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Novel Strategies in the Development of New Therapies, Drug Substances and Drug Carriers

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (30 September 2021) | Viewed by 62281

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Prof. Dr. Andrzej Kutner

E-Mail Website1 Website2
Guest Editor
Department of Bioanalysis and Drug Analysis, Pharmacy Department, Medical University of Warsaw, 02-097 Warsaw, 1 Banacha, Poland
Interests: medicinal chemistry; structure-activity relationship; synthetic strategies of pharmaceutical substances; design and synthesis of vitamin A and D anticancer analogs; structure analysis of nuclear receptor ligands
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Geoffrey Brown

E-Mail Website
Guest Editor
School of Biomedical Sciences, Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
Interests: the use of synthetic retinoids and vitamins D as drug substances; cancer and normal stem cells; anticancer therapies; blood cell development; abnormalities in cancer stem cells
Special Issues, Collections and Topics in MDPI journals
Dr. Enikö Kallay

E-Mail Website
Guest Editor
Department of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology & Immunology, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria
Interests: to understand and unveil biochemical and molecular mechanisms of the anti-tumourigenic effects of vitamin D and dietary calcium for colon cancer prevention; to examine the role of the calcium sensing receptor (CaSR) and of its natural and pharmacologic modulators in colon carcinogenesis and inflammation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Currently, the need for the fast development of effective and safe therapies for widespread diseases is stronger than ever. In developing new therapies, areas of current interest are the efficacy of drug development-related strategies, entirely new therapeutic molecules, new drug delivery systems, and personalized and digital medicine. There is also the need to integrate scientific and industrial activities that focus on these different aspects of drug research and various scientific disciplines.

The theme of the Special Issue is to promote synergy between research and activities in the fields that contribute to conceiving and developing a new drug. This Special Issue is not limited to any specific aspect of drug development. On the contrary, it aims to cover the entire process from the identification of the molecular target of a new drug, studies of drug-protein interactions, the modeling and optimization of the functional activity, pre-formulation studies, new pharmaceutical carrier development, preclinical development to clinical trials.

All interested researchers are invited to submit review articles or original papers related to the topic of this Special Issue, guided by the keywords, below.

Prof. Dr. Andrzej Kutner
Dr. Geoffrey Brown
Dr. Enikö Kallay
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • drug design and discovery, drug lead, drug-protein interactions, drug response, drug solubility
  • antimicrobial drugs, antiviral drugs, antibiotics, anticancer drugs, cancer prevention
  • molecular modeling, molecular mechanisms, spectroscopic imaging, crystallography, anti-crystal engineering
  • preclinical study, clinical trials, pharmacokinetics, pharmacodynamics, pharmacognosy
  • nuclear receptors, receptor agonist and antagonist, stem cells, activity profiling, viral proteases, vaccines, markers, and diagnostics
  • drug carriers, dosage form, nanoparticles, 3D printing, dissolution testing

Published Papers (22 papers)

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Editorial

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6 pages, 218 KiB  
Editorial
Novel Strategies in the Development of New Therapies, Drug Substances, and Drug Carriers Volume I
by Andrzej Kutner, Geoffrey Brown and Enikö Kallay
Int. J. Mol. Sci. 2022, 23(12), 6635; https://doi.org/10.3390/ijms23126635 - 14 Jun 2022
Viewed by 1084
Abstract
At present, there is a strong need for new therapies that are effective and safe for widespread diseases [...] Full article
(This article belongs to the Special Issue Novel Strategies in the Development of New Therapies, Drug Substances and Drug Carriers)

Research

Jump to: Editorial, Review

12 pages, 3254 KiB  
Article
Vitamin D Analogs Regulate the Vitamin D System and Cell Viability in Ovarian Cancer Cells
by Karina Piatek, Andrzej Kutner, Dan Cacsire Castillo-Tong, Teresa Manhardt, Nadja Kupper, Urszula Nowak, Michał Chodyński, Ewa Marcinkowska, Enikö Kallay and Martin Schepelmann
Int. J. Mol. Sci. 2022, 23(1), 172; https://doi.org/10.3390/ijms23010172 - 24 Dec 2021
Cited by 6 | Viewed by 3206
Abstract
Background: Ovarian cancer (OC) is one of the most lethal cancers in women. The active form of vitamin D3, 1,25-dihydroxyvitamin D3 (1,25D3, calcitriol) has anticancer activity in several cancers, including ovarian cancer, but the required pharmacological doses may [...] Read more.
Background: Ovarian cancer (OC) is one of the most lethal cancers in women. The active form of vitamin D3, 1,25-dihydroxyvitamin D3 (1,25D3, calcitriol) has anticancer activity in several cancers, including ovarian cancer, but the required pharmacological doses may cause hypercalcemia. We hypothesized that newly developed, low calcemic, vitamin D analogs (an1,25Ds) may be used as anticancer agents instead of calcitriol in ovarian cancer cells. Methods: We used two patient-derived high-grade serous ovarian cancer (HGSOC) cell lines with low (13781) and high (14433) mRNA expression levels of the gene encoding 1,25-dihydroxyvitamin D3 24-hydroxylase CYP24A1, one of the main target genes of calcitriol. We tested the effect of calcitriol and four structurally related series of an1,25Ds (PRI-1906, PRI-1907, PRI-5201, PRI-5202) on cell number, viability, the expression of CYP24A1, and the vitamin D receptor (VDR). Results: CYP24A1 mRNA expression increased in a concentration-dependent manner after treatment with all compounds. In both cell lines, after 4 h, PRI-5202 was the most potent analog (in 13781 cells: EC50 = 2.98 ± 1.10 nmol/L, in 14433 cells: EC50 = 0.92 ± 0.20 nmol/L), while PRI-1907 was the least active one (in 13781 cells: EC50 = n/d, in 14433 cells: EC50 = n/d). This difference among the analogs disappeared after 5 days of treatment. The 13781 cells were more sensitive to the an1,25Ds compared with 14433 cells. The an1,25Ds increased nuclear VDR levels and reduced cell viability, but only in the 13781 cell line. Conclusions: The an1,25Ds had different potencies in the HGSOC cell lines and their efficacy in increasing CYP24A1 expression was cell line- and chemical structure-dependent. Therefore, choosing sensitive cancer cell lines and further optimization of the analogs’ structure might lead to new treatment options against ovarian cancer. Full article
(This article belongs to the Special Issue Novel Strategies in the Development of New Therapies, Drug Substances and Drug Carriers)
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16 pages, 10169 KiB  
Communication
Synthesis, Molecular Docking and Antiplasmodial Activities of New Tetrahydro-β-Carbolines
by Anna Jaromin, Beata Gryzło, Marek Jamrozik, Silvia Parapini, Nicoletta Basilico, Marek Cegła, Donatella Taramelli and Agnieszka Zagórska
Int. J. Mol. Sci. 2021, 22(24), 13569; https://doi.org/10.3390/ijms222413569 - 17 Dec 2021
Cited by 5 | Viewed by 2464
Abstract
Malaria is still one of the most dangerous infectious diseases and the emergence of drug resistant parasites only worsens the situation. A series of new tetrahydro-β-carbolines were designed, synthesized by the Pictet–Spengler reaction, and characterized. Further, the compounds were screened for their in [...] Read more.
Malaria is still one of the most dangerous infectious diseases and the emergence of drug resistant parasites only worsens the situation. A series of new tetrahydro-β-carbolines were designed, synthesized by the Pictet–Spengler reaction, and characterized. Further, the compounds were screened for their in vitro antiplasmodial activity against chloroquine-sensitive (D10) and chloroquine-resistant (W2) strains of Plasmodium falciparum. Moreover, molecular modeling studies were performed to assess the potential action of the designed molecules and toxicity assays were conducted on the human microvascular endothelial (HMEC-1) cell line and human red blood cells. Our studies identified N-(3,3-dimethylbutyl)-1-octyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b] indole-3-carboxamide (7) (a mixture of diastereomers) as the most promising compound endowed with the highest antiplasmodial activity, highest selectivity, and lack of cytotoxicity. In silico simulations carried out for (1S,3R)-7 provided useful insights into its possible interactions with enzymes essential for parasite metabolism. Further studies are underway to develop the optimal nanosized lipid-based delivery system for this compound and to determine its precise mechanism of action. Full article
(This article belongs to the Special Issue Novel Strategies in the Development of New Therapies, Drug Substances and Drug Carriers)
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16 pages, 2046 KiB  
Article
Combined Protein and Alkaloid Research of Chelidonium majus Latex Reveals CmMLP1 Accompanied by Alkaloids with Cytotoxic Potential to Human Cervical Carcinoma Cells
by Robert Nawrot, Alicja Warowicka, Piotr Józef Rudzki, Oskar Musidlak, Katarzyna Magdalena Dolata, Jacek Musijowski, Elżbieta Urszula Stolarczyk and Anna Goździcka-Józefiak
Int. J. Mol. Sci. 2021, 22(21), 11838; https://doi.org/10.3390/ijms222111838 - 31 Oct 2021
Cited by 5 | Viewed by 2105
Abstract
Chelidonium majus L. is a latex-bearing plant used in traditional folk medicine to treat human papillomavirus (HPV)-caused warts, papillae, and condylomas. Its latex and extracts are rich in many low-molecular compounds and proteins, but there is little or no information on their potential [...] Read more.
Chelidonium majus L. is a latex-bearing plant used in traditional folk medicine to treat human papillomavirus (HPV)-caused warts, papillae, and condylomas. Its latex and extracts are rich in many low-molecular compounds and proteins, but there is little or no information on their potential interaction. We describe the isolation and identification of a novel major latex protein (CmMLP1) composed of 147 amino acids and present a model of its structure containing a conserved hydrophobic cavity with high affinity to berberine, 8-hydroxycheleritrine, and dihydroberberine. CmMLP1 and the accompanying three alkaloids were present in the eluted chromatographic fractions of latex. They decreased in vitro viability of human cervical cancer cells (HPV-negative and HPV-positive). We combined, for the first time, research on macromolecular and low-molecular-weight compounds of latex-bearing plants in contrast to other studies that investigated proteins and alkaloids separately. The observed interaction between latex protein and alkaloids may influence our knowledge on plant defense. The proposed toolbox may help in further understanding of plant disease resistance and in pharmacological research. Full article
(This article belongs to the Special Issue Novel Strategies in the Development of New Therapies, Drug Substances and Drug Carriers)
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25 pages, 7317 KiB  
Article
The Cytotoxic Effect of Copper (II) Complexes with Halogenated 1,3-Disubstituted Arylthioureas on Cancer and Bacterial Cells
by Alicja Chrzanowska, Aleksandra Drzewiecka-Antonik, Katarzyna Dobrzyńska, Joanna Stefańska, Piotr Pietrzyk, Marta Struga and Anna Bielenica
Int. J. Mol. Sci. 2021, 22(21), 11415; https://doi.org/10.3390/ijms222111415 - 22 Oct 2021
Cited by 9 | Viewed by 2284
Abstract
A series of eight copper (II) complexes with 3-(4-chloro-3-nitrophenyl)thiourea were designed and synthesized. The cytotoxic activity of all compounds was assessed in three human cancer cell lines (SW480, SW620, PC3) and human normal keratinocytes (HaCaT). The complexes 1, 3, 5, [...] Read more.
A series of eight copper (II) complexes with 3-(4-chloro-3-nitrophenyl)thiourea were designed and synthesized. The cytotoxic activity of all compounds was assessed in three human cancer cell lines (SW480, SW620, PC3) and human normal keratinocytes (HaCaT). The complexes 1, 3, 5, 7 and 8 were cytotoxic to the studied tumor cells in the low micromolar range, without affecting the normal cells. The complexes 1, 3, 7 and 8 induced lactate dehydrogenase (LDH) release in all cancer cell lines, but not in the HaCaT cells. They provoked early apoptosis in pathological cells, especially in SW480 and PC3 cells. The ability of compounds 1, 3, 7 and 8 to diminish interleukin-6 (IL-6) concentration in a cell was established. For the first time, the influence of the most promising Cu (II) complexes on intensities of detoxifying and reactive oxygen species (ROS) scavenging the enzymes of tumor cells was studied. The cytotoxic effect of all copper (II) conjugates against standard and hospital bacterial strains was also proved. Full article
(This article belongs to the Special Issue Novel Strategies in the Development of New Therapies, Drug Substances and Drug Carriers)
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17 pages, 18317 KiB  
Article
Antitumor Activity and Mechanism of Action of Hormonotoxin, an LHRH Analog Conjugated to Dermaseptin-B2, a Multifunctional Antimicrobial Peptide
by Mickael Couty, Marie Dusaud, Mickael Miro-Padovani, Liuhui Zhang, Patricia Zadigue, Loussiné Zargarian, Olivier Lequin, Alexandre de la Taille, Jean Delbe, Yamina Hamma-Kourbali and Mohamed Amiche
Int. J. Mol. Sci. 2021, 22(21), 11303; https://doi.org/10.3390/ijms222111303 - 20 Oct 2021
Cited by 5 | Viewed by 2497
Abstract
Prostate cancer is the most common cancer in men. For patients with advanced or metastatic prostate cancer, available treatments can slow down its progression but cannot cure it. The development of innovative drugs resulting from the exploration of biodiversity could open new therapeutic [...] Read more.
Prostate cancer is the most common cancer in men. For patients with advanced or metastatic prostate cancer, available treatments can slow down its progression but cannot cure it. The development of innovative drugs resulting from the exploration of biodiversity could open new therapeutic alternatives. Dermaseptin-B2, a natural multifunctional antimicrobial peptide isolated from Amazonian frog skin, has been reported to possess antitumor activity. To improve its pharmacological properties and to decrease its peripheral toxicity and lethality we developed a hormonotoxin molecule composed of dermaseptin-B2 combined with d-Lys6-LHRH to target the LHRH receptor. This hormonotoxin has a significant antiproliferative effect on the PC3 tumor cell line, with an IC50 value close to that of dermaseptin-B2. Its antitumor activity has been confirmed in vivo in a xenograft mouse model with PC3 tumors and appears to be better tolerated than dermaseptin-B2. Biophysical experiments showed that the addition of LHRH to dermaseptin-B2 did not alter its secondary structure or biological activity. The combination of different experimental approaches indicated that this hormonotoxin induces cell death by an apoptotic mechanism instead of necrosis, as observed for dermaseptin-B2. These results could explain the lower toxicity observed for this hormonotoxin compared to dermaseptin-B2 and may represent a promising targeting approach for cancer therapy. Full article
(This article belongs to the Special Issue Novel Strategies in the Development of New Therapies, Drug Substances and Drug Carriers)
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37 pages, 8552 KiB  
Article
New N-Substituted-1,2,4-triazole Derivatives of Pyrrolo[3,4-d]pyridazinone with Significant Anti-Inflammatory Activity—Design, Synthesis and Complementary In Vitro, Computational and Spectroscopic Studies
by Łukasz Szczukowski, Edward Krzyżak, Benita Wiatrak, Paulina Jawień, Aleksandra Marciniak, Aleksandra Kotynia and Piotr Świątek
Int. J. Mol. Sci. 2021, 22(20), 11235; https://doi.org/10.3390/ijms222011235 - 18 Oct 2021
Cited by 12 | Viewed by 2229
Abstract
Regarding that the chronic use of commonly available non-steroidal and anti-inflammatory drugs (NSAIDs) is often restricted by their adverse effects, there is still a current need to search for and develop new, safe and effective anti-inflammatory agents. As a continuation of our previous [...] Read more.
Regarding that the chronic use of commonly available non-steroidal and anti-inflammatory drugs (NSAIDs) is often restricted by their adverse effects, there is still a current need to search for and develop new, safe and effective anti-inflammatory agents. As a continuation of our previous work, we designed and synthesized a series of 18 novel N-substituted-1,2,4-triazole-based derivatives of pyrrolo[3,4-d]pyridazinone 4a-c-9a-c. The target compounds were afforded via a convenient way of synthesis, with good yields. The executed cell viability assay revealed that molecules 4a-7a, 9a, 4b-7b, 4c-7c do not exert a cytotoxic effect and were qualified for further investigations. According to the performed in vitro test, compounds 4a-7a, 9a, 4b, 7b, 4c show significant cyclooxygenase-2 (COX-2) inhibitory activity and a promising COX-2/COX-1 selectivity ratio. These findings are supported by a molecular docking study which demonstrates that new derivatives take position in the active site of COX-2 very similar to Meloxicam. Moreover, in the carried out in vitro evaluation within cells, the title molecules increase the viability of cells pre-incubated with the pro-inflammatory lipopolysaccharide and reduce the level of reactive oxygen and nitrogen species (RONS) in induced oxidative stress. The spectroscopic and molecular modeling study discloses that new compounds bind favorably to site II(m) of bovine serum albumin. Finally, we have also performed some in silico pharmacokinetic and drug-likeness predictions. Taking all of the results into consideration, the molecules belonging to series a (4a-7a, 9a) show the most promising biological profile. Full article
(This article belongs to the Special Issue Novel Strategies in the Development of New Therapies, Drug Substances and Drug Carriers)
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14 pages, 2807 KiB  
Article
Stereo-Specific Modulation of the Extracellular Calcium-Sensing Receptor in Colon Cancer Cells
by Martin Schepelmann, Nadja Kupper, Marta Sladczyk, Bethan Mansfield, Teresa Manhardt, Karina Piatek, Luca Iamartino, Daniela Riccardi, Benson M. Kariuki, Marcella Bassetto and Enikö Kallay
Int. J. Mol. Sci. 2021, 22(18), 10124; https://doi.org/10.3390/ijms221810124 - 19 Sep 2021
Cited by 8 | Viewed by 2843
Abstract
Pharmacological allosteric agonists (calcimimetics) of the extracellular calcium-sensing receptor (CaSR) have substantial gastro-intestinal side effects and induce the expression of inflammatory markers in colon cancer cells. Here, we compared the effects of both CaSR-specific (R enantiomers) and -unspecific (S enantiomers) enantiomers [...] Read more.
Pharmacological allosteric agonists (calcimimetics) of the extracellular calcium-sensing receptor (CaSR) have substantial gastro-intestinal side effects and induce the expression of inflammatory markers in colon cancer cells. Here, we compared the effects of both CaSR-specific (R enantiomers) and -unspecific (S enantiomers) enantiomers of a calcimimetic (NPS 568) and a calcilytic (allosteric CaSR antagonists; NPS 2143) to prove that these effects are indeed mediated via the CaSR, rather than via off-target effects, e.g., on β-adrenoceptors or calcium channels, of these drugs. The unspecific S enantiomer of NPS 2143 and NPS S-2143 was prepared using synthetic chemistry and characterized using crystallography. NPS S-2143 was then tested in HEK-293 cells stably transfected with the human CaSR (HEK-CaSR), where it did not inhibit CaSR-mediated intracellular Ca2+ signals, as expected. HT29 colon cancer cells transfected with the CaSR were treated with both enantiomers of NPS 568 and NPS 2143 alone or in combination, and the expression of CaSR and the pro-inflammatory cytokine interleukin 8 (IL-8) was measured by RT-qPCR and ELISA. Only the CaSR-selective enantiomers of the calcimimetic NPS 568 and NPS 2143 were able to modulate CaSR and IL-8 expression. We proved that pro-inflammatory effects in colon cancer cells are indeed mediated through CaSR activation. The non-CaSR selective enantiomer NPS S-2143 will be a valuable tool for investigations in CaSR-mediated processes. Full article
(This article belongs to the Special Issue Novel Strategies in the Development of New Therapies, Drug Substances and Drug Carriers)
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21 pages, 5742 KiB  
Article
Anti-Cancer and Electrochemical Properties of Thiogenistein—New Biologically Active Compound
by Elżbieta U. Stolarczyk, Weronika Strzempek, Marta Łaszcz, Andrzej Leś, Elżbieta Menaszek, Katarzyna Sidoryk and Krzysztof Stolarczyk
Int. J. Mol. Sci. 2021, 22(16), 8783; https://doi.org/10.3390/ijms22168783 - 16 Aug 2021
Cited by 3 | Viewed by 1962
Abstract
Pharmacological and nutraceutical effects of isoflavones, which include genistein (GE), are attributed to their antioxidant activity protecting cells against carcinogenesis. The knowledge of the oxidation mechanisms of an active substance is crucial to determine its pharmacological properties. The aim of the present work [...] Read more.
Pharmacological and nutraceutical effects of isoflavones, which include genistein (GE), are attributed to their antioxidant activity protecting cells against carcinogenesis. The knowledge of the oxidation mechanisms of an active substance is crucial to determine its pharmacological properties. The aim of the present work was to explain complex oxidation processes that have been simulated during voltammetric experiments for our new thiolated genistein analog (TGE) that formed the self-assembled monolayer (SAM) on the gold electrode. The thiol linker assured a strong interaction of sulfur nucleophiles with the gold surface. The research comprised of the study of TGE oxidative properties, IR-ATR, and MALDI-TOF measurements of SAM before and after electrochemical oxidation. TGE has been shown to be electrochemically active. It undergoes one irreversible oxidation reaction and one quasi-reversible oxidation reaction in PBS buffer at pH 7.4. The oxidation of TGE results in electroactive products composed likely from TGE conjugates (e.g., trimers) as part of polymer. The electroactive centers of TGE and its oxidation mechanism were discussed using IR supported by quantum chemical and molecular mechanics calculations. Preliminary in-vitro studies indicate that TGE exhibits higher cytotoxic activity towards DU145 human prostate cancer cells and is safer for normal prostate epithelial cells (PNT2) than genistein itself. Full article
(This article belongs to the Special Issue Novel Strategies in the Development of New Therapies, Drug Substances and Drug Carriers)
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16 pages, 2566 KiB  
Article
In Vitro and In Silico Characterization of an Antimalarial Compound with Antitumor Activity Targeting Human DNA Topoisomerase IB
by Bini Chhetri Soren, Jagadish Babu Dasari, Alessio Ottaviani, Beatrice Messina, Giada Andreotti, Alice Romeo, Federico Iacovelli, Mattia Falconi, Alessandro Desideri and Paola Fiorani
Int. J. Mol. Sci. 2021, 22(14), 7455; https://doi.org/10.3390/ijms22147455 - 12 Jul 2021
Cited by 5 | Viewed by 2077
Abstract
Human DNA topoisomerase IB controls the topological state of supercoiled DNA through a complex catalytic cycle that consists of cleavage and religation reactions, allowing the progression of fundamental DNA metabolism. The catalytic steps of human DNA topoisomerase IB were analyzed in the presence [...] Read more.
Human DNA topoisomerase IB controls the topological state of supercoiled DNA through a complex catalytic cycle that consists of cleavage and religation reactions, allowing the progression of fundamental DNA metabolism. The catalytic steps of human DNA topoisomerase IB were analyzed in the presence of a drug, obtained by the open-access drug bank Medicines for Malaria Venture. The experiments indicate that the compound strongly and irreversibly inhibits the cleavage step of the enzyme reaction and reduces the cell viability of three different cancer cell lines. Molecular docking and molecular dynamics simulations suggest that the drug binds to the human DNA topoisomerase IB-DNA complex sitting inside the catalytic site of the enzyme, providing a molecular explanation for the cleavage-inhibition effect. For all these reasons, the aforementioned drug could be a possible lead compound for the development of an efficient anti-tumor molecule targeting human DNA topoisomerase IB. Full article
(This article belongs to the Special Issue Novel Strategies in the Development of New Therapies, Drug Substances and Drug Carriers)
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19 pages, 17703 KiB  
Article
Poly(chitosan-ester-ether-urethane) Hydrogels as Highly Controlled Genistein Release Systems
by Martyna Zagórska-Dziok, Patrycja Kleczkowska, Ewa Olędzka, Ramona Figat and Marcin Sobczak
Int. J. Mol. Sci. 2021, 22(7), 3339; https://doi.org/10.3390/ijms22073339 - 24 Mar 2021
Cited by 10 | Viewed by 2200
Abstract
Polymeric hydrogels play an increasingly important role in medicine, pharmacy and cosmetology. They appear to be one of the most promising groups of biomaterials due to their favorable physicochemical properties and biocompatibility. The objective of the presented study was to synthesize new poly(chitosan-ester-ether-urethane) [...] Read more.
Polymeric hydrogels play an increasingly important role in medicine, pharmacy and cosmetology. They appear to be one of the most promising groups of biomaterials due to their favorable physicochemical properties and biocompatibility. The objective of the presented study was to synthesize new poly(chitosan-ester-ether-urethane) hydrogels and to study the kinetic release of genistein (GEN) from these biomaterials. In view of the above, six non-toxic hydrogels were synthesized via the Ring-Opening Polymerization (ROP) and polyaddition processes. The poly(ester-ether) components of the hydrogels have been produced in the presence of the enzyme as a biocatalyst. In some cases, the in vitro release rate of GEN from the obtained hydrogels was characterized by near-zero-order kinetics, without “burst release” and with non-Fickian transport. It is important to note that developed hydrogels have been shown to possess the desired safety profile due to lack of cytotoxicity to skin cells (keratinocytes and fibroblasts). Taking into account the non-toxicity of hydrogels and the relatively highly controlled release profile of GEN, these results may provide fresh insight into polymeric hydrogels as an effective dermatological and/or cosmetological tool. Full article
(This article belongs to the Special Issue Novel Strategies in the Development of New Therapies, Drug Substances and Drug Carriers)
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22 pages, 3075 KiB  
Article
Differential Response of Lung Cancer Cells, with Various Driver Mutations, to Plant Polyphenol Resveratrol and Vitamin D Active Metabolite PRI-2191
by Ewa Maj, Beata Maj, Klaudia Bobak, Michalina Gos, Michał Chodyński, Andrzej Kutner and Joanna Wietrzyk
Int. J. Mol. Sci. 2021, 22(5), 2354; https://doi.org/10.3390/ijms22052354 - 26 Feb 2021
Cited by 13 | Viewed by 2776
Abstract
Plant polyphenols and vitamins D exhibit chemopreventive and therapeutic anticancer effects. We first evaluated the biological effects of the plant polyphenol resveratrol (RESV) and vitamin D active metabolite PRI-2191 on lung cancer cells having different genetic backgrounds. RESV and PRI-2191 showed divergent responses [...] Read more.
Plant polyphenols and vitamins D exhibit chemopreventive and therapeutic anticancer effects. We first evaluated the biological effects of the plant polyphenol resveratrol (RESV) and vitamin D active metabolite PRI-2191 on lung cancer cells having different genetic backgrounds. RESV and PRI-2191 showed divergent responses depending on the genetic profile of cells. Antiproliferative activity of PRI-2191 was noticeable in EGFRmut cells, while RESV showed the highest antiproliferative and caspase-3-inducing activity in KRASmut cells. RESV upregulated p53 expression in wtp53 cells, while downregulated it in mutp53 cells with simultaneous upregulation of p21 expression in both cases. The effect of PRI-2191 on the induction of CYP24A1 expression was enhanced by RESV in two KRASmut cell lines. The effect of RESV combined with PRI-2191 on cytokine production was pronounced and modulated. RESV cooperated with PRI-2191 in regulating the expression of IL-8 in EGFRmut cells, while OPN in KRASmut cells and PD-L1 in both cell subtypes. We hypothesize that the differences in response to RESV and PRI-2191 between EGFRmut and KRASmut cell lines result from the differences in epigenetic modifications since both cell subtypes are associated with the divergent smoking history that can induce epigenetic alterations. Full article
(This article belongs to the Special Issue Novel Strategies in the Development of New Therapies, Drug Substances and Drug Carriers)
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21 pages, 14825 KiB  
Article
Synthesis of Novel Pyrido[1,2-c]pyrimidine Derivatives with 6-Fluoro-3-(4-piperidynyl)-1,2-benzisoxazole Moiety as Potential SSRI and 5-HT1A Receptor Ligands
by Marek Król, Grzegorz Ślifirski, Jerzy Kleps, Szymon Ulenberg, Mariusz Belka, Tomasz Bączek, Agata Siwek, Katarzyna Stachowicz, Bernadeta Szewczyk, Gabriel Nowak, Beata Duszyńska and Franciszek Herold
Int. J. Mol. Sci. 2021, 22(5), 2329; https://doi.org/10.3390/ijms22052329 - 26 Feb 2021
Cited by 7 | Viewed by 2320
Abstract
Two series of novel 4-aryl-2H-pyrido[1,2-c]pyrimidine (6a–i) and 4-aryl-5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine (7a–i) derivatives were synthesized. The chemical structures of the new compounds were confirmed by 1H and 13C NMR spectroscopy and ESI-HRMS spectrometry. The affinities of all compounds for the 5-HT1A [...] Read more.
Two series of novel 4-aryl-2H-pyrido[1,2-c]pyrimidine (6a–i) and 4-aryl-5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine (7a–i) derivatives were synthesized. The chemical structures of the new compounds were confirmed by 1H and 13C NMR spectroscopy and ESI-HRMS spectrometry. The affinities of all compounds for the 5-HT1A receptor and serotonin transporter protein (SERT) were determined by in vitro radioligand binding assays. The test compounds demonstrated very high binding affinities for the 5-HT1A receptor of all derivatives in the series (6a–i and 7a–i) and generally low binding affinities for the SERT protein, with the exception of compounds 6a and 7g. Extended affinity tests for the receptors D2, 5-HT2A, 5-HT6 and 5-HT7 were conducted with regard to selected compounds (6a, 7g, 6d and 7i). All four compounds demonstrated very high affinities for the D2 and 5-HT2A receptors. Compounds 6a and 7g also had high affinities for 5-HT7, while 6d and 7i held moderate affinities for this receptor. Compounds 6a and 7g were also tested in vivo to identify their functional activity profiles with regard to the 5-HT1A receptor, with 6a demonstrating the activity profile of a presynaptic agonist. Metabolic stability tests were also conducted for 6a and 6d. Full article
(This article belongs to the Special Issue Novel Strategies in the Development of New Therapies, Drug Substances and Drug Carriers)
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13 pages, 8191 KiB  
Article
In Vitro and In Vivo Efficacy of a Novel Glucose–Methotrexate Conjugate in Targeted Cancer Treatment
by Marta Woźniak, Gabriela Pastuch-Gawołek, Sebastian Makuch, Jerzy Wiśniewski, Tibor Krenács, Peter Hamar, Andrzej Gamian, Wiesław Szeja, Danuta Szkudlarek, Monika Krawczyk and Siddarth Agrawal
Int. J. Mol. Sci. 2021, 22(4), 1748; https://doi.org/10.3390/ijms22041748 - 09 Feb 2021
Cited by 17 | Viewed by 3876
Abstract
Methotrexate (MTX) is a commonly used antimetabolite, which inhibits folate and DNA synthesis to be effective in the treatment of various malignancies. However, MTX therapy is hindered by the lack of target tumor selectivity. We have designed, synthesized and evaluated a novel glucose–methotrexate [...] Read more.
Methotrexate (MTX) is a commonly used antimetabolite, which inhibits folate and DNA synthesis to be effective in the treatment of various malignancies. However, MTX therapy is hindered by the lack of target tumor selectivity. We have designed, synthesized and evaluated a novel glucose–methotrexate conjugate (GLU–MTX) both in vitro and in vivo, in which a cleavable linkage allows intracellular MTX release after selective uptake through glucose transporter−1 (GLUT1). GLU–MTX inhibited the growth of colorectal (DLD-1), breast (MCF-7) and lung (A427) adenocarcinomas, squamous cell carcinoma (SCC-25), osteosarcoma (MG63) cell lines, but not in WI-38 healthy fibroblasts. In tumor cells, GLU–MTX uptake increased 17-fold compared to unconjugated MTX. 4,6-O-ethylidene-α-D-glucose (EDG), a GLUT1 inhibitor, significantly interfered with GLU–MTX induced growth inhibition, suggesting a glucose-mediated drug uptake. Glu-MTX also caused significant tumor growth delay in vivo in breast cancer-bearing mice. These results show that our GLUT-MTX conjugate can be selectively uptake by a range of tumor cells to cause their significant growth inhibition in vitro, which was also confirmed in a breast cancer model in vivo. GLUT1 inhibitor EDG interfered with these effects verifying the selective drug uptake. Accordingly, GLU–MTX offers a considerable tumor selectivity and may offer cancer growth inhibition at reduced toxicity. Full article
(This article belongs to the Special Issue Novel Strategies in the Development of New Therapies, Drug Substances and Drug Carriers)
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21 pages, 4295 KiB  
Article
Alpha Ketoglutarate Exerts In Vitro Anti-Osteosarcoma Effects through Inhibition of Cell Proliferation, Induction of Apoptosis via the JNK and Caspase 9-Dependent Mechanism, and Suppression of TGF-β and VEGF Production and Metastatic Potential of Cells
by Katarzyna Kaławaj, Adrianna Sławińska-Brych, Magdalena Mizerska-Kowalska, Aleksandra Żurek, Agnieszka Bojarska-Junak, Martyna Kandefer-Szerszeń and Barbara Zdzisińska
Int. J. Mol. Sci. 2020, 21(24), 9406; https://doi.org/10.3390/ijms21249406 - 10 Dec 2020
Cited by 14 | Viewed by 2680
Abstract
Osteosarcoma (OS) is the most common type of primary bone tumor. Currently, there are limited treatment options for metastatic OS. Alpha-ketoglutarate (AKG), i.e., a multifunctional intermediate of the Krebs cycle, is one of the central metabolic regulators of tumor fate and plays an [...] Read more.
Osteosarcoma (OS) is the most common type of primary bone tumor. Currently, there are limited treatment options for metastatic OS. Alpha-ketoglutarate (AKG), i.e., a multifunctional intermediate of the Krebs cycle, is one of the central metabolic regulators of tumor fate and plays an important role in cancerogenesis and tumor progression. There is growing evidence suggesting that AKG may represent a novel adjuvant therapeutic opportunity in anti-cancer therapy. The present study was intended to check whether supplementation of Saos-2 and HOS osteosarcoma cell lines (harboring a TP53 mutation) with exogenous AKG exerted an anti-cancer effect. The results revealed that AKG inhibited the proliferation of both OS cell lines in a concentration-dependent manner. As evidenced by flow cytometry, AKG blocked cell cycle progression at the G1 stage in both cell lines, which was accompanied by a decreased level of cyclin D1 in HOS and increased expression of p21Waf1/Cip1 protein in Saos-2 cells (evaluated with the ELISA method). Moreover, AKG induced apoptotic cell death and caspase-3 activation in both OS cell lines (determined by cytometric analysis). Both the immunoblotting and cytometric analysis revealed that the AKG-induced apoptosis proceeded predominantly through activation of an intrinsic caspase 9-dependent apoptotic pathway and an increased Bax/Bcl-2 ratio. The apoptotic process in the AKG-treated cells was mediated via c-Jun N-terminal protein kinase (JNK) activation, as the specific inhibitor of this kinase partially rescued the cells from apoptotic death. In addition, the AKG treatment led to reduced activation of extracellular signal-regulated kinase (ERK1/2) and significant inhibition of cell migration and invasion in vitro concomitantly with decreased production of pro-metastatic transforming growth factor β (TGF-β) and pro-angiogenic vascular endothelial growth factor (VEGF) in both OS cell lines suggesting the anti-metastatic potential of this compound. In conclusion, we showed the anti-osteosarcoma potential of AKG and provided a rationale for a further study of the possible application of AKG in OS therapy. Full article
(This article belongs to the Special Issue Novel Strategies in the Development of New Therapies, Drug Substances and Drug Carriers)
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Review

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20 pages, 13869 KiB  
Review
Gold (III) Derivatives in Colon Cancer Treatment
by Agata Gurba, Przemysław Taciak, Mariusz Sacharczuk, Izabela Młynarczuk-Biały, Magdalena Bujalska-Zadrożny and Jakub Fichna
Int. J. Mol. Sci. 2022, 23(2), 724; https://doi.org/10.3390/ijms23020724 - 10 Jan 2022
Cited by 22 | Viewed by 3144
Abstract
Cancer is one of the leading causes of morbidity and mortality worldwide. Colorectal cancer (CRC) is the third most frequently diagnosed cancer in men and the second in women. Standard patterns of antitumor therapy, including cisplatin, are ineffective due to their lack of [...] Read more.
Cancer is one of the leading causes of morbidity and mortality worldwide. Colorectal cancer (CRC) is the third most frequently diagnosed cancer in men and the second in women. Standard patterns of antitumor therapy, including cisplatin, are ineffective due to their lack of specificity for tumor cells, development of drug resistance, and severe side effects. For this reason, new methods and strategies for CRC treatment are urgently needed. Current research includes novel platinum (Pt)- and other metal-based drugs such as gold (Au), silver (Ag), iridium (Ir), or ruthenium (Ru). Au(III) compounds are promising drug candidates for CRC treatment due to their structural similarity to Pt(II). Their advantage is their relatively good solubility in water, but their disadvantage is an unsatisfactory stability under physiological conditions. Due to these limitations, work is still underway to improve the formula of Au(III) complexes by combining with various types of ligands capable of stabilizing the Au(III) cation and preventing its reduction under physiological conditions. This review summarizes the achievements in the field of stable Au(III) complexes with potential cytotoxic activity restricted to cancer cells. Moreover, it has been shown that not nucleic acids but various protein structures such as thioredoxin reductase (TrxR) mediate the antitumor effects of Au derivatives. The state of the art of the in vivo studies so far conducted is also described. Full article
(This article belongs to the Special Issue Novel Strategies in the Development of New Therapies, Drug Substances and Drug Carriers)
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25 pages, 7323 KiB  
Review
Functional Studies of Plant Latex as a Rich Source of Bioactive Compounds: Focus on Proteins and Alkaloids
by Joanna Gracz-Bernaciak, Oliwia Mazur and Robert Nawrot
Int. J. Mol. Sci. 2021, 22(22), 12427; https://doi.org/10.3390/ijms222212427 - 17 Nov 2021
Cited by 19 | Viewed by 4112
Abstract
Latex, a sticky emulsion produced by specialized cells called laticifers, is a crucial part of a plant’s defense system against herbivory and pathogens. It consists of a broad spectrum of active compounds, which are beneficial not only for plants, but for human health [...] Read more.
Latex, a sticky emulsion produced by specialized cells called laticifers, is a crucial part of a plant’s defense system against herbivory and pathogens. It consists of a broad spectrum of active compounds, which are beneficial not only for plants, but for human health as well, enough to mention the use of morphine or codeine from poppy latex. Here, we reviewed latex’s general role in plant physiology and the significance of particular compounds (alkaloids and proteins) to its defense system with the example of Chelidonium majus L. from the poppy family. We further attempt to present latex chemicals used so far in medicine and then focus on functional studies of proteins and other compounds with potential pharmacological activities using modern techniques such as CRISPR/Cas9 gene editing. Despite the centuries-old tradition of using latex-bearing plants in therapies, there are still a lot of promising molecules waiting to be explored. Full article
(This article belongs to the Special Issue Novel Strategies in the Development of New Therapies, Drug Substances and Drug Carriers)
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17 pages, 1011 KiB  
Review
New Approaches to Assess Mechanisms of Action of Selective Vitamin D Analogues
by John Wesley Pike and Mark B. Meyer
Int. J. Mol. Sci. 2021, 22(22), 12352; https://doi.org/10.3390/ijms222212352 - 16 Nov 2021
Cited by 4 | Viewed by 2012
Abstract
Recent studies of transcription have revealed an advanced set of overarching principles that govern vitamin D action on a genome-wide scale. These tenets of vitamin D transcription have emerged as a result of the application of now well-established techniques of chromatin immunoprecipitation coupled [...] Read more.
Recent studies of transcription have revealed an advanced set of overarching principles that govern vitamin D action on a genome-wide scale. These tenets of vitamin D transcription have emerged as a result of the application of now well-established techniques of chromatin immunoprecipitation coupled to next-generation DNA sequencing that have now been linked directly to CRISPR-Cas9 genomic editing in culture cells and in mouse tissues in vivo. Accordingly, these techniques have established that the vitamin D hormone modulates sets of cell-type specific genes via an initial action that involves rapid binding of the VDR–ligand complex to multiple enhancer elements at open chromatin sites that drive the expression of individual genes. Importantly, a sequential set of downstream events follows this initial binding that results in rapid histone acetylation at these sites, the recruitment of additional histone modifiers across the gene locus, and in many cases, the appearance of H3K36me3 and RNA polymerase II across gene bodies. The measured recruitment of these factors and/or activities and their presence at specific regions in the gene locus correlate with the emerging presence of cognate transcripts, thereby highlighting sequential molecular events that occur during activation of most genes both in vitro and in vivo. These features provide a novel approach to the study of vitamin D analogs and their actions in vivo and suggest that they can be used for synthetic compound evaluation and to select for novel tissue- and gene-specific features. This may be particularly useful for ligand activation of nuclear receptors given the targeting of these factors directly to genetic sites in the nucleus. Full article
(This article belongs to the Special Issue Novel Strategies in the Development of New Therapies, Drug Substances and Drug Carriers)
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15 pages, 4656 KiB  
Review
Development of In Vitro and In Vivo Evaluation Systems for Vitamin D Derivatives and Their Application to Drug Discovery
by Kaori Yasuda, Miyu Nishikawa, Hiroki Mano, Masashi Takano, Atsushi Kittaka, Shinichi Ikushiro and Toshiyuki Sakaki
Int. J. Mol. Sci. 2021, 22(21), 11839; https://doi.org/10.3390/ijms222111839 - 31 Oct 2021
Cited by 2 | Viewed by 2014
Abstract
We have developed an in vitro system to easily examine the affinity for vitamin D receptor (VDR) and CYP24A1-mediated metabolism as two methods of assessing vitamin D derivatives. Vitamin D derivatives with high VDR affinity and resistance to CYP24A1-mediated metabolism could be good [...] Read more.
We have developed an in vitro system to easily examine the affinity for vitamin D receptor (VDR) and CYP24A1-mediated metabolism as two methods of assessing vitamin D derivatives. Vitamin D derivatives with high VDR affinity and resistance to CYP24A1-mediated metabolism could be good therapeutic agents. This system can effectively select vitamin D derivatives with these useful properties. We have also developed an in vivo system including a Cyp27b1-gene-deficient rat (a type I rickets model), a Vdr-gene-deficient rat (a type II rickets model), and a rat with a mutant Vdr (R270L) (another type II rickets model) using a genome editing method. For Cyp27b1-gene-deficient and Vdr mutant (R270L) rats, amelioration of rickets symptoms can be used as an index of the efficacy of vitamin D derivatives. Vdr-gene-deficient rats can be used to assess the activities of vitamin D derivatives specialized for actions not mediated by VDR. One of our original vitamin D derivatives, which displays high affinity VDR binding and resistance to CYP24A1-dependent metabolism, has shown good therapeutic effects in Vdr (R270L) rats, although further analysis is needed. Full article
(This article belongs to the Special Issue Novel Strategies in the Development of New Therapies, Drug Substances and Drug Carriers)
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32 pages, 2440 KiB  
Review
5-HT Receptors and the Development of New Antidepressants
by Grzegorz Ślifirski, Marek Król and Jadwiga Turło
Int. J. Mol. Sci. 2021, 22(16), 9015; https://doi.org/10.3390/ijms22169015 - 20 Aug 2021
Cited by 39 | Viewed by 5810
Abstract
Serotonin modulates several physiological and cognitive pathways throughout the human body that affect emotions, memory, sleep, and thermal regulation. The complex nature of the serotonergic system and interactions with other neurochemical systems indicate that the development of depression may be mediated by various [...] Read more.
Serotonin modulates several physiological and cognitive pathways throughout the human body that affect emotions, memory, sleep, and thermal regulation. The complex nature of the serotonergic system and interactions with other neurochemical systems indicate that the development of depression may be mediated by various pathomechanisms, the common denominator of which is undoubtedly the disturbed transmission in central 5-HT synapses. Therefore, the deliberate pharmacological modulation of serotonergic transmission in the brain seems to be one of the most appropriate strategies for the search for new antidepressants. As discussed in this review, the serotonergic system offers great potential for the development of new antidepressant therapies based on the combination of SERT inhibition with different pharmacological activity towards the 5-HT system. The aim of this article is to summarize the search for new antidepressants in recent years, focusing primarily on the possibility of benefiting from interactions with various 5-HT receptors in the pharmacotherapy of depression. Full article
(This article belongs to the Special Issue Novel Strategies in the Development of New Therapies, Drug Substances and Drug Carriers)
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25 pages, 6865 KiB  
Review
Design and Synthesis of Fluoro Analogues of Vitamin D
by Fumihiro Kawagoe, Sayuri Mototani and Atsushi Kittaka
Int. J. Mol. Sci. 2021, 22(15), 8191; https://doi.org/10.3390/ijms22158191 - 30 Jul 2021
Cited by 8 | Viewed by 2264
Abstract
The discovery of a large variety of functions of vitamin D3 and its metabolites has led to the design and synthesis of a vast amount of vitamin D3 analogues in order to increase the potency and reduce toxicity. The introduction of [...] Read more.
The discovery of a large variety of functions of vitamin D3 and its metabolites has led to the design and synthesis of a vast amount of vitamin D3 analogues in order to increase the potency and reduce toxicity. The introduction of highly electronegative fluorine atom(s) into vitamin D3 skeletons alters their physical and chemical properties. To date, many fluorinated vitamin D3 analogues have been designed and synthesized. This review summarizes the molecular structures of fluoro-containing vitamin D3 analogues and their synthetic methodologies. Full article
(This article belongs to the Special Issue Novel Strategies in the Development of New Therapies, Drug Substances and Drug Carriers)
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16 pages, 683 KiB  
Review
Epigenetic Targeting of Histone Deacetylases in Diagnostics and Treatment of Depression
by Hyun-Sun Park, Jongmin Kim, Seong Hoon Ahn and Hong-Yeoul Ryu
Int. J. Mol. Sci. 2021, 22(10), 5398; https://doi.org/10.3390/ijms22105398 - 20 May 2021
Cited by 18 | Viewed by 3890
Abstract
Depression is a highly prevalent, disabling, and often chronic illness that places substantial burdens on patients, families, healthcare systems, and the economy. A substantial minority of patients are unresponsive to current therapies, so there is an urgent need to develop more broadly effective, [...] Read more.
Depression is a highly prevalent, disabling, and often chronic illness that places substantial burdens on patients, families, healthcare systems, and the economy. A substantial minority of patients are unresponsive to current therapies, so there is an urgent need to develop more broadly effective, accessible, and tolerable therapies. Pharmacological regulation of histone acetylation level has been investigated as one potential clinical strategy. Histone acetylation status is considered a potential diagnostic biomarker for depression, while inhibitors of histone deacetylases (HDACs) have garnered interest as novel therapeutics. This review describes recent advances in our knowledge of histone acetylation status in depression and the therapeutic potential of HDAC inhibitors. Full article
(This article belongs to the Special Issue Novel Strategies in the Development of New Therapies, Drug Substances and Drug Carriers)
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