors

by Mégane Pons, Ludovic Jean, Sylvain Routier, Frédéric Buron, Sylvie Chalon and Pierre-Yves Renard

Proceedings 2019, 22(1), 88; https://doi.org/10.3390/proceedings2019022088 - 27 Aug 2019

Viewed by 1446

Abstract

Alzheimer’s disease (AD) is a complex and progressive neurodegenerative disorder. The available therapy is limited to symptomatic treatment, and its efficacy remains unsatisfactory. In view of the prevalence and expected increase in the incidence of AD, the development of an effective therapy is [...] Read more.

Alzheimer’s disease (AD) is a complex and progressive neurodegenerative disorder. The available therapy is limited to symptomatic treatment, and its efficacy remains unsatisfactory. In view of the prevalence and expected increase in the incidence of AD, the development of an effective therapy is crucial for public health. Since the therapeutic paradigm “one compound–one-target” has shown its limits in the treatment of AD, new strategies are emerging to overcome the lack of efficiency of the current pharmacotherapy in the past decade. The most promising is the multitarget-directed ligands (MTDLs) strategy. This project consists of the development of new multifunctional agents, which will act simultaneously on the different players in AD pathology by combining an AChE inhibitory activity based on the structures of a well-known AChE inhibitor (Rivastigmine) with an α-7 nAChR activation. Indeed, nAChRs were recently put forward as potential targets for the treatment of central nervous system (CNS) diseases, such as AD. Because of their distribution and abundance in the CNS, the α-7 subtypes are potential therapeutic targets for this disorder. Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 139 KiB

Open AccessAbstract

Sag/Rbx2 E3 Ubiquitin Ligase: From Target Validation to Drug Discovery

by Yi Sun

Proceedings 2019, 22(1), 102; https://doi.org/10.3390/proceedings2019022102 - 14 Nov 2019

Viewed by 795

Abstract

SCF (SKP1, Cullins, and F-box proteins) E3 ligase, also known. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 140 KiB

Open AccessAbstract

Tracing Potential Covalent Inhibitors of an E3 Ubiquitin Ligase Through Target-Focused Modelling

by Imane Bjij, Pritika Ramharack, Shama Khan, Driss Cherqaoui and Mahmoud Soliman

Proceedings 2019, 22(1), 103; https://doi.org/10.3390/proceedings2019022103 - 14 Nov 2019

Viewed by 864

Abstract

The Nedd4-1 E3 Ubiquitin ligase has been implicated in multiple disease conditions due its overexpression. Although the Nedd4-1 E3 Ubiquitin ligase is an enzyme that may be targeted either covalently, or non-covalently, there are few studies that demonstrate effective inhibitors of the enzyme. [...] Read more.

The Nedd4-1 E3 Ubiquitin ligase has been implicated in multiple disease conditions due its overexpression. Although the Nedd4-1 E3 Ubiquitin ligase is an enzyme that may be targeted either covalently, or non-covalently, there are few studies that demonstrate effective inhibitors of the enzyme. In this work, we aimed to identify covalent inhibitors of Nedd4-1. This task however, proved to be challenging due to the limited available electrophilic moieties in virtual libraries. We therefore opted to divide an existing covalent Nedd4-1 inhibitor in two parts: A non-covalent binding part and a pre-selected α, β-unsaturated ester that forms the covalent linkage with the protein. A non-covalent pharmacophore model was built based on the active site binding investigations followed by validating the covalent conjugation. Thirty compounds were selected and covalently docked into the catalytic site of the Nedd4-1. Multiple filtrations were effected before selecting 5 hits that were later analysed by molecular dynamic simulations to check their stability and explore their binding landscape in complex with the protein. All in all, two inhibitors with optimum overall stability and more stabilising interactions were kept for eventual biological evaluation. Our improved pharmacophore model approach serves as a robust method that will illuminate the screening for novel covalent inhibitor in drug discovery. Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 134 KiB

Open AccessAbstract

New Methodology to Access 1,5-Disubstituted 1,2,3-Triazoles

by Virgyl Camberlein, Ronan Gealageas, Benoit Deprez, Rebecca Deprez and Damien Bosc

Proceedings 2019, 22(1), 104; https://doi.org/10.3390/proceedings2019022104 - 14 Nov 2019

Viewed by 797

Abstract

1,2,3-triazole is a well-known scaffold that is. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 117 KiB

Open AccessAbstract

How Size Matters: Designing Diverse Fragment Libraries for Novel Drug Discovery

by Yun Shi and Mark von Itzstein

Proceedings 2019, 22(1), 107; https://doi.org/10.3390/proceedings2019022107 - 14 Nov 2019

Viewed by 981

Abstract

Fragment-based drug discovery (FBDD) has become a major strategy to derive novel lead candidates for both new and established therapeutic targets, as it promises efficient exploration of chemical space by employing fragment-sized (MW 300) compounds. One of the first challenges in implementing a [...] Read more.

Fragment-based drug discovery (FBDD) has become a major strategy to derive novel lead candidates for both new and established therapeutic targets, as it promises efficient exploration of chemical space by employing fragment-sized (MW 300) compounds. One of the first challenges in implementing a FBDD approach is the design of a fragment library, and more specifically, the choice of its size and individual members. In order to construct a library that maximises the chances of discovering novel chemical matter, a large number of fragments with sufficient structural diversity are often sought. However, the exact diversity of a certain collection of fragments remains elusive, which hinders direct comparisons among different selections of fragments. Building upon structural fingerprints that are commonly utilised in cheminformatics, we herein introduced quantitative measures for the structural diversity of fragment libraries. Structures of commercially available fragments were retrieved from the ZINC database and filtered by physicochemical properties, after which they were subject to selections with library sizes ranging from 100 to 100,000 compounds. The selected libraries were evaluated and compared quantitatively, resulting in interesting size-diversity relationships. Our results suggested the existence of an optimal size for structural diversity and demonstrated that such quantitative measures can guide the design of diverse fragment libraries under various circumstances Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 178 KiB

Open AccessAbstract

Inhibitors of Phospholipid-Hydrolyzing Enzymes as Novel Agents against Pulmonary Fibrosis and Diabetes Type-1

by George Kokotos

Proceedings 2019, 22(1), 111; https://doi.org/10.3390/proceedings2019022111 - 4 Dec 2019

Viewed by 850

Abstract

Phospholipid-hydrolyzing enzymes, such as phospholipases A₂ (PLA₂s) and autotaxin (ATX), have attracted medicinal interest because they are involved in the generation of various inflammatory mediators. PLA₂s hydrolyze membrane phospholipids initiating the arachidonic acid cascade, and in particular calcium-independent [...] Read more.

Phospholipid-hydrolyzing enzymes, such as phospholipases A₂ (PLA₂s) and autotaxin (ATX), have attracted medicinal interest because they are involved in the generation of various inflammatory mediators. PLA₂s hydrolyze membrane phospholipids initiating the arachidonic acid cascade, and in particular calcium-independent PLA₂ (iPLA₂), have been recognized as a participant in biological processes underlying diabetes development and autoimmune-based disorders. ATX hydrolyzes lysophosphatidylcholine, generating lysophosphatidic acid; both ATX and lysophosphatidic acid are involved in pathological conditions, such as fibrosis and cancer. We have developed several classes of potent PLA₂ inhibitors. In this presentation, we will present new β-lactones as highly potent inhibitors of iPLA₂ and a novel class of ATX inhibitors containing the zinc binding functionality of hydroxamic acid. Various novel hydroxamic acids based on either 4-aminophenylacetic acid or non-natural δ-amino acids were synthesized and evaluated (J. Med Chem. 2018, 61, 3697–3711). Hydroxamic acids that incorporate a δ-amino acid residue exhibit high in vitro inhibitory potency over ATX. Inhibitor GK442 (IC₅₀ 60 nM), based on δ-norleucine, was tested for its efficacy in a mouse model of pulmonary inflammation and fibrosis induced by bleomycin and exhibited promising efficacy. New β-lactones have been synthesized and evaluated for inhibitory potency over iPLA₂(J. Med Chem. 2019, 62, 2916–2927). A β-lactone substituted at position-3 by a four-carbon chain carrying a phenyl group, and at position-4 by a n-propyl group (GK563), was identified as being the most potent iPLA₂ inhibitor ever reported (X_I(50) 0.0000021). GK563 was found to reduce β-cell apoptosis induced by pro-inflammatory cytokines, raising the possibility that it can be beneficial in countering autoimmune diseases, such as type-1 diabetes. Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 128 KiB

Open AccessAbstract

3D and 4D-QSAR of Dopamine Transporter Inhibitors (DAT) Using the LQTA-QSAR Approach

by Eduardo Borges de Melo, Aline Thais Bruni and João Paulo Ataide Martins

Proceedings 2019, 22(1), 112; https://doi.org/10.3390/proceedings2019022112 - 4 Dec 2019

Viewed by 929

Abstract

At present, drug abuse has developed into a social problem. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 164 KiB

Open AccessAbstract

2D-QSAR Studies of Dopamine Transporter Inhibitors (DAT) Using OPS and GA Variable Selection Approaches

by Eduardo Borges de Melo, Aline Thais Bruni and João Paulo Ataide Martins

Proceedings 2019, 22(1), 114; https://doi.org/10.3390/proceedings2019022114 - 4 Dec 2019

Viewed by 948

Abstract

Today, drug abuse has developed into a social problem and begun to demand specific measures from different social sectors and government agencies all over the world. Despite significant efforts made toward relevant mechanistic targets, such as the dopamine transporter (DAT), the development of [...] Read more.

Today, drug abuse has developed into a social problem and begun to demand specific measures from different social sectors and government agencies all over the world. Despite significant efforts made toward relevant mechanistic targets, such as the dopamine transporter (DAT), the development of pharmacotherapeutic treatments of psychostimulant abuse has remained a challenge so far. Using a set of 49 2-[(diphenylmethyl)sulfanyl]ethanamines described as DAT inhibitors, 2D-QSAR/PLS studies were performed using two different approaches of variable selection: Ordered predictors selection (OPS) and genetic algorithm (GA). All structures were optimized at the B3LYP/6-311G++(d,p) level of theory. The molecular descriptors were obtained in the Dragon 6 program (topological, geometric, molecular, and constitutional) and GaussView 03 (electronic). Both models were formed by two latent variables. Model 1 (OPS) was constructed with four molecular descriptors (GATS3m, Mor15p, SpMin3_Bh(s), and HOMO-1), while six (Mor13m, CATS2D_09_LL, RDF110u, RDF085m, Mor24s, and RDF010s) were required to obtain model 2 (GA). The models can be considered reasonably different: In model 1, electronic features predominate, whereas in model 2, steric and geometric effects do. The overall test indicated that models 1 and 2 have equivalent predictive ability (Average r²_m Overall = 0.730 versus 0.710 and Delta r²_m Overall = 0.122 versus 0.151). However, model 1 is simpler (it has only four descriptors, which facilitates its interpretation), presents more relevant information used in the construction of its two latent variables (75.99% versus 64.07%), and its calibration is more significant than that of model 2 (F_n_,_n₋_p₋₁ = 115.814 versus 80.888, for the same tabled F value, where n = 36, and n − p − 1 = 3.256, with alfa = 0.05). Considering these results, although model 2 may also be considered a good result, model 1, obtained using the OPS approach for variable selection, may be considered more reliable for prediction purposes. This result is in agreement with good results previously obtained using the OPS methodology. Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 121 KiB

Open AccessAbstract

Targeted Protein Degradation with Small Molecules: How PROTACs Work

by Alessio Ciulli

Proceedings 2019, 22(1), 115; https://doi.org/10.3390/proceedings2019022115 - 16 Dec 2019

Viewed by 1213

Abstract

Bivalent degrader molecules (also termed PROTACs) target proteins for degradation through recruitment to E3 ligases. PROTACs are a revolutionary new modality class with therapeutic potential. Formation of a ternary complex between the degrader, the ligase, and the target leads to tagging by ubiquitination [...] Read more.

Bivalent degrader molecules (also termed PROTACs) target proteins for degradation through recruitment to E3 ligases. PROTACs are a revolutionary new modality class with therapeutic potential. Formation of a ternary complex between the degrader, the ligase, and the target leads to tagging by ubiquitination and proteasomal degradation of the target protein. In 2015, we disclosed MZ1, a potent degrader made of a ligand we had previously discovered for the E3 ligase von Hippel–Lindau (VHL), and a pan-selective ligand for the BET proteins Brd2, Brd3, and Brd4. We made the unexpected but fascinating observation that MZ1 induces preferential degradation of Brd4 over Brd2 and Brd3—despite engaging BET proteins with the same binary affinity. This demonstrated a now well-established feature of PROTACs: They can achieve a narrower degradation profile in spite of broad target engagement. Our co-crystal structure of a PROTAC ternary complex (VHL:MZ1:Brd4) illuminated the role of cooperative molecular recognition inducing de novo contacts to form a stable ternary. Our work is revealing the structural basis and guiding principles of PROTAC degradation selectivity and mode of action. Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

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1 pages, 284 KiB

Open AccessExtended Abstract

Promising Approach to Inhibit E. coli FimH Adhesion by C-Linked Mannosides

by Leila Mousavifar and René Roy

Proceedings 2019, 22(1), 1; https://doi.org/10.3390/proceedings2019022001 - 6 Aug 2019

Viewed by 1074

Abstract

Antagonists of the uropathogenic Escherichia coli type-1 fimbrial adhesin (FimH) are recognized as attractive alternatives for antibiotic therapies and prophylactic strategies against acute and recurrent bacterial infections. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

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1 pages, 148 KiB

Open AccessExtended Abstract

A Novel Series of Sialic Acid-Based Influenza Virus Inhibitors that Target Influenza Virus Neuraminidase

by Mark von Itzstein

Proceedings 2019, 22(1), 8; https://doi.org/10.3390/proceedings2019022008 - 7 Aug 2019

Viewed by 1124

Abstract

Influenza virus continues to be a clinically-significant human pathogen that causes both
epidemics and pandemics. Successful inhibition of the viral neuraminidase hinders the release of
virion progeny from the infected host cell and significantly reduces further virus spread [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

2 pages, 176 KiB

Open AccessExtended Abstract

In Silico Design of E3 Ubiquitin-Protein Ligase NEDD4-1 Inhibitors: An Alternative Approach for Targeting the MAPK Pathway in Cancer Therapy

by Davide Pirolli, Benedetta Righino, Beatrice Tropea, Fiorella Gurrieri, Eugenio Sangiorgi and Maria Cristina De Rosa

Proceedings 2019, 22(1), 10; https://doi.org/10.3390/proceedings2019022010 - 7 Aug 2019

Cited by 1 | Viewed by 1204

Abstract

Among all the several targets in common use in the antitumor therapies, the pharmacologic
inhibition of the MAPK (Mitogen Activated Protein Kinase) pathway represents an efficient
therapeutic approach [1]. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

2 pages, 185 KiB

Open AccessExtended Abstract

Understanding the Mechanism of Direct Activation of AMP-Kinase: Towards a Fine Allosteric Tuning of the Kinase Activity

by Elnaz Aledavood, Gleiciane Moraes, Jeronimo Lameira, Ana Castro, Francisco Javier Luque and Carolina Estarellas

Proceedings 2019, 22(1), 12; https://doi.org/10.3390/proceedings2019022012 - 7 Aug 2019

Viewed by 1220

Abstract

This research deals with the regulation of the AMPK activity by direct activators, such as
compound A-769662 [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 179 KiB

Open AccessExtended Abstract

Chemically Modified Hemocyanins with Enhanced Antibreast Cancer Activities

by Maya Guncheva, Elena Stoyanova, Svetla Todinova and Krasimira Idakieva

Proceedings 2019, 22(1), 13; https://doi.org/10.3390/proceedings2019022013 - 7 Aug 2019

Cited by 1 | Viewed by 1240

Abstract

Some cancer cells hyperexpress folate receptors (FR); therefore, folate-derivatized delivery
systems are applied for a selective delivery of chemotherapeutics. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

2 pages, 173 KiB

Open AccessExtended Abstract

Facing Novel Challenges in Neurodegenerative Diseases Drug Discovery: From Small Molecules to Targeted Therapies

by Maria João Matos, Dolores Viña, Lourdes Santana and Eugenio Uriarte

Proceedings 2019, 22(1), 14; https://doi.org/10.3390/proceedings2019022014 - 7 Aug 2019

Viewed by 1306

Abstract

Neurodegenerative diseases are becoming increasingly prevalent with the aging of the general
population [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 147 KiB

Open AccessExtended Abstract

Chiral Resolution of a New Agent against Memory Impairment Connected to Neurodegenerative Diseases

by Valeria Cavalloro, Marta Rui, Giacomo Rossino, Daniela Rossi, Federica Rapetti, Chiara Brullo, Olga Bruno and Simona Collina

Proceedings 2019, 22(1), 15; https://doi.org/10.3390/proceedings2019022015 - 7 Aug 2019

Viewed by 1095

Abstract

Nowadays, the incidence of neurodegenerative diseases is increasing, and these disorders will become one of the main challenges for medicine and public health in future years. Particularly, memory loss characterizes many neurodegenerative pathologies, and it is often related to low levels of cyclic [...] Read more.

Nowadays, the incidence of neurodegenerative diseases is increasing, and these disorders will become one of the main challenges for medicine and public health in future years. Particularly, memory loss characterizes many neurodegenerative pathologies, and it is often related to low levels of cyclic adenosine monophosphate (cAMP). [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

2 pages, 197 KiB

Open AccessExtended Abstract

Small Molecules as Potential Inhibitors of the 14-3-3/c-Abl Interaction for the Treatment of CML

by Leire Iralde-Lorente, Giusy Tassone, Ylenia Cau, Claire Munier, Lorenzo Franci, Cecilia Pozzi, Adriano Angelucci, Mario Chiariello, Matthew Perry, Stefano Mangani and Maurizio Botta

Proceedings 2019, 22(1), 17; https://doi.org/10.3390/proceedings2019022017 - 7 Aug 2019

Viewed by 1915

Abstract

c-Abl is a tyrosine kinase implicated in the regulation of proliferation, adhesion, motility, and
cell survival [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 155 KiB

Open AccessExtended Abstract

Adamantane Analogs: From Anti-Influenza Drugs to Soluble Epoxide Hydrolase Inhibitors for Acute Pancreatitis

by Santiago Vázquez

Proceedings 2019, 22(1), 18; https://doi.org/10.3390/proceedings2019022018 - 7 Aug 2019

Viewed by 1074

Abstract

The adamantane scaffold is present in eight approved drugs. […] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

2 pages, 200 KiB

Open AccessExtended Abstract

New Diarylureas as Activators of the Heme-Regulated EIF2α Kinase for the Treatment of Type 2 Diabetes Mellitus

by Eugènia Pujol, Mohammad Zarei, Javier Pizarro, M aria Isabel Loza, José Manuel Brea, Manuel Vázquez-Carrera and Santiago Vázquez

Proceedings 2019, 22(1), 19; https://doi.org/10.3390/proceedings2019022019 - 7 Aug 2019

Viewed by 736

Abstract

Type 2 diabetes mellitus (T2DM) has reached epidemic proportions. […] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 150 KiB

Open AccessExtended Abstract

Double Modification of Polyether Ionophores: Synthesis and Biological Activity of Novel Salinomycin Derivatives

by Michał Antoszczak, Dominika Czerwonka, Alicja Urbaniak, Szymon Sobczak, Timothy C. Chambers and Adam Huczyński

Proceedings 2019, 22(1), 20; https://doi.org/10.3390/proceedings2019022020 - 7 Aug 2019

Viewed by 1284

Abstract

Polyether ionophore antibiotics represent a large group of more than 120 lipid-soluble
compounds that are widely used in veterinary medicine because of their significant antimicrobial
activity [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

2 pages, 171 KiB

Open AccessExtended Abstract

Discovery of a Selective NEK6 Kinase Inhibitor by Virtual Screening

by Benedetta Righino, Marta De Donato, Flavia Filippetti, Alessandra Battaglia, Marco Petrillo, Davide Pirolli, Giovanni Scambia, Daniela Gallo and Maria Cristina De Rosa

Proceedings 2019, 22(1), 21; https://doi.org/10.3390/proceedings2019022021 - 7 Aug 2019

Viewed by 1314

Abstract

NIMA-related kinases (Neks) are a conserved serine/threonine protein kinase family related to
cell cycle progression and cell division [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 156 KiB

Open AccessExtended Abstract

Design, Synthesis, and Biological Evaluation of 4-aminoquinazoline Appended-Benzofuran Hybrids as Epidermal Growth Factor Receptor Inhibitors

by Marole Maria Maluleka and Malose Jack Mphahlele

Proceedings 2019, 22(1), 22; https://doi.org/10.3390/proceedings2019022022 - 7 Aug 2019

Viewed by 1543

Abstract

Nitrogen-containing heterocycles such as quinazolines and benzofurans have received a great amount of interest in targeted therapies as antitumor drugs [1]. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

2 pages, 185 KiB

Open AccessExtended Abstract

Novel Sortase A Inhibitors to Counteract Gram-Positive Bacterial Biofilms

by Maria Valeria Raimondi, Roberta Listro, Maria Grazia Cusimano, Mery La Franca, Teresa Faddetta, Giuseppe Gallo, Domenico Schillaci, Simona Collina, Ainars Leonchiks and Giampaolo Barone

Proceedings 2019, 22(1), 23; https://doi.org/10.3390/proceedings2019022023 - 7 Aug 2019

Cited by 2 | Viewed by 1320

Abstract

Sortase A (SrtA) is a membrane enzyme responsible for the covalent anchoring of surface proteins on the cell wall of Gram-positive bacteria. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 187 KiB

Open AccessExtended Abstract

Mechanisms of Inhibitory Effects of Polysubstituted Pyrimidines on Prostaglandin E₂ Production

by Zdeněk Zídek, Viktor Kolman, Ondřej Baszczyňski, Filip Kalčic, Daniel Board and Zlatko Janeba

Proceedings 2019, 22(1), 24; https://doi.org/10.3390/proceedings2019022024 - 7 Aug 2019

Viewed by 1129

Abstract

The pyrimidine heterocycle represents an elemental structural motif of numerous drugs. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 139 KiB

Open AccessExtended Abstract

Steroid Sulfatase Inhibition: From Concept to Clinic and Beyond

by Barry V L Potter

Proceedings 2019, 22(1), 25; https://doi.org/10.3390/proceedings2019022025 - 7 Aug 2019

Viewed by 1045

Abstract

Many tumours are hormone-dependent, and estrogens (E1/E2) play a key role in development.
Despite aromatase inhibitor (AI) therapy [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

2 pages, 174 KiB

Open AccessExtended Abstract

Comparative Studies on the Human Serum Albumin Binding of the Investigational EGFR Inhibitor KP2187, Its Hypoxia-Activated Cobalt Complex, and a Series of Clinically Approved Inhibitors

by Eva Anna Enyedy, Orsolya Dömötör, Attila Borics, Bernhard K. Keppler and Christian R. Kowol

Proceedings 2019, 22(1), 27; https://doi.org/10.3390/proceedings2019022027 - 7 Aug 2019

Viewed by 1214

Abstract

Binding interactions between human serum albumin and four clinically approved epidermal [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 172 KiB

Open AccessExtended Abstract

Searching for Selective Scaffolds against Plasmodium falciparum Glucose-6-Phosphate Dehydrogenase 6-Phosphogluconolactonase

by Antonio Viayna, David Vílchez, Javier Vázquez, Susana Pérez-Benavente, José Manuel Bautista and Francisco Javier Luque

Proceedings 2019, 22(1), 28; https://doi.org/10.3390/proceedings2019022028 - 7 Aug 2019

Cited by 1 | Viewed by 1426

Abstract

Malaria is a parasitic disease caused by Plasmodium spp., being one of the major causes of death worldwide with two-hundred million new infections and hundreds of thousands of deaths in 2015. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

2 pages, 180 KiB

Open AccessExtended Abstract

Design, Synthesis, and Biological Evaluation of Bimodal Glycopeptides as Inhibitors of Neurotoxic Protein Aggregation

by Philip Ryan, Mingming Xu, Andrew K. Davey, George D. Mellick and Santosh Rudrawar

Proceedings 2019, 22(1), 32; https://doi.org/10.3390/proceedings2019022032 - 7 Aug 2019

Viewed by 1840

Abstract

Post-translational modifications (PTM) of proteins are becoming the focus of a growing base of [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

2 pages, 151 KiB

Open AccessExtended Abstract

Regression of an Epidermoid Carcinomas in Domestic Canine Treated with Casiopeína^® IIgly

by Paola Aranda-Vargas, Orlando Chávez-Moreno, Sandra Rodríguez, Manuel Trejo-Mandujano, Paola Martínez Patiño, Lena Ruiz-Azuara and Carmen Mejía

Proceedings 2019, 22(1), 34; https://doi.org/10.3390/proceedings2019022034 - 7 Aug 2019

Viewed by 1192

Abstract

Squamous cell carcinoma (SCC) is a malignancy that has no treatment. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 203 KiB

Open AccessExtended Abstract

Tdp1 Inhibition as a Promising Approach to New Anticancer Drugs

by Konstantin Volcho, Alexandra Zakharenko, Olga Luzina, Tatyana Khomenko, Evgeniy Suslov, Oksana Salomatina, Olga Zakharova, Nikolai Li-Zhulanov, Jóhannes Reynisson, Olga Lavrik and Nariman Salakhutdinov

Proceedings 2019, 22(1), 35; https://doi.org/10.3390/proceedings2019022035 - 7 Aug 2019

Cited by 1 | Viewed by 1467

Abstract

The cytotoxic effects of chemotherapy and radiation that are clinically used to treat malignancies are directly related to their propensity to generate DNA damage. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 179 KiB

Open AccessExtended Abstract

Can Short Peptides Be Inhibitors of Serum Amyloid a Protein Aggregation?

by Sandra Skibiszewska and Elzbieta Jankowska

Proceedings 2019, 22(1), 38; https://doi.org/10.3390/proceedings2019022038 - 7 Aug 2019

Viewed by 1072

Abstract

One of the approaches in the design of anti-amyloid drugs is to find compounds that are able to hamper self-association of amyloidogenic protein molecules. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 153 KiB

Open AccessExtended Abstract

Design of New Probes for Oxidized Amino Acids Localization

by Mathieu Esgulian, Luc Camoin, Mathieu Cassien, Yves Toiron, Sylvia Pietri and Sophie Thétiot-Laurent

Proceedings 2019, 22(1), 39; https://doi.org/10.3390/proceedings2019022039 - 8 Aug 2019

Viewed by 1150

Abstract

Protein carbonyls (PC) are oxidative damage observed in many diseases. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 181 KiB

Open AccessExtended Abstract

Amphidinolides and Iriomoteolides, Potent Anticancer Macrolides

by Lluís Bosch, Víctor Cascales, Alejandro Castro-Alvarez, Cristian Marco, Elena Petit, Anna M. Costa and Jaume Vilarrasa

Proceedings 2019, 22(1), 41; https://doi.org/10.3390/proceedings2019022041 - 8 Aug 2019

Viewed by 1309

Abstract

Amphidinolides and iriomoteolides are complex macrolides isolated from cultured marine
dinoflagellates of the genus Amphidinium sp. [1–4]. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 144 KiB

Open AccessExtended Abstract

Synthesis and Evaluation of Thymoquinone Analogues as Anti-Ovarian Cancer Agents

by Okiemute Rosa Johnson-Ajinwo, Alan Richardson and Wen-Wu Li

Proceedings 2019, 22(1), 42; https://doi.org/10.3390/proceedings2019022042 - 8 Aug 2019

Cited by 1 | Viewed by 1435

Abstract

Thymoquinone (TQ), 2-isopropyl-5-methyl-1,4-benzoquinone, a natural product isolated from
Nigella sativa L. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 126 KiB

Open AccessExtended Abstract

Recent Advances in Discovery of New Tyrosine Kinase Inhibitors Using Computational Methods

by Vesna Rastija

Proceedings 2019, 22(1), 44; https://doi.org/10.3390/proceedings2019022044 - 8 Aug 2019

Viewed by 1034

Abstract

Tyrosine–protein kinases catalyze chemical reactions that. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 116 KiB

Open AccessExtended Abstract

Novel Dual PDK1/AurK-A Inhibitors for Cancer Therapy: Med Chem Evolution and Crystallographic Investigation

by Simona Sestito, Sara Chiarugi, Eleonora Margheritis, Massimiliano Runfola, Simone Bertini, Gianpiero Garau and Simona Rapposelli

Proceedings 2019, 22(1), 45; https://doi.org/10.3390/proceedings2019022045 - 8 Aug 2019

Cited by 1 | Viewed by 1483

Abstract

The struggle to find novel efficacious pharmacological approaches for cancer treatment has led
to the identification of several kinases involved in neoplastic genesis and cell development. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

2 pages, 190 KiB

Open AccessExtended Abstract

Rational Design, Synthesis, and Characterization of Glycoconjugates as Potential Vaccines against Tuberculosis

by Teodora Bavaro, Francesca Rinaldi, Sara Tengattini, Loredana Lupu, Luciano Piubelli, Francesca Mangione, Roberta Bernardini, Vincenzina Monzillo, Piero Marone, Loredano Pollegioni, Caterina Temporini, Michael Przybylski and Marco Terreni

Proceedings 2019, 22(1), 46; https://doi.org/10.3390/proceedings2019022046 - 8 Aug 2019

Viewed by 1372

Abstract

Tuberculosis (TB) is the first cause of death from infectious diseases. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 152 KiB

Open AccessExtended Abstract

Synthesis of Enantiomeric Halolactones with Aromatic Ring, Their Anticancer Activity and Interactions with Biological Membranes

by Witold Gładkowski, Aleksandra Pawlak, Aleksandra Włoch, Marcelina Mazur, Halina Kleszczyńska and Bożena Obmińska-Mrukowicz

Proceedings 2019, 22(1), 47; https://doi.org/10.3390/proceedings2019022047 - 8 Aug 2019

Viewed by 1126

Abstract

Studying the effect of chirality on the activity of tested compounds, we synthesized new series of the enantiomeric (ee = 98–100%) β-aryl-δ-halo-γ-lactones with defined configurations of stereogenic centers. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

2 pages, 184 KiB

Open AccessExtended Abstract

Antibacterial N-Arylcinnamamides as Anti-inflammatory Agents

by Jiri Kos, Lubos Danisovic, Zuzana Varchulova Novakova, Radoslav Zamborsky, Ferdinand Devinsky and Josef Jampilek

Proceedings 2019, 22(1), 48; https://doi.org/10.3390/proceedings2019022048 - 8 Aug 2019

Viewed by 1274

Abstract

A series of ring-substituted N-arylcinnamamides was prepared, characterized, and investigated
for their antimicrobial efficacy in detail [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

2 pages, 183 KiB

Open AccessExtended Abstract

Novel Dual Ligands Targeting Sigma1 Receptor and Acetylcholinesterase Endowed with Antioxidant Properties

by Giacomo Rossino, Marta Rui, Dirk Schepmann, Bernard Wünsch, Stefania Monteleone, Klaus Liedl, Vittorio Pace, Daniela Rossi and Simona Collina

Proceedings 2019, 22(1), 49; https://doi.org/10.3390/proceedings2019022049 - 8 Aug 2019

Viewed by 1375

Abstract

Neurodegenerative disorders represent one of the main therapeutic challenges of our time. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

2 pages, 164 KiB

Open AccessExtended Abstract

Clove Buds Affect MCF-7 Breast Cancer Cell Stress/Survival Pathways and Induce Oxidative Stress, DNA Damage, Cell Cycle Arrest, and Apoptosis

by Martin Kello, Lenka Varinska, Matus Coma, Peter Kubatka, Klaudia Petrova, Tomas Kuruc and Jan Mojzis

Proceedings 2019, 22(1), 51; https://doi.org/10.3390/proceedings2019022051 - 8 Aug 2019

Viewed by 1148

Abstract

Breast cancer is reportedly the second most diagnosed cancer worldwide. Several recent [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 138 KiB

Open AccessExtended Abstract

Understanding the Pathophysiology and Searching for Biomarkers for Rare Genetic Developmental Diseases

by Laura Castilla-Vallmanya, Roser Urreizti, Héctor Franco, Jeanne Amiel, Tiong Y. Tan, Luitgard Graul Neumann, Christopher T. Gordon, Daniel Grinberg and Susana Balcells

Proceedings 2019, 22(1), 53; https://doi.org/10.3390/proceedings2019022053 - 8 Aug 2019

Viewed by 1169

Abstract

Opitz C syndrome (OCS, MIM #211750) is an extremely rare genetic disorder characterized by
multiple malformations (e.g., trigonocephaly, congenital heart defects) and variable intellectual and
psychomotor delay. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

2 pages, 183 KiB

Open AccessExtended Abstract

In Vitro Assessment of the Neuroprotective and Antioxidant Properties of New Benzimidazole Derivatives as Potential Drug Candidates for the Treatment of Parkinson’s Disease

by Neda Anastassova, Maria Argirova, Denitsa Yancheva, Denitsa Aluani, Virginia Tzankova, Nadya Hristova-Avakumova and Vera Hadjimitova

Proceedings 2019, 22(1), 54; https://doi.org/10.3390/proceedings2019022054 - 8 Aug 2019

Cited by 3 | Viewed by 1516

Abstract

Oxidative stress is related to the pathogenesis of many neurodegenerative disorders, including [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 145 KiB

Open AccessExtended Abstract

Induction of Biofilm Formation in Klebsiella pneumoniae by Acetaminophen. Quorum Quenching Compounds to Overcome the Resistance

by Fernando Echeverri, Elizabeth Cadavid, Sara Robledo and Wiston Quiñones

Proceedings 2019, 22(1), 55; https://doi.org/10.3390/proceedings2019022055 - 8 Aug 2019

Viewed by 1218

Abstract

Bacterial resistance to antibiotics is a serious world health problem; consequently, there is a high recurrence of nosocomial infections. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

2 pages, 189 KiB

Open AccessExtended Abstract

Strategies to Discover p53 Activators and a p73 Activator for Neuroblastoma

by Emília Sousa, Sara Gomes, Liliana Raimundo, Joana Soares, Joana Loureiro, Mariana Leão, Helena Ramos, Madalena Monteiro, Petr Chlapek, Renata Veselská, Agostinho Lemos, Joana Moreira, Madalena Pinto and Lucilia Saraiva

Proceedings 2019, 22(1), 56; https://doi.org/10.3390/proceedings2019022056 - 9 Aug 2019

Viewed by 1262

Abstract

In our quest to discover antitumor agents with novel mechanisms of action, our strategy
concerned multiple molecular modifications in a chemical core. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 140 KiB

Open AccessExtended Abstract

New 3rd Generation of Casiopeinas Family Compounds with Indomethacin as a Secondary Ligand: Synthesis, Characterization, Antiproliferative Activity, and Nanoencapsulation

by Yokari Godínez-Loyola, María Josefa Bernad-Bernad, Jesus Gracia-Mora, Ramón Enrique Robles-Zepeda and Lena Ruiz-Azuara

Proceedings 2019, 22(1), 57; https://doi.org/10.3390/proceedings2019022057 - 9 Aug 2019

Viewed by 1392

Abstract

The search for new molecules with greater antitumor activity as well as new forms of administration of chemotherapeutic drugs are the task of this work. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 180 KiB

Open AccessExtended Abstract

Design and Evaluation of New Phosphorus Substituted Aziridines as Antiproliferative Agents

by Jesús M. de los Santos, Victor Carramiñana, Ana María Ochoa de Retana, Ander Vélez del Burgo and Francisco Palacios

Proceedings 2019, 22(1), 60; https://doi.org/10.3390/proceedings2019022060 - 9 Aug 2019

Viewed by 1057

Abstract

Covalent bond formation has become a safe and effective strategy applied not only by nature
but also by the pharmaceutical industry to improve disease pharmacology [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

2 pages, 179 KiB

Open AccessExtended Abstract

Searching for Molecules against Cancer in the Azores: Plants, Macroalgae, and Synthetic Compounds

by Maria do Carmo Barreto, Vera Lúcia Gouveia, Gonçalo Pereira Rosa and Ana Maria Loureiro Seca

Proceedings 2019, 22(1), 61; https://doi.org/10.3390/proceedings2019022061 - 12 Aug 2019

Viewed by 1328

Abstract

Pursuing the goal of finding active molecules against cancer using various approaches, we
focused on natural-based scaffolds in terrestrial plants and in marine macroalgae, taking advantage
of the rich biodiversity of the Azores islands. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

2 pages, 192 KiB

Open AccessExtended Abstract

Synthesis and Biological Evaluation of Aminobisphosphonates—Analogues of Incadronate

by Ewa Chmielewska, Jan Kuryszko, Joanna Wietrzyk, Zdzisław Kiełbowicz and Paweł Kafarski

Proceedings 2019, 22(1), 64; https://doi.org/10.3390/proceedings2019022064 - 12 Aug 2019

Viewed by 1238

Abstract

Bisphosphonates had been found to act as strong metal ion complexing agents with useful
industrial and household applications. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

2 pages, 193 KiB

Open AccessExtended Abstract

Towards the Modulation of RNA-Binding Proteins: New Compounds Targeting Protein HuR

by Serena Della Volpe, Rita Nasti, Michele Queirolo, Yagiz M. Unver, Varsha R. Jumde, Alexander Dömling, Francesca Vasile, Donatella Potenza, Francesca Alessandra Ambrosio, Giosué Costa, Stefano Alcaro, Chiara Zucal, Alessandro Provenzani, Marcello Di Giacomo, Daniela Rossi, Anna K. H. Hirsch and Simona Collina

Proceedings 2019, 22(1), 65; https://doi.org/10.3390/proceedings2019022065 - 12 Aug 2019

Viewed by 1215

Abstract

RNA-binding proteins (RBPs) have been widely recognized for their pivotal role in the
regulation of post-transcriptional processes. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 129 KiB

Open AccessExtended Abstract

Development of Novel, Potent Phosphatidyl–Choline-Specific Phospholipase C Inhibitors

by Lisa I. Pilkington, Euphemia Leung and David Barker

Proceedings 2019, 22(1), 67; https://doi.org/10.3390/proceedings2019022067 - 12 Aug 2019

Viewed by 1234

Abstract

The phosphatidyl–choline-specific phospholipase C (PC-PLC) enzyme has been shown to be an important enzyme involved in various cell-signaling processes. Furthermore, PC-PLC has been shown to be upregulated in various cancer cell lines, thereby presenting itself as a potential anti-cancer therapeutic target. Current PC-PLC [...] Read more.

The phosphatidyl–choline-specific phospholipase C (PC-PLC) enzyme has been shown to be an important enzyme involved in various cell-signaling processes. Furthermore, PC-PLC has been shown to be upregulated in various cancer cell lines, thereby presenting itself as a potential anti-cancer therapeutic target. Current PC-PLC inhibitors, including the literature standard inhibitor D609 possess characteristics making them unsuitable for clinical use. We have discovered a new class of potent PC-PLC inhibitors with much improved activity and drug-like properties than D609. The synthesis and SAR study of this class of active compounds is presented. Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 138 KiB

Open AccessExtended Abstract

The Targeting of Quadruplex Nucleic Acids in Human Cancers

by Stephen Neidle

Proceedings 2019, 22(1), 68; https://doi.org/10.3390/proceedings2019022068 - 13 Aug 2019

Viewed by 1147

Abstract

The overwhelming majority of DNA in the human genome is double-stranded. However,
regions comprising several short guanine-tracts are capable of forming higher-order structures,
termed quadruplexes. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 150 KiB

Open AccessExtended Abstract

Design and Synthesis of Immunostimulating Mannosylated Muropeptide Analogs Containing 2-Aminoadamantane-2-carboxylic Acid

by Rosana Ribić, Marija Paurević and Srđanka Tomić

Proceedings 2019, 22(1), 69; https://doi.org/10.3390/proceedings2019022069 - 13 Aug 2019

Viewed by 1234

Abstract

Muramyl dipeptide (MDP, N-acetylmuramyl-l-alanyl-d-isoglutamine) is known as the smallest synthetic adjuvant molecule capable of replacing whole Mycobacteria in Freund’s adjuvant. Numerous MDP derivatives were synthesized with the aim to avoid MDP unwanted side-effects. Many of them have therapeutic potential, including clinical use. [...] Read more.

Muramyl dipeptide (MDP, N-acetylmuramyl-l-alanyl-d-isoglutamine) is known as the smallest synthetic adjuvant molecule capable of replacing whole Mycobacteria in Freund’s adjuvant. Numerous MDP derivatives were synthesized with the aim to avoid MDP unwanted side-effects. Many of them have therapeutic potential, including clinical use. A very important parameter in the improvement of pharmacological properties of MDP is lipophilicity, e.g., it eliminates drawbacks caused by poor macrophage penetration and rapid elimination. On the other side, mannose receptors (MR), present on immunocompetent cells (such as macrophages and dendritic cells), are considered to be pattern-recognition receptors and responsible for the binding, among others, of mannosylated antigens or relevant biologically active molecules containing mannose, thus affecting the immune reactions. Up to now, our research was directed towards desmuramyl peptides which contain adamantylglycine and mannosylated adamantylglycine moieties bound to the essential part of MDP, l-Ala-d-isoGln. Here, we present the design and synthesis of novel mannosylated muropeptide analogs containing 2-aminoadamantane-2-carboxylic acid. Prepared desmuramyl peptides have lipophilic 2-aminoadamantane-2-carboxylic acid attached at the N-terminus of desmuramy dipeptide core and mannose connected to the tripeptide over a glycolyl linker. Immunostimulating activities of prepared compounds will be evaluated in the mice model using ovalbumin as an antigen and compared with previously prepared derivatives. Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 142 KiB

Open AccessExtended Abstract

Multicomponent Reaction-Based Trimethoprim Analogues as Potential Antibiotics for Resistant Bacteria

by Rodolfo Lavilla, Marina Pedrola, Ouldouz Ghashghaei, Eda Jardas, Ferran Jardí, Marta Jorba and Miquel Viñas

Proceedings 2019, 22(1), 70; https://doi.org/10.3390/proceedings2019022070 - 13 Aug 2019

Viewed by 1718

Abstract

Aminoimidazoles are relevant scaffolds in medicinal. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

2 pages, 189 KiB

Open AccessExtended Abstract

Synthesis, In Vitro Profiling, and In Vivo Efficacy Studies of a New Family of Multitarget Anti-Alzheimer Compounds

by Francisco Javier Pérez-Areales, María Garrido, Ester Aso, Manuela Bartolini, Angela De Simone, Alba Espargaró, Tiziana Ginex, Raimon Sabate, Belén Pérez, Vincenza Andrisano, Francisco Javier Luque, Isidro Ferrer, Francisco Ciruela, Angel Messeguer and Diego Muñoz-Torrero

Proceedings 2019, 22(1), 71; https://doi.org/10.3390/proceedings2019022071 - 14 Aug 2019

Viewed by 1496

Abstract

Simultaneous modulation of several targets or pathological events with a key pathogenic role is
a promising strategy to tackle thus far difficult-to-cure or incurable multifactorial diseases [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

2 pages, 188 KiB

Open AccessExtended Abstract

Peptidomimetic 1-Benzyl-5-methyl-4-(n-octylamino)pyrimidin-2(1H)-one Showed Cardioprotection Effect in a Myocardial Ischemia (MI) Mouse Model

by Lena Trifonov, Vadim Nudelman, Michael Zhenin, Guy Cohen, Krzysztof Jozwiak, Edward Korshin, Hanoch Senderowitz, Asher Shainberg, Edith Hochhauser and Arie Gruzman

Proceedings 2019, 22(1), 72; https://doi.org/10.3390/proceedings2019022072 - 14 Aug 2019

Viewed by 1183

Abstract

TLR4, a member of the toll-like receptors (TLRs) family, serves as a pattern recognition receptor in the innate immune response to different microbial pathogens. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 162 KiB

Open AccessExtended Abstract

New Compounds against Leishmania infantum from Eremurus persicus

by Emanuela Martino, Valeria Cavalloro, Elisa Vignoni, Serena Della Volpe, Karzan M. Ahmed, Maria Do Céu Sousa, Daniela Rossi and Simona Collina

Proceedings 2019, 22(1), 74; https://doi.org/10.3390/proceedings2019022074 - 15 Aug 2019

Viewed by 1359

Abstract

Leishmaniasis is a complex of vector-borne diseases caused by several species of the protozoan
parasite of the genus Leishmania [...]
Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 135 KiB

Open AccessExtended Abstract

The Content of Phenolic Compounds and Flavonoids in Medical Herbs Depending on the Area of Growth

by Mariam Gyurjyan

Proceedings 2019, 22(1), 75; https://doi.org/10.3390/proceedings2019022075 - 15 Aug 2019

Viewed by 1154

Abstract

Background: The aim of this study was to investigate the process of accumulation of
antioxidants in the herbal extracts depending on the stage of the herbal vegetation and the natural
conditions of the growth. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

2 pages, 399 KiB

Open AccessExtended Abstract

www.3d-qsar.com: A Portal to Build 3-D QSAR Models

by Rino Ragno

Proceedings 2019, 22(1), 76; https://doi.org/10.3390/proceedings2019022076 - 15 Aug 2019

Cited by 3 | Viewed by 3335

Abstract

The underlying idea of any field-based 3-D QSAR is that differences in a target propriety, e.g.,
biological activity, are often closely related to equivalent changes in shapes and intensities of
noncovalent calculated interaction surrounding the molecules [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

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Figure 1

2 pages, 192 KiB

Open AccessExtended Abstract

3,5-Substituted Oxadiazoles as Catalytic Inhibitors of the Human Topoisomerase IIα Molecular Motor

by Kaja Bergant, Katja Valjavec, Matej Janežič, Marija Sollner Dolenc and Andrej Perdih

Proceedings 2019, 22(1), 78; https://doi.org/10.3390/proceedings2019022078 - 16 Aug 2019

Viewed by 1251

Abstract

Cancer constitutes a group of diseases linked to abnormal cell growth that can potentially spread to other parts of the body and is one of the most common causes of death. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 135 KiB

Open AccessExtended Abstract

Dibenzylxanthines as PPEPCK-M Inhibitors for Cancer Therapy

by Marc Aragó, Sergio Rodríguez-Arévalo, Petra Hyrossova, Juan Moreno, Sònia Abás, Agnès Figueras, Belén Pérez, Francesc Viñals, María Carmen Escolano and José Carlos Perales

Proceedings 2019, 22(1), 79; https://doi.org/10.3390/proceedings2019022079 - 16 Aug 2019

Viewed by 1238

Abstract

Phosphoenolpyruvate carboxykinase (PEPCK) is the key enzyme in gluconeogenesis/glyceroneogenesis, which catalyzes the decarboxylation of oxaloacetate to phosphoenolpyruvate. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 155 KiB

Open AccessExtended Abstract

Hydrophobic Waters in Bromodomains

by Serena G. Piticchio, Miriam Martínez-Cartró, Salvatore Scaffidi, Sergio Rodríguez-Arévalo, Andrea Bagán, Ainoa Sánchez-Arfelis, Carmen Escolano, Carles Galdeano and Xavier Barril

Proceedings 2019, 22(1), 80; https://doi.org/10.3390/proceedings2019022080 - 16 Aug 2019

Viewed by 1432

Abstract

Targeting epigenetic proteins is a rapidly growing area for medicinal chemistry and drug [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

2 pages, 176 KiB

Open AccessExtended Abstract

Identification of Inhibitors of the Anti-Infective Target DXS Using Dynamic Combinatorial Chemistry

by Ravindra P. Jumde, Alaa Alhayek, Robin M. Gierse and Anna K. H. Hirsch

Proceedings 2019, 22(1), 81; https://doi.org/10.3390/proceedings2019022081 - 16 Aug 2019

Viewed by 1244

Abstract

Antibiotic resistance is one of the biggest threats to humankind [1,2]. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 126 KiB

Open AccessExtended Abstract

Natural Products as Sources of New Drugs for the Regulation of Mast Cell Activation

by Roberto Coll, María Laura Mariani and Alicia Penissi

Proceedings 2019, 22(1), 82; https://doi.org/10.3390/proceedings2019022082 - 16 Aug 2019

Viewed by 1149

Abstract

Taking into account that the identification of novel molecules for the effective treatment of inflammatory and immune diseases is one of the main present medical needs and one of the major goals of the pharmaceutical industry, the aim of our work is intended [...] Read more.

Taking into account that the identification of novel molecules for the effective treatment of inflammatory and immune diseases is one of the main present medical needs and one of the major goals of the pharmaceutical industry, the aim of our work is intended to provide new therapeutic strategies and a deeper understanding of the mechanism of action of new drugs related to such disorders. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

2 pages, 179 KiB

Open AccessExtended Abstract

Metformin-Derived Hybrid Molecules for Glioblastoma Treatment

by Caroline Delehedde, Mathieu Chocry, Sophie Thétiot-Laurent, Françoise Garrouste, Marcel Culcasi, Hervé Kovacic and Sylvia Pietri

Proceedings 2019, 22(1), 83; https://doi.org/10.3390/proceedings2019022083 - 19 Aug 2019

Viewed by 1281

Abstract

Glioblastoma is the most common cerebral tumor in adults. The median survival of glioblastoma patients is 12 months. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

2 pages, 196 KiB

Open AccessExtended Abstract

Novel Dipyridothiazines with 1,2,3-Triazole Substituents—Synthesis and Anticancer Activities

by Beata Morak-Młodawska, Krystian Pluta, Małgorzata Jeleń, Małgorzata Latocha and Dariusz Kuśmierz

Proceedings 2019, 22(1), 85; https://doi.org/10.3390/proceedings2019022085 - 21 Aug 2019

Viewed by 758

Abstract

Cancer has now become a global problem and been ranked as the top leading cause of death
worldwide after cardiovascular disease [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 181 KiB

Open AccessExtended Abstract

Design and Synthesis of Cysteine Proteases Inhibitors

by Florenci V. Gonzalez

Proceedings 2019, 22(1), 86; https://doi.org/10.3390/proceedings2019022086 - 26 Aug 2019

Viewed by 999

Abstract

Cysteine proteases belonging to the papain superfamily have been recognized as interesting therapeutic targets for the search for new drugs against infectious tropical diseases such as malaria (falcipain), Chagas’ disease (curtain), leishmaniasis, and Sleeping sickness (rhodesian), and a number of human pathologies, including [...] Read more.

Cysteine proteases belonging to the papain superfamily have been recognized as interesting therapeutic targets for the search for new drugs against infectious tropical diseases such as malaria (falcipain), Chagas’ disease (curtain), leishmaniasis, and Sleeping sickness (rhodesian), and a number of human pathologies, including cancer, Alzheimer’s disease, and osteoporosis (cathepsins). [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

2 pages, 176 KiB

Open AccessExtended Abstract

Targeting Novel Allosteric Sites with Confidence: Methods and Applications

by Xavier Barril

Proceedings 2019, 22(1), 87; https://doi.org/10.3390/proceedings2019022087 - 26 Aug 2019

Viewed by 960

Abstract

Allosteric sites create opportunities to act on novel targets when their orthosteric sites are not
druggable. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

2 pages, 220 KiB

Open AccessExtended Abstract

Synthesis of Polyfluorinated KRN7000 Analogues and Biological Implications

by M. Isabel Matheu, David Collado, Miquel Mulero, Yolanda Díaz, Sergio Castillón and Omar Boutureira

Proceedings 2019, 22(1), 89; https://doi.org/10.3390/proceedings2019022089 - 27 Aug 2019

Viewed by 1085

Abstract

KRN7000 is a synthetic glycosphingolipid developed as an anticancer drug candidate, which
upon association with the CD1d protein activates NKT cells. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 142 KiB

Open AccessExtended Abstract

Targeting Neuronal Transcription Factor BRN2 in Neuroendocrine Tumors

by Ravi Munuganti, Daksh Thaper, Sahil Kumar, Soojin Kim, Olena Sivak and Amina Zoubeidi

Proceedings 2019, 22(1), 90; https://doi.org/10.3390/proceedings2019022090 - 30 Aug 2019

Viewed by 1081

Abstract

No targeted therapies exist against aggressive neuroendocrine tumors; hence, these patients are limited to platinum-based chemotherapy that has not advanced in over three decades. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 155 KiB

Open AccessExtended Abstract

Computational Study of Benzimidazole Derivatives as Potential Antifungal Drugs

by Dorian Acevedo and Gian Pietro MIscione

Proceedings 2019, 22(1), 91; https://doi.org/10.3390/proceedings2019022091 - 2 Sep 2019

Viewed by 1159

Abstract

The infection of fungal diseases has increased in these last years due to the rise in immunodeficient patients, the resistance to current drugs, and the lack of design of new and efficient molecules against those pathogens [1]. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

2 pages, 187 KiB

Open AccessExtended Abstract

Design, Synthesis, and Pharmacological Evaluation of Novel Quinolone Aryl Sulfonamide Derivatives as Potent GPR55 Antagonists

by Paula Morales, Laura Figuerola-Asencio, Dow H. Hurst, Pingwei Zhao, Mary E. Abood, Patricia H. Reggio and Nadine Jagerovic

Proceedings 2019, 22(1), 92; https://doi.org/10.3390/proceedings2019022092 - 2 Sep 2019

Viewed by 1308

Abstract

Docking studies of identified GPR55 ligands using a GPR55 inactive state model allow rationalizing key structural features involved in ligand–receptor binding. On this molecular basis, we have designed novel quinolone sulfonamide derivatives with optimized potency and efficacy. These novel molecules compounds are being [...] Read more.

Docking studies of identified GPR55 ligands using a GPR55 inactive state model allow rationalizing key structural features involved in ligand–receptor binding. On this molecular basis, we have designed novel quinolone sulfonamide derivatives with optimized potency and efficacy. These novel molecules compounds are being synthesized and evaluated using a β-arrestin recruitment assay in CHO cells overexpressing human GPR55 and βarr2-GFP. Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

2 pages, 184 KiB

Open AccessExtended Abstract

Synthesis of Heterocyclic Fused [1,5]naphthyridines by Intramolecular HDA Reactions

by Concepcion Alonso, Endika Martin-Encinas, Gloria Rubiales and Francisco Palacios

Proceedings 2019, 22(1), 93; https://doi.org/10.3390/proceedings2019022093 - 6 Sep 2019

Viewed by 1043

Abstract

Povarov reaction [1] can be considered as an example of HDA reactions and represents an [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

2 pages, 170 KiB

Open AccessExtended Abstract

Syntheses of Hydrazino-and Azo-Sphingosine Derivatives and Their Evaluation as SphK Inhibitors

by Yolanda Díaz, Macarena Corro-Morón, Raúl Beltrán-Debón, M. Isabel Matheu and Sergio Castillón

Proceedings 2019, 22(1), 94; https://doi.org/10.3390/proceedings2019022094 - 9 Sep 2019

Viewed by 932

Abstract

Bioactive sphingolipids have been recognized to play important roles in both normal and pathological physiology related to the regulations of cell proliferation, differentiation, survival, trafficking, and cell death. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

2 pages, 185 KiB

Open AccessExtended Abstract

Biological Evaluation of a Mitochondrial Phosphoenolpyruvate Carboxykinase Inhibitor

by Sergio Rodríguez-Arévalo, Sònia Abás, Marc Aragó, Juan Moreno-Felici, Petra Hyroššová, Jose Carlos Perales, Carles Galdeano, Tiziana Ginex, Francisco Javier Luque and Carmen Escolano

Proceedings 2019, 22(1), 95; https://doi.org/10.3390/proceedings2019022095 - 10 Sep 2019

Viewed by 1036

Abstract

Phosphoenolpyruvate carboxykinase (PEPCK) is a key enzyme in gluconeogenesis, catalyzing
the decarboxylation of oxaloacetate to phosphoenolpyruvate. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 129 KiB

Open AccessExtended Abstract

Epigenetic and PPI Targeted Libraries from Life Chemicals

by Vasily Pinchuk, George Bondar and Olga Balabon

Proceedings 2019, 22(1), 96; https://doi.org/10.3390/proceedings2019022096 - 10 Sep 2019

Viewed by 967

Abstract

Herein, we report our novel epigenetic and PPI. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

2 pages, 196 KiB

Open AccessExtended Abstract

(2-Imidazolin-4-yl)phosphonates: Green Chemistry and Biology Walk Together

by Andrea Bagán, Sònia Abás, Sergio Rodríguez-Arévalo, Gemma Rodríguez-Arévalo, Fotini Vasilopoulou, Christian Griñán-Ferré, Mercè Pallàs, Pilar Pérez-Lozano, Milica Radan, Teodora Djikic, Katarina Nikolić and Carmen Escolano

Proceedings 2019, 22(1), 97; https://doi.org/10.3390/proceedings2019022097 - 10 Sep 2019

Viewed by 1062

Abstract

2-Imidazoline-containing compounds constitute a valuable class of agents that modulate α2-
adrenergic receptors and often show a high affinity for imidazoline I2-receptors (I2-IR). [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 132 KiB

Open AccessExtended Abstract

Drugging the Undruggable: Inhibiting MYCN Signalling

by Jessica K. Holien, Michael W. Parker, Belamy B. Cheung and Glenn M. Marshall

Proceedings 2019, 22(1), 98; https://doi.org/10.3390/proceedings2019022098 - 9 Oct 2019

Viewed by 1280

Abstract

Neuroblastoma is the most common solid malignancy in early. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

2 pages, 181 KiB

Open AccessExtended Abstract

Determination of the Binding Sites of Activators within the Proteasome Structure

by Malgorzata Gizynska, Julia Witkowska, Przemyslaw Karpowicz, Fabian Henneberg, Ashwin Chari, Artur Gieldon and Elzbieta Jankowska

Proceedings 2019, 22(1), 99; https://doi.org/10.3390/proceedings2019022099 - 12 Nov 2019

Viewed by 920

Abstract

The proteasome degrade most of the proteins in eukaryotic cells, thereby controlling the key
cellular processes [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

2 pages, 186 KiB

Open AccessExtended Abstract

Synthesis and Bioactivity Studies of Some Naphthoquinone Derivatives as Potential Proteasome Inhibitors

by Şirin Uysal, Zeynep Soyer, Recep İlhan and Petek BALLAR Kirmizibayrak

Proceedings 2019, 22(1), 100; https://doi.org/10.3390/proceedings2019022100 - 12 Nov 2019

Viewed by 804

Abstract

The ubiquitine–proteasome pathway (UPP) plays. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 126 KiB

Open AccessExtended Abstract

Expanding the Toolbox of E3 Ligases for Protein Degradation: Targeting the “Undruggable” Fbw7 E3 Ligase

by Carles Galdeano

Proceedings 2019, 22(1), 101; https://doi.org/10.3390/proceedings2019022101 - 12 Nov 2019

Viewed by 932

Abstract

Proteolysis targeting chimera molecules (PROTACS) are heterobifunctional small molecules
designed to induce intracellular protein degradation [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

2 pages, 200 KiB

Open AccessExtended Abstract

In Silico Design of Bacterial N-acetylglucosaminidase Inhibitors with Potential Antibacterial Activity

by Janja Sluga, Tihomir Tomašič, Tjaša Tibaut, Marko Anderluh, Gregor Bajc, Sara Pintar, Dušan Turk and Marjana Novič

Proceedings 2019, 22(1), 105; https://doi.org/10.3390/proceedings2019022105 - 14 Nov 2019

Viewed by 886

Abstract

Staphylococcus aureus is a widespread gram-positive pathogen in humans and animals. Autolysin
E (AtlE) is an enzyme from S. aureus which belongs to the glycoside hydrolase 73 family. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 144 KiB

Open AccessExtended Abstract

1,2,3-triazole-oxazolidinone Derivatives as Inhibitors of the Plasminogen System

by Oriol Bosch Sanz, Noemí Balà Palasí, Xavier Biarnés Fontal, Mercedes Balcells Camps, Jordi Martorell López, Francisco Javier Pedreño Egea and David Sánchez García

Proceedings 2019, 22(1), 106; https://doi.org/10.3390/proceedings2019022106 - 14 Nov 2019

Viewed by 831

Abstract

The Plasminogen system is known for being responsible. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 140 KiB

Open AccessExtended Abstract

4,4-Disubstituted N-benzylpiperidines: A Novel Class of Fusion Inhibitors of Influenza Virus H1N1 Targeting a New Binding Site in Hemagglutinin

by Sonia De Castro, Evelien Vanderlinden, Tiziana Ginex, Manon Laporte, Annelies Stevaert, Lieve Naesens, Francisco Javier Luque, María José Camarasa and Sonsoles Velázquez

Proceedings 2019, 22(1), 108; https://doi.org/10.3390/proceedings2019022108 - 14 Nov 2019

Viewed by 939

Abstract

Influenza epidemics are estimated to result in 3–5 million cases of severe illness and 290.000–650.000 deaths per year. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

2 pages, 191 KiB

Open AccessExtended Abstract

Immobilized Enzyme Reactors Based on Nucleoside Phosphorylases (NPs) and Nucleoside 2′-Deoxyribosyltransferases (NDTs) for the In-Flow Synthesis of Nucleoside Analogues

by Marco Terreni, Francesca Rinaldi, Caterina Temporini, Enrica Calleri, Gabriella Massolini and Daniela Ubiali

Proceedings 2019, 22(1), 109; https://doi.org/10.3390/proceedings2019022109 - 21 Nov 2019

Viewed by 926

Abstract

Enzymes are increasingly used as biocatalysts for the production of Active Pharmaceutical [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 149 KiB

Open AccessExtended Abstract

How Proteins Catalyze Ligand Formation: Protein-Templated Fragment Ligation Employed in the Validation of Cancer Targets

by Jörg Rademann

Proceedings 2019, 22(1), 110; https://doi.org/10.3390/proceedings2019022110 - 21 Nov 2019

Viewed by 962

Abstract

Fragment-based drug discovery has been established as a powerful method for the assembly of
optimized protein ligands [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 144 KiB

Open AccessExtended Abstract

Quorum Sensing in Cyanobacteria and the Origin of Blooms. Lessons for Human Pharmacology

by Natalia Herrera, Juan Pablo Velasquez and Fernando Echeverri

Proceedings 2019, 22(1), 113; https://doi.org/10.3390/proceedings2019022113 - 4 Dec 2019

Viewed by 963

Abstract

Quorum Sensing (QS) is a bacterial communication system. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 135 KiB

Open AccessExtended Abstract

Drugging the Fbw7 E3 Ligase with a Fragment-Based Approach

by Salvatore Scaffidi, Míriam Martínez-Cartró, Xavier Barril and Carles Galdeano

Proceedings 2019, 22(1), 116; https://doi.org/10.3390/proceedings2019022116 - 16 Dec 2019

Viewed by 953

Abstract

Fbw7 is an important E3 ligase and one of the most commonly deregulated proteins in human cancers. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

1 pages, 163 KiB

Open AccessExtended Abstract

Kinetic Target-Guided Synthesis as a Tool for Drug Discovery: Successes, Challenges, and Applications to Metalloproteases

by Rebecca Deprez-Poulain

Proceedings 2019, 22(1), 117; https://doi.org/10.3390/proceedings2019022117 - 17 Dec 2019

Viewed by 1100

Abstract

Target-guided synthesis has emerged as an elegant and efficient lead- and drug-discovery strategy. [...] Full article

(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)

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