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Proceedings, 2019, MMCS 2019

The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery

Barcelona, Spain | 15–17 May 2019


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Cover Story (view full-size image) This issue of Proceedings gathers papers presented at 2nd MMCS (Barcelona, Spain, 15-17 May 2019). [...] Read more.
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Open AccessAbstract
Development of Thienopyridines as Potent Antiproliferative Agents
Proceedings 2019, 22(1), 2; https://doi.org/10.3390/proceedings2019022002 - 06 Aug 2019
Viewed by 496
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
Open AccessAbstract
The Indole Phytoalexin Derivatives Induced a Significant Inhibition on Src Kinase Activity of Human Cancer Cells
Proceedings 2019, 22(1), 3; https://doi.org/10.3390/proceedings2019022003 - 06 Aug 2019
Viewed by 509
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
Open AccessAbstract
A Lipoaminopeptaibol Secreted by Alkalophilic Fungus Emericellopsis alkalina Demonstrates a Strong Cytotoxic Effect against Tumor Cell Lines
Proceedings 2019, 22(1), 4; https://doi.org/10.3390/proceedings2019022004 - 06 Aug 2019
Viewed by 447
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
Open AccessAbstract
Anticancer Activities and Underlying Molecular Mechanisms of Novel Mangostin Glycosides in Human Hepatocellular Carcinoma Hep3B Cells
Proceedings 2019, 22(1), 5; https://doi.org/10.3390/proceedings2019022005 - 06 Aug 2019
Viewed by 501
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
Open AccessAbstract
Bis-Pyridazine Derivatives with Anticancer Activity
Proceedings 2019, 22(1), 6; https://doi.org/10.3390/proceedings2019022006 - 06 Aug 2019
Viewed by 504
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
Open AccessAbstract
Repositioning of Dantrolene as a Multitarget Agent for Neurodegenerative Diseases
Proceedings 2019, 22(1), 7; https://doi.org/10.3390/proceedings2019022007 - 07 Aug 2019
Viewed by 530
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
Open AccessAbstract
Novel Antimalarial Inhibitors That Specifically Target the Invasion Motor Protein Myosin A in Malaria Parasites
Proceedings 2019, 22(1), 9; https://doi.org/10.3390/proceedings2019022009 - 07 Aug 2019
Viewed by 794
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
Open AccessAbstract
Use of a Zebrafish Model to Evaluate Toxicity of Schiff Base Complexes of Copper (II) and Zinc (II) as Possible Antineoplastic Agents
Proceedings 2019, 22(1), 11; https://doi.org/10.3390/proceedings2019022011 - 07 Aug 2019
Viewed by 601
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
Open AccessAbstract
Ferrocenes as Potential Anticancer Drugs: Determination of the Mechanism of Action
Proceedings 2019, 22(1), 16; https://doi.org/10.3390/proceedings2019022016 - 07 Aug 2019
Viewed by 528
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
Open AccessAbstract
Design, Synthesis, and Anticancer Evaluation of Fused 1,2-diazine Derivatives
Proceedings 2019, 22(1), 26; https://doi.org/10.3390/proceedings2019022026 - 07 Aug 2019
Viewed by 576
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
Open AccessAbstract
Design of Novel GPR6 Inverse Agonists Using a Fragment Replacement Scaffold Hopping Approach
Proceedings 2019, 22(1), 29; https://doi.org/10.3390/proceedings2019022029 - 07 Aug 2019
Viewed by 549
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
Open AccessAbstract
New TRPV1 Antagonists as Candidates for Effective Anticonvulsant and Antinociceptive Agents
Proceedings 2019, 22(1), 30; https://doi.org/10.3390/proceedings2019022030 - 07 Aug 2019
Viewed by 599
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
Open AccessAbstract
CNS-Selective Estrogen Therapy
Proceedings 2019, 22(1), 31; https://doi.org/10.3390/proceedings2019022031 - 07 Aug 2019
Viewed by 522
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
Open AccessAbstract
Tools and Drugs for Purine-Binding Targets—Important Players in Inflammation and Cancer
Proceedings 2019, 22(1), 33; https://doi.org/10.3390/proceedings2019022033 - 07 Aug 2019
Viewed by 507
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 A2A and A2B receptor subtypes (A2AAR, A2BAR) on immune cells. In addition, activation of A2BARs by adenosine enhances cancer cell proliferation, metastasis, and angiogenesis. Blockade of A2A and A2B 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
Open AccessAbstract
The Ameliorating Effect of Phenylsulfonamide Derivatives on Scopolamine-Induced Memory Impairment in Mice via Inhibition of mPGES-1
Proceedings 2019, 22(1), 36; https://doi.org/10.3390/proceedings2019022036 - 07 Aug 2019
Viewed by 498
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
Open AccessAbstract
Inhibition of LPS-Induced PGE2 Production by Arylsulfonamide Derivatives via the Selective Inhibition of mPGES-1 Enzyme
Proceedings 2019, 22(1), 37; https://doi.org/10.3390/proceedings2019022037 - 07 Aug 2019
Viewed by 519
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
Open AccessAbstract
Why Does the Type of Halogen Atom Matter for Radiosensitizing Properties of 5-Substituted 4-Thio-2′-Deoxyuridines?
Proceedings 2019, 22(1), 40; https://doi.org/10.3390/proceedings2019022040 - 08 Aug 2019
Viewed by 507
Abstract
In order to explain the unexpected difference between radiosensitizing. [...] Full article
Open AccessAbstract
Rhenium(I) Complexes with Pincer Ligands as a New Class of Potential Antitumor Agents
Proceedings 2019, 22(1), 43; https://doi.org/10.3390/proceedings2019022043 - 08 Aug 2019
Viewed by 524
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
Open AccessAbstract
Physicochemical and Pharmacokinetic Properties of New Dual-Acting Compounds for the Treatment of Mental Disorders
Proceedings 2019, 22(1), 50; https://doi.org/10.3390/proceedings2019022050 - 08 Aug 2019
Viewed by 528
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-HT1A 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-HT1A 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
Open AccessAbstract
Inhibitors of the Inducible Nitric Oxide Synthase as Antiglioma Agents
Proceedings 2019, 22(1), 52; https://doi.org/10.3390/proceedings2019022052 - 08 Aug 2019
Viewed by 470
Abstract
Malignant gliomas are highly lethal brain tumors with poor prognosis for patients. The current [...] Full article
Open AccessAbstract
FOXM1 Inhibitors: Emergence of a Neglected Binding Force
Proceedings 2019, 22(1), 58; https://doi.org/10.3390/proceedings2019022058 - 09 Aug 2019
Viewed by 777
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
Open AccessAbstract
Photoprotective and Therapeutic Potential in Skin Cancer of Amaryllidaceae Alkaloids
Proceedings 2019, 22(1), 59; https://doi.org/10.3390/proceedings2019022059 - 09 Aug 2019
Viewed by 527
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
Open AccessAbstract
Organometallic Nucleosides: Synthesis and Biological Evaluation of Substituted Dicobalt Hexacarbonyl Alkynyl Modified 2′-Deoxyuridines
Proceedings 2019, 22(1), 62; https://doi.org/10.3390/proceedings2019022062 - 12 Aug 2019
Viewed by 622
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
Open AccessAbstract
In Search of Selectivity: Design, Synthesis, and Biological Evaluation of New Classes of HDAC Inhibitors
Proceedings 2019, 22(1), 63; https://doi.org/10.3390/proceedings2019022063 - 12 Aug 2019
Viewed by 597
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
Open AccessAbstract
Amaryllidaceae Alkaloids from Zephyrantes Carinata and Their Evaluation as Cholinesterases (AChE and BChE) Inhibitors
Proceedings 2019, 22(1), 66; https://doi.org/10.3390/proceedings2019022066 - 12 Aug 2019
Cited by 1 | Viewed by 638
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
Open AccessAbstract
Potent and Selective Estrogen Receptor-Beta Agonists Which Enhance Memory Consolidation in an Ovariectomized Mouse Model
Proceedings 2019, 22(1), 73; https://doi.org/10.3390/proceedings2019022073 - 15 Aug 2019
Viewed by 526
Abstract
Estrogen receptor-beta (ER-beta) is a drug target for memory consolidation in postmenopausal [...] Full article
Open AccessAbstract
Kinetic Characterization of Novel HIV-1 Entry Inhibitors: Discovery of a Relationship between Off-Rate and Potency
Proceedings 2019, 22(1), 77; https://doi.org/10.3390/proceedings2019022077 - 15 Aug 2019
Viewed by 485
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
Open AccessAbstract
Selective Activity-Based Probes Targeting Fibroblast Activation Protein (FAP)
Proceedings 2019, 22(1), 84; https://doi.org/10.3390/proceedings2019022084 - 20 Aug 2019
Viewed by 535
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
Open AccessAbstract
Toward an Innovative Treatment of Alzheimer’s Disease: Design of MTDLs Targeting Acetylcholinesterase and α-7 Nicotinic Receptors
Proceedings 2019, 22(1), 88; https://doi.org/10.3390/proceedings2019022088 - 27 Aug 2019
Viewed by 543
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
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 219
Abstract
SCF (SKP1, Cullins, and F-box proteins) E3 ligase, also known. [...] Full article
Open AccessAbstract
Tracing Potential Covalent Inhibitors of an E3 Ubiquitin Ligase Through Target-Focused Modelling
Proceedings 2019, 22(1), 103; https://doi.org/10.3390/proceedings2019022103 - 14 Nov 2019
Viewed by 240
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
Open AccessAbstract
New Methodology to Access 1,5-Disubstituted 1,2,3-Triazoles
Proceedings 2019, 22(1), 104; https://doi.org/10.3390/proceedings2019022104 - 14 Nov 2019
Viewed by 225
Abstract
1,2,3-triazole is a well-known scaffold that is. [...] Full article
Open AccessAbstract
How Size Matters: Designing Diverse Fragment Libraries for Novel Drug Discovery
Proceedings 2019, 22(1), 107; https://doi.org/10.3390/proceedings2019022107 - 14 Nov 2019
Viewed by 290
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
Open AccessAbstract
Inhibitors of Phospholipid-Hydrolyzing Enzymes as Novel Agents against Pulmonary Fibrosis and Diabetes Type-1
Proceedings 2019, 22(1), 111; https://doi.org/10.3390/proceedings2019022111 - 04 Dec 2019
Viewed by 287
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 (XI(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
Open AccessAbstract
3D and 4D-QSAR of Dopamine Transporter Inhibitors (DAT) Using the LQTA-QSAR Approach
Proceedings 2019, 22(1), 112; https://doi.org/10.3390/proceedings2019022112 - 04 Dec 2019
Viewed by 279
Abstract
At present, drug abuse has developed into a social problem. [...] Full article
Open AccessAbstract
2D-QSAR Studies of Dopamine Transporter Inhibitors (DAT) Using OPS and GA Variable Selection Approaches
Proceedings 2019, 22(1), 114; https://doi.org/10.3390/proceedings2019022114 - 04 Dec 2019
Viewed by 282
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 r2m Overall = 0.730 versus 0.710 and Delta r2m 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 (Fn,np−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
Open AccessAbstract
Targeted Protein Degradation with Small Molecules: How PROTACs Work
Proceedings 2019, 22(1), 115; https://doi.org/10.3390/proceedings2019022115 - 16 Dec 2019
Viewed by 322
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

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Open AccessExtended Abstract
Promising Approach to Inhibit E. coli FimH Adhesion by C-Linked Mannosides
Proceedings 2019, 22(1), 1; https://doi.org/10.3390/proceedings2019022001 - 06 Aug 2019
Viewed by 451
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
Open AccessExtended Abstract
A Novel Series of Sialic Acid-Based Influenza Virus Inhibitors that Target Influenza Virus Neuraminidase
Proceedings 2019, 22(1), 8; https://doi.org/10.3390/proceedings2019022008 - 07 Aug 2019
Viewed by 478
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
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
Proceedings 2019, 22(1), 10; https://doi.org/10.3390/proceedings2019022010 - 07 Aug 2019
Viewed by 463
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
Open AccessExtended Abstract
Understanding the Mechanism of Direct Activation of AMP-Kinase: Towards a Fine Allosteric Tuning of the Kinase Activity
Proceedings 2019, 22(1), 12; https://doi.org/10.3390/proceedings2019022012 - 07 Aug 2019
Viewed by 497
Abstract
This research deals with the regulation of the AMPK activity by direct activators, such as
compound A-769662 [...] Full article
Open AccessExtended Abstract
Chemically Modified Hemocyanins with Enhanced Antibreast Cancer Activities
Proceedings 2019, 22(1), 13; https://doi.org/10.3390/proceedings2019022013 - 07 Aug 2019
Viewed by 458
Abstract
Some cancer cells hyperexpress folate receptors (FR); therefore, folate-derivatized delivery
systems are applied for a selective delivery of chemotherapeutics. [...] Full article
Open AccessExtended Abstract
Facing Novel Challenges in Neurodegenerative Diseases Drug Discovery: From Small Molecules to Targeted Therapies
Proceedings 2019, 22(1), 14; https://doi.org/10.3390/proceedings2019022014 - 07 Aug 2019
Viewed by 509
Abstract
Neurodegenerative diseases are becoming increasingly prevalent with the aging of the general
population [...] Full article
Open AccessExtended Abstract
Chiral Resolution of a New Agent against Memory Impairment Connected to Neurodegenerative Diseases
Proceedings 2019, 22(1), 15; https://doi.org/10.3390/proceedings2019022015 - 07 Aug 2019
Viewed by 461
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
Open AccessExtended Abstract
Small Molecules as Potential Inhibitors of the 14-3-3/c-Abl Interaction for the Treatment of CML
Proceedings 2019, 22(1), 17; https://doi.org/10.3390/proceedings2019022017 - 07 Aug 2019
Viewed by 593
Abstract
c-Abl is a tyrosine kinase implicated in the regulation of proliferation, adhesion, motility, and
cell survival [...] Full article
Open AccessExtended Abstract
Adamantane Analogs: From Anti-Influenza Drugs to Soluble Epoxide Hydrolase Inhibitors for Acute Pancreatitis
Proceedings 2019, 22(1), 18; https://doi.org/10.3390/proceedings2019022018 - 07 Aug 2019
Viewed by 463
Abstract
The adamantane scaffold is present in eight approved drugs. […] Full article
Open AccessExtended Abstract
New Diarylureas as Activators of the Heme-Regulated EIF2α Kinase for the Treatment of Type 2 Diabetes Mellitus
Proceedings 2019, 22(1), 19; https://doi.org/10.3390/proceedings2019022019 - 07 Aug 2019
Viewed by 101
Abstract
Type 2 diabetes mellitus (T2DM) has reached epidemic proportions. […] Full article
Open AccessExtended Abstract
Double Modification of Polyether Ionophores: Synthesis and Biological Activity of Novel Salinomycin Derivatives
Proceedings 2019, 22(1), 20; https://doi.org/10.3390/proceedings2019022020 - 07 Aug 2019
Viewed by 510
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
Open AccessExtended Abstract
Discovery of a Selective NEK6 Kinase Inhibitor by Virtual Screening
Proceedings 2019, 22(1), 21; https://doi.org/10.3390/proceedings2019022021 - 07 Aug 2019
Viewed by 498
Abstract
NIMA-related kinases (Neks) are a conserved serine/threonine protein kinase family related to
cell cycle progression and cell division [...] Full article
Open AccessExtended Abstract
Design, Synthesis, and Biological Evaluation of 4-aminoquinazoline Appended-Benzofuran Hybrids as Epidermal Growth Factor Receptor Inhibitors
Proceedings 2019, 22(1), 22; https://doi.org/10.3390/proceedings2019022022 - 07 Aug 2019
Viewed by 707
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
Open AccessExtended Abstract
Novel Sortase A Inhibitors to Counteract Gram-Positive Bacterial Biofilms
Proceedings 2019, 22(1), 23; https://doi.org/10.3390/proceedings2019022023 - 07 Aug 2019
Cited by 1 | Viewed by 555
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
Open AccessExtended Abstract
Mechanisms of Inhibitory Effects of Polysubstituted Pyrimidines on Prostaglandin E2 Production
Proceedings 2019, 22(1), 24; https://doi.org/10.3390/proceedings2019022024 - 07 Aug 2019
Viewed by 459
Abstract
The pyrimidine heterocycle represents an elemental structural motif of numerous drugs. [...] Full article
Open AccessExtended Abstract
Steroid Sulfatase Inhibition: From Concept to Clinic and Beyond
Proceedings 2019, 22(1), 25; https://doi.org/10.3390/proceedings2019022025 - 07 Aug 2019
Viewed by 451
Abstract
Many tumours are hormone-dependent, and estrogens (E1/E2) play a key role in development.
Despite aromatase inhibitor (AI) therapy [...] Full article
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
Proceedings 2019, 22(1), 27; https://doi.org/10.3390/proceedings2019022027 - 07 Aug 2019
Viewed by 471
Abstract
Binding interactions between human serum albumin and four clinically approved epidermal [...] Full article
Open AccessExtended Abstract
Searching for Selective Scaffolds against Plasmodium falciparum Glucose-6-Phosphate Dehydrogenase 6-Phosphogluconolactonase
Proceedings 2019, 22(1), 28; https://doi.org/10.3390/proceedings2019022028 - 07 Aug 2019
Viewed by 483
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
Open AccessExtended Abstract
Design, Synthesis, and Biological Evaluation of Bimodal Glycopeptides as Inhibitors of Neurotoxic Protein Aggregation
Proceedings 2019, 22(1), 32; https://doi.org/10.3390/proceedings2019022032 - 07 Aug 2019
Viewed by 539
Abstract
Post-translational modifications (PTM) of proteins are becoming the focus of a growing base of [...] Full article
Open AccessExtended Abstract
Regression of an Epidermoid Carcinomas in Domestic Canine Treated with Casiopeína® IIgly
Proceedings 2019, 22(1), 34; https://doi.org/10.3390/proceedings2019022034 - 07 Aug 2019
Viewed by 461
Abstract
Squamous cell carcinoma (SCC) is a malignancy that has no treatment. [...] Full article
Open AccessExtended Abstract
Tdp1 Inhibition as a Promising Approach to New Anticancer Drugs
Proceedings 2019, 22(1), 35; https://doi.org/10.3390/proceedings2019022035 - 07 Aug 2019
Cited by 1 | Viewed by 608
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
Open AccessExtended Abstract
Can Short Peptides Be Inhibitors of Serum Amyloid a Protein Aggregation?
Proceedings 2019, 22(1), 38; https://doi.org/10.3390/proceedings2019022038 - 07 Aug 2019
Viewed by 457
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
Open AccessExtended Abstract
Design of New Probes for Oxidized Amino Acids Localization
Proceedings 2019, 22(1), 39; https://doi.org/10.3390/proceedings2019022039 - 08 Aug 2019
Viewed by 473
Abstract
Protein carbonyls (PC) are oxidative damage observed in many diseases. [...] Full article
Open AccessExtended Abstract
Amphidinolides and Iriomoteolides, Potent Anticancer Macrolides
Proceedings 2019, 22(1), 41; https://doi.org/10.3390/proceedings2019022041 - 08 Aug 2019
Viewed by 515
Abstract
Amphidinolides and iriomoteolides are complex macrolides isolated from cultured marine
dinoflagellates of the genus Amphidinium sp. [1–4]. [...] Full article
Open AccessExtended Abstract
Synthesis and Evaluation of Thymoquinone Analogues as Anti-Ovarian Cancer Agents
Proceedings 2019, 22(1), 42; https://doi.org/10.3390/proceedings2019022042 - 08 Aug 2019
Cited by 1 | Viewed by 538
Abstract
Thymoquinone (TQ), 2-isopropyl-5-methyl-1,4-benzoquinone, a natural product isolated from
Nigella sativa L. [...] Full article
Open AccessExtended Abstract
Recent Advances in Discovery of New Tyrosine Kinase Inhibitors Using Computational Methods
Proceedings 2019, 22(1), 44; https://doi.org/10.3390/proceedings2019022044 - 08 Aug 2019
Viewed by 479
Abstract
Tyrosine–protein kinases catalyze chemical reactions that. [...] Full article
Open AccessExtended Abstract
Novel Dual PDK1/AurK-A Inhibitors for Cancer Therapy: Med Chem Evolution and Crystallographic Investigation
Proceedings 2019, 22(1), 45; https://doi.org/10.3390/proceedings2019022045 - 08 Aug 2019
Viewed by 603
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
Open AccessExtended Abstract
Rational Design, Synthesis, and Characterization of Glycoconjugates as Potential Vaccines against Tuberculosis
Proceedings 2019, 22(1), 46; https://doi.org/10.3390/proceedings2019022046 - 08 Aug 2019
Viewed by 576
Abstract
Tuberculosis (TB) is the first cause of death from infectious diseases. [...] Full article
Open AccessExtended Abstract
Synthesis of Enantiomeric Halolactones with Aromatic Ring, Their Anticancer Activity and Interactions with Biological Membranes
Proceedings 2019, 22(1), 47; https://doi.org/10.3390/proceedings2019022047 - 08 Aug 2019
Viewed by 539
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
Open AccessExtended Abstract
Antibacterial N-Arylcinnamamides as Anti-inflammatory Agents
Proceedings 2019, 22(1), 48; https://doi.org/10.3390/proceedings2019022048 - 08 Aug 2019
Viewed by 590
Abstract
A series of ring-substituted N-arylcinnamamides was prepared, characterized, and investigated
for their antimicrobial efficacy in detail [...] Full article
Open AccessExtended Abstract
Novel Dual Ligands Targeting Sigma1 Receptor and Acetylcholinesterase Endowed with Antioxidant Properties
Proceedings 2019, 22(1), 49; https://doi.org/10.3390/proceedings2019022049 - 08 Aug 2019
Viewed by 543
Abstract
Neurodegenerative disorders represent one of the main therapeutic challenges of our time. [...] Full article
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
Proceedings 2019, 22(1), 51; https://doi.org/10.3390/proceedings2019022051 - 08 Aug 2019
Viewed by 473
Abstract
Breast cancer is reportedly the second most diagnosed cancer worldwide. Several recent [...] Full article
Open AccessExtended Abstract
Understanding the Pathophysiology and Searching for Biomarkers for Rare Genetic Developmental Diseases
Proceedings 2019, 22(1), 53; https://doi.org/10.3390/proceedings2019022053 - 08 Aug 2019
Viewed by 490
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
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
Proceedings 2019, 22(1), 54; https://doi.org/10.3390/proceedings2019022054 - 08 Aug 2019
Cited by 1 | Viewed by 613
Abstract
Oxidative stress is related to the pathogenesis of many neurodegenerative disorders, including [...] Full article
Open AccessExtended Abstract
Induction of Biofilm Formation in Klebsiella pneumoniae by Acetaminophen. Quorum Quenching Compounds to Overcome the Resistance
Proceedings 2019, 22(1), 55; https://doi.org/10.3390/proceedings2019022055 - 08 Aug 2019
Viewed by 496
Abstract
Bacterial resistance to antibiotics is a serious world health problem; consequently, there is a high recurrence of nosocomial infections. [...] Full article
Open AccessExtended Abstract
Strategies to Discover p53 Activators and a p73 Activator for Neuroblastoma
Proceedings 2019, 22(1), 56; https://doi.org/10.3390/proceedings2019022056 - 09 Aug 2019
Viewed by 518
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
Open AccessExtended Abstract
New 3rd Generation of Casiopeinas Family Compounds with Indomethacin as a Secondary Ligand: Synthesis, Characterization, Antiproliferative Activity, and Nanoencapsulation
Proceedings 2019, 22(1), 57; https://doi.org/10.3390/proceedings2019022057 - 09 Aug 2019
Viewed by 559
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
Open AccessExtended Abstract
Design and Evaluation of New Phosphorus Substituted Aziridines as Antiproliferative Agents
Proceedings 2019, 22(1), 60; https://doi.org/10.3390/proceedings2019022060 - 09 Aug 2019
Viewed by 440
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
Open AccessExtended Abstract
Searching for Molecules against Cancer in the Azores: Plants, Macroalgae, and Synthetic Compounds
Proceedings 2019, 22(1), 61; https://doi.org/10.3390/proceedings2019022061 - 12 Aug 2019
Viewed by 587
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
Open AccessExtended Abstract
Synthesis and Biological Evaluation of Aminobisphosphonates—Analogues of Incadronate
Proceedings 2019, 22(1), 64; https://doi.org/10.3390/proceedings2019022064 - 12 Aug 2019
Viewed by 538
Abstract
Bisphosphonates had been found to act as strong metal ion complexing agents with useful
industrial and household applications. [...] Full article
Open AccessExtended Abstract
Towards the Modulation of RNA-Binding Proteins: New Compounds Targeting Protein HuR
Proceedings 2019, 22(1), 65; https://doi.org/10.3390/proceedings2019022065 - 12 Aug 2019
Viewed by 551
Abstract
RNA-binding proteins (RBPs) have been widely recognized for their pivotal role in the
regulation of post-transcriptional processes. [...] Full article
Open AccessExtended Abstract
Development of Novel, Potent Phosphatidyl–Choline-Specific Phospholipase C Inhibitors
Proceedings 2019, 22(1), 67; https://doi.org/10.3390/proceedings2019022067 - 12 Aug 2019
Viewed by 496
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
Open AccessExtended Abstract
The Targeting of Quadruplex Nucleic Acids in Human Cancers
Proceedings 2019, 22(1), 68; https://doi.org/10.3390/proceedings2019022068 - 13 Aug 2019
Viewed by 515
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
Open AccessExtended Abstract
Design and Synthesis of Immunostimulating Mannosylated Muropeptide Analogs Containing 2-Aminoadamantane-2-carboxylic Acid
Proceedings 2019, 22(1), 69; https://doi.org/10.3390/proceedings2019022069 - 13 Aug 2019
Viewed by 478
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
Open AccessExtended Abstract
Multicomponent Reaction-Based Trimethoprim Analogues as Potential Antibiotics for Resistant Bacteria
Proceedings 2019, 22(1), 70; https://doi.org/10.3390/proceedings2019022070 - 13 Aug 2019
Viewed by 724
Abstract
Aminoimidazoles are relevant scaffolds in medicinal. [...] Full article
Open AccessExtended Abstract
Synthesis, In Vitro Profiling, and In Vivo Efficacy Studies of a New Family of Multitarget Anti-Alzheimer Compounds
Proceedings 2019, 22(1), 71; https://doi.org/10.3390/proceedings2019022071 - 14 Aug 2019
Viewed by 626
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
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
Proceedings 2019, 22(1), 72; https://doi.org/10.3390/proceedings2019022072 - 14 Aug 2019
Viewed by 428
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
Open AccessExtended Abstract
New Compounds against Leishmania infantum from Eremurus persicus
Proceedings 2019, 22(1), 74; https://doi.org/10.3390/proceedings2019022074 - 15 Aug 2019
Viewed by 559
Abstract
Leishmaniasis is a complex of vector-borne diseases caused by several species of the protozoan
parasite of the genus Leishmania [...]
Full article
Open AccessExtended Abstract
The Content of Phenolic Compounds and Flavonoids in Medical Herbs Depending on the Area of Growth
Proceedings 2019, 22(1), 75; https://doi.org/10.3390/proceedings2019022075 - 15 Aug 2019
Viewed by 470
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
Open AccessExtended Abstract
www.3d-qsar.com: A Portal to Build 3-D QSAR Models
Proceedings 2019, 22(1), 76; https://doi.org/10.3390/proceedings2019022076 - 15 Aug 2019
Cited by 1 | Viewed by 720
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
Open AccessExtended Abstract
3,5-Substituted Oxadiazoles as Catalytic Inhibitors of the Human Topoisomerase IIα Molecular Motor
Proceedings 2019, 22(1), 78; https://doi.org/10.3390/proceedings2019022078 - 16 Aug 2019
Viewed by 508
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
Open AccessExtended Abstract
Dibenzylxanthines as PPEPCK-M Inhibitors for Cancer Therapy
Proceedings 2019, 22(1), 79; https://doi.org/10.3390/proceedings2019022079 - 16 Aug 2019
Viewed by 509
Abstract
Phosphoenolpyruvate carboxykinase (PEPCK) is the key enzyme in gluconeogenesis/glyceroneogenesis, which catalyzes the decarboxylation of oxaloacetate to phosphoenolpyruvate. [...] Full article
Open AccessExtended Abstract
Hydrophobic Waters in Bromodomains
Proceedings 2019, 22(1), 80; https://doi.org/10.3390/proceedings2019022080 - 16 Aug 2019
Viewed by 521
Abstract
Targeting epigenetic proteins is a rapidly growing area for medicinal chemistry and drug [...] Full article
Open AccessExtended Abstract
Identification of Inhibitors of the Anti-Infective Target DXS Using Dynamic Combinatorial Chemistry
Proceedings 2019, 22(1), 81; https://doi.org/10.3390/proceedings2019022081 - 16 Aug 2019
Viewed by 447
Abstract
Antibiotic resistance is one of the biggest threats to humankind [1,2]. [...] Full article
Open AccessExtended Abstract
Natural Products as Sources of New Drugs for the Regulation of Mast Cell Activation
Proceedings 2019, 22(1), 82; https://doi.org/10.3390/proceedings2019022082 - 16 Aug 2019
Viewed by 453
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
Open AccessExtended Abstract
Metformin-Derived Hybrid Molecules for Glioblastoma Treatment
Proceedings 2019, 22(1), 83; https://doi.org/10.3390/proceedings2019022083 - 19 Aug 2019
Viewed by 507
Abstract
Glioblastoma is the most common cerebral tumor in adults. The median survival of glioblastoma patients is 12 months. [...] Full article
Open AccessExtended Abstract
Novel Dipyridothiazines with 1,2,3-Triazole Substituents—Synthesis and Anticancer Activities
Proceedings 2019, 22(1), 85; https://doi.org/10.3390/proceedings2019022085 - 21 Aug 2019
Viewed by 139
Abstract
Cancer has now become a global problem and been ranked as the top leading cause of death
worldwide after cardiovascular disease [...] Full article
Open AccessExtended Abstract
Design and Synthesis of Cysteine Proteases Inhibitors
Proceedings 2019, 22(1), 86; https://doi.org/10.3390/proceedings2019022086 - 26 Aug 2019
Viewed by 409
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
Open AccessExtended Abstract
Targeting Novel Allosteric Sites with Confidence: Methods and Applications
Proceedings 2019, 22(1), 87; https://doi.org/10.3390/proceedings2019022087 - 26 Aug 2019
Viewed by 353
Abstract
Allosteric sites create opportunities to act on novel targets when their orthosteric sites are not
druggable. [...] Full article
Open AccessExtended Abstract
Synthesis of Polyfluorinated KRN7000 Analogues and Biological Implications
Proceedings 2019, 22(1), 89; https://doi.org/10.3390/proceedings2019022089 - 27 Aug 2019
Viewed by 333
Abstract
KRN7000 is a synthetic glycosphingolipid developed as an anticancer drug candidate, which
upon association with the CD1d protein activates NKT cells. [...] Full article
Open AccessExtended Abstract
Targeting Neuronal Transcription Factor BRN2 in Neuroendocrine Tumors
Proceedings 2019, 22(1), 90; https://doi.org/10.3390/proceedings2019022090 - 30 Aug 2019
Viewed by 386
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
Open AccessExtended Abstract
Computational Study of Benzimidazole Derivatives as Potential Antifungal Drugs
Proceedings 2019, 22(1), 91; https://doi.org/10.3390/proceedings2019022091 - 02 Sep 2019
Viewed by 383
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
Open AccessExtended Abstract
Design, Synthesis, and Pharmacological Evaluation of Novel Quinolone Aryl Sulfonamide Derivatives as Potent GPR55 Antagonists
Proceedings 2019, 22(1), 92; https://doi.org/10.3390/proceedings2019022092 - 02 Sep 2019
Viewed by 435
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
Open AccessExtended Abstract
Synthesis of Heterocyclic Fused [1,5]naphthyridines by Intramolecular HDA Reactions
Proceedings 2019, 22(1), 93; https://doi.org/10.3390/proceedings2019022093 - 06 Sep 2019
Viewed by 369
Abstract
Povarov reaction [1] can be considered as an example of HDA reactions and represents an [...] Full article
Open AccessExtended Abstract
Syntheses of Hydrazino-and Azo-Sphingosine Derivatives and Their Evaluation as SphK Inhibitors
Proceedings 2019, 22(1), 94; https://doi.org/10.3390/proceedings2019022094 - 09 Sep 2019
Viewed by 312
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
Open AccessExtended Abstract
Biological Evaluation of a Mitochondrial Phosphoenolpyruvate Carboxykinase Inhibitor
Proceedings 2019, 22(1), 95; https://doi.org/10.3390/proceedings2019022095 - 10 Sep 2019
Viewed by 387
Abstract
Phosphoenolpyruvate carboxykinase (PEPCK) is a key enzyme in gluconeogenesis, catalyzing
the decarboxylation of oxaloacetate to phosphoenolpyruvate. [...] Full article
Open AccessExtended Abstract
Epigenetic and PPI Targeted Libraries from Life Chemicals
Proceedings 2019, 22(1), 96; https://doi.org/10.3390/proceedings2019022096 - 10 Sep 2019
Viewed by 333
Abstract
Herein, we report our novel epigenetic and PPI. [...] Full article
Open AccessExtended Abstract
(2-Imidazolin-4-yl)phosphonates: Green Chemistry and Biology Walk Together
Proceedings 2019, 22(1), 97; https://doi.org/10.3390/proceedings2019022097 - 10 Sep 2019
Viewed by 338
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
Open AccessExtended Abstract
Drugging the Undruggable: Inhibiting MYCN Signalling
Proceedings 2019, 22(1), 98; https://doi.org/10.3390/proceedings2019022098 - 09 Oct 2019
Viewed by 361
Abstract
Neuroblastoma is the most common solid malignancy in early. [...] Full article
Open AccessExtended Abstract
Determination of the Binding Sites of Activators within the Proteasome Structure
Proceedings 2019, 22(1), 99; https://doi.org/10.3390/proceedings2019022099 - 12 Nov 2019
Viewed by 238
Abstract
The proteasome degrade most of the proteins in eukaryotic cells, thereby controlling the key
cellular processes [...] Full article
Open AccessExtended Abstract
Synthesis and Bioactivity Studies of Some Naphthoquinone Derivatives as Potential Proteasome Inhibitors
Proceedings 2019, 22(1), 100; https://doi.org/10.3390/proceedings2019022100 - 12 Nov 2019
Viewed by 233
Abstract
The ubiquitine–proteasome pathway (UPP) plays. [...] Full article
Open AccessExtended Abstract
Expanding the Toolbox of E3 Ligases for Protein Degradation: Targeting the “Undruggable” Fbw7 E3 Ligase
Proceedings 2019, 22(1), 101; https://doi.org/10.3390/proceedings2019022101 - 12 Nov 2019
Viewed by 309
Abstract
Proteolysis targeting chimera molecules (PROTACS) are heterobifunctional small molecules
designed to induce intracellular protein degradation [...] Full article
Open AccessExtended Abstract
In Silico Design of Bacterial N-acetylglucosaminidase Inhibitors with Potential Antibacterial Activity
Proceedings 2019, 22(1), 105; https://doi.org/10.3390/proceedings2019022105 - 14 Nov 2019
Viewed by 236
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
Open AccessExtended Abstract
1,2,3-triazole-oxazolidinone Derivatives as Inhibitors of the Plasminogen System
Proceedings 2019, 22(1), 106; https://doi.org/10.3390/proceedings2019022106 - 14 Nov 2019
Viewed by 235
Abstract
The Plasminogen system is known for being responsible. [...] Full article
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
Proceedings 2019, 22(1), 108; https://doi.org/10.3390/proceedings2019022108 - 14 Nov 2019
Viewed by 290
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
Open AccessExtended Abstract
Immobilized Enzyme Reactors Based on Nucleoside Phosphorylases (NPs) and Nucleoside 2′-Deoxyribosyltransferases (NDTs) for the In-Flow Synthesis of Nucleoside Analogues
Proceedings 2019, 22(1), 109; https://doi.org/10.3390/proceedings2019022109 - 21 Nov 2019
Viewed by 277
Abstract
Enzymes are increasingly used as biocatalysts for the production of Active Pharmaceutical [...] Full article
Open AccessExtended Abstract
How Proteins Catalyze Ligand Formation: Protein-Templated Fragment Ligation Employed in the Validation of Cancer Targets
Proceedings 2019, 22(1), 110; https://doi.org/10.3390/proceedings2019022110 - 21 Nov 2019
Viewed by 285
Abstract
Fragment-based drug discovery has been established as a powerful method for the assembly of
optimized protein ligands [...] Full article
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Quorum Sensing in Cyanobacteria and the Origin of Blooms. Lessons for Human Pharmacology
Proceedings 2019, 22(1), 113; https://doi.org/10.3390/proceedings2019022113 - 04 Dec 2019
Viewed by 310
Abstract
Quorum Sensing (QS) is a bacterial communication system. [...] Full article
Open AccessExtended Abstract
Drugging the Fbw7 E3 Ligase with a Fragment-Based Approach
Proceedings 2019, 22(1), 116; https://doi.org/10.3390/proceedings2019022116 - 16 Dec 2019
Viewed by 266
Abstract
Fbw7 is an important E3 ligase and one of the most commonly deregulated proteins in human cancers. [...] Full article
Open AccessExtended Abstract
Kinetic Target-Guided Synthesis as a Tool for Drug Discovery: Successes, Challenges, and Applications to Metalloproteases
Proceedings 2019, 22(1), 117; https://doi.org/10.3390/proceedings2019022117 - 17 Dec 2019
Viewed by 288
Abstract
Target-guided synthesis has emerged as an elegant and efficient lead- and drug-discovery strategy. [...] Full article
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