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4101MCID_676f086a6ad28246900a9297 35755340 Mohamed Nabil Abd Al Moaty[author] Moaty, Mohamed Nabil Abd Al[Full Author Name] OR Abd Al Moaty, Mohamed Nabil[Full Author Name] moaty, mohamed nabil abd al[Author] OR abd al moaty, mohamed nabil[Author] trying2...
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2470-13437242022Jun21ACS omegaACS OmegaHarnessing ROS-Induced Oxidative Stress for Halting Colorectal Cancer via Thiazolidinedione-Based SOD Inhibitors.212672127921267-2127910.1021/acsomega.2c02410Based on the "canonical" view of reactive oxygen species' (ROS) contribution to carcinogenesis, ROS induce oxidative stress and promote various tumor progression events. However, tumor cells also need to defend themselves against oxidative damage. This "heresy" was supported by several recent studies underlining the role of cellular antioxidant capacity in promoting metastasis and resistance to chemotherapy. Accordingly, harnessing the ROS-induced oxidative stress via selective suppression of the cancer antioxidant defense machinery has been launched as an innovative anticancer strategy. Within this approach, pharmacological inhibition of superoxide dismutases (SODs), the first-line defense antioxidant enzymes for cancer cells, selectively kills tumor cells and circumvents their acquired resistance. Various SOD inhibitors have been introduced, of which some were tolerated in clinical trials. However, the hit SOD inhibitors belong to diverse chemical classes and lack comprehensive structure-activity relationships (SAR). Herein, we probe the potential of newly synthesized benzylidene thiazolidinedione derivatives to inhibit SOD in colorectal cancer with special emphasis on their effects on correlated antioxidant enzymes aldehyde dehydrogenase 1 (ALDH1) and glutathione peroxidase (GPx). This may possibly bring a new dawn for utilizing thiazolidinediones (TZDs) in cancer therapy through SOD inhibition mechanisms. The preliminary 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that all of the evaluated TZDs exhibited excellent safety profiles on normal human cells, recording an EC100 of up to 47.5-folds higher than that of doxorubicin. Compounds 3c, 6a, and 6e (IC50 = 4.4-4.7 μM) were superior to doxorubicin and other derivatives against Caco-2 colorectal cancer cells within their safe doses. The hit anticancer agents inhibited SOD (IC50 = 97.2-228.8 μM). Then, they were selected for further in-depth evaluation on the cellular level. The anticancer IC50 doses of 3c, 6a, and 6e diminished the antioxidant activities of SOD (by 29.7, 70.1, and 33.3%, respectively), ALDH1A (by 85.92, 95.84, and 86.48%, respectively), and GPX (by 50.17, 87.03, and 53.28%, respectively) in the treated Caco-2 cells, elevating the Caco-2 cellular content of ROS by 21.42, 7.863, and 8.986-folds, respectively. Docking simulations were conducted to display their possible binding modes and essential structural features. Also, their physicochemical parameters and pharmacokinetic profiles formulating drug-likeness were computed.© 2022 The Authors. Published by American Chemical Society.Abd Al MoatyMohamed NabilMN0000-0003-2843-9704Chemistry Department, Faculty of Science, Alexandria University, Alexandria 21321, Egypt.El AshryEl Sayed HESH0000-0001-5480-239XChemistry Department, Faculty of Science, Alexandria University, Alexandria 21321, Egypt.AwadLaila FathyLF0000-0001-9521-5511Chemistry Department, Faculty of Science, Alexandria University, Alexandria 21321, Egypt.MostafaAsmaaAChemistry Department, Faculty of Science, Alexandria University, Alexandria 21321, Egypt.Abu-SerieMarwa MMMMedical Biotechnology Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications (SRTA-City), Alexandria 21934, Egypt.TelebMohamedMDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt.engJournal Article20220607
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1420-30492782022Apr08Molecules (Basel, Switzerland)MoleculesEnhancing the Anticancer Potential of Targeting Tumor-Associated Metalloenzymes via VEGFR Inhibition by New Triazolo[4,3-a]pyrimidinone Acyclo C-Nucleosides Multitarget Agents.242210.3390/molecules27082422The role of metalloenzymes in tumor progression had broadened their application in cancer therapy. Of these, MMPs and CAs are validated druggable targets that share some pivotal signaling pathways. The majority of MMPs or CAs inhibitors are designed as single-target agents. Despite their transient efficacy, these agents are often susceptible to resistance. This set the stage to introduce dual inhibitors of correlated MMPs and CAs. The next step is expected to target the common vital signaling nodes as well. In this regard, VEGFR-2 is central to various tumorigenesis events involving both families, especially MMP-2 and CA II. Herein, we report simultaneous inhibition of MMP-2, CA II, and VEGFR-2 via rationally designed hybrid 1,2,4-triazolo[4,3-a]pyrimidinone acyclo C-nucleosides. The promising derivatives were nanomolar inhibitors of VEGFR-2 (8; IC50 = 5.89 nM, 9; IC50 = 10.52 nM) and MMP-2 (8; IC50 = 17.44 nM, 9; IC50 = 30.93 nM) and submicromolar inhibitors of CA II (8; IC50 = 0.21 µM, 9; IC50 = 0.36 µM). Docking studies predicted their binding modes into the enzyme active sites and the structural determinants of activity regarding substitution and regioselectivity. MTT assay demonstrated that both compounds were 12 folds safer than doxorubicin with superior anticancer activities against three human cancers recording single-digit nanomolar IC50, thus echoing their enzymatic activities. Up to our knowledge, this study introduces the first in class triazolopyrimidinone acyclo C-nucleosides VEGFR-2/MMP-2/CA II inhibitors that deserve further investigation.Abd Al MoatyMohamed NabilMN0000-0003-2843-9704Chemistry Department, Faculty of Science, Alexandria University, Alexandria 21321, Egypt.El AshryEl Sayed HelmyESHChemistry Department, Faculty of Science, Alexandria University, Alexandria 21321, Egypt.AwadLaila FathyLFChemistry Department, Faculty of Science, Alexandria University, Alexandria 21321, Egypt.IbrahimNihal AhmedNAChemistry Department, Faculty of Science, Alexandria University, Alexandria 21321, Egypt.Abu-SerieMarwa MuhammadMMMedical Biotechnology Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications (SRTA-City), Alexandria 21934, Egypt.BarakatAssemA0000-0002-7885-3201Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia.AltowyanMezna SalehMS0000-0002-7038-8018Department of Chemistry, College of Science, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia.TelebMohamedMDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt.engPNURSP2022R86Princess Nourah bint Abdulrahman UniversityJournal Article20220408
SwitzerlandMolecules1009640091420-30490Antineoplastic Agents0Metalloproteins0Nucleosides0Protein Kinase Inhibitors0Pyrimidinones0TriazolesEC 2.7.10.1Vascular Endothelial Growth Factor Receptor-2EC 3.4.24.24Matrix Metalloproteinase 2IMAntineoplastic AgentschemistrypharmacologyCell Line, TumorCell ProliferationDrug Screening Assays, AntitumorHumansMatrix Metalloproteinase 2metabolismMetalloproteinsmetabolismMolecular Docking SimulationMolecular StructureNucleosideschemistrypharmacologyProtein Kinase InhibitorspharmacologyPyrimidinonespharmacologyStructure-Activity RelationshipTriazolespharmacologyVascular Endothelial Growth Factor Receptor-2antagonists & inhibitors1,2,4-triazolo[4,3-a]pyrimidinone acyclo C-nucleosidesCAIIMMP-2VEGFR-2multitarget anticancer agentsThe authors declare no conflict of interest.202221020223182022412022423115202242460202242760202248epublish35458618PMC902610910.3390/molecules27082422molecules27082422Arneth B. Tumor microenvironment. 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1422-006722192021Sep25International journal of molecular sciencesInt J Mol SciHalting Tumor Progression via Novel Non-Hydroxamate Triazole-Based Mannich Bases MMP-2/9 Inhibitors; Design, Microwave-Assisted Synthesis, and Biological Evaluation.1032410.3390/ijms221910324Matrix metalloproteinases (MMPs) are key signaling modulators in the tumor microenvironment. Among MMPs, MMP-2 and MMP-9 are receiving renewed interest as validated druggable targets for halting different tumor progression events. Over the last decades, a diverse range of MMP-2/9 inhibitors has been identified starting from the early hydroxamic acid-based peptidomimetics to the next generation non-hydroxamates. Herein, focused 1,2,4-triazole-1,2,3-triazole molecular hybrids with varying lengths and decorations, mimicking the thematic features of non-hydroxamate inhibitors, were designed and synthesized using efficient protocols and were alkylated with pharmacophoric amines to develop new Mannich bases. After full spectroscopic characterization the newly synthesized triazoles tethering Mannich bases were subjected to safety assessment via MTT assay against normal human fibroblasts, then evaluated for their potential anticancer activities against colon (Caco-2) and breast (MDA-MB 231) cancers. The relatively lengthy bis-Mannich bases 15 and 16 were safer and more potent than 5-fluorouracil with sub-micromolar IC50 and promising selectivity to the screened cancer cell lines rather than normal cells. Both compounds upregulated p53 (2-5.6-fold) and suppressed cyclin D expression (0.8-0.2-fold) in the studied cancers, and thus, induced apoptosis. 15 was superior to 16 in terms of cytotoxic activities, p53 induction, and cyclin D suppression. Mechanistically, both were efficient MMP-2/9 inhibitors with comparable potencies to the reference prototype hydroxamate-based MMP inhibitor NNGH at their anticancer IC50 concentrations. 15 (IC50 = 0.143 µM) was 4-fold more potent than NNGH against MMP-9 with promising selectivity (3.27-fold) over MMP-2, whereas 16 was comparable to NNGH. Concerning MMP-2, 16 (IC50 = 0.376 µM) was 1.2-fold more active than 15. Docking simulations predicted their possible binding modes and highlighted the possible structural determinants of MMP-2/9 inhibitory activities. Computational prediction of their physicochemical properties, ADMET, and drug-likeness metrics revealed acceptable drug-like criteria.AlbelwiFawzia FalehFFDepartment of Chemistry, Faculty of Science, Taibah University, Al-Madinah Al-Munawarah 30002, Saudi Arabia.TelebMohamedMDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt.Abu-SerieMarwa MMMMedical Biotechnology Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications (SRTA-City), Alexandria 21934, Egypt.MoatyMohamed Nabil Abd AlMNAAChemistry Department, Faculty of Science, Alexandria University, Alexandria 21321, Egypt.AlsubaieMai SMSChemistry Department, Faculty of Science, Alexandria University, Alexandria 21321, Egypt.ZakariaMohamed AMA0000-0001-8785-3046Chemistry Department, Faculty of Science, Alexandria University, Alexandria 21321, Egypt.El KilanyYeldezYChemistry Department, Faculty of Science, Alexandria University, Alexandria 21321, Egypt.AouadMohamed RedaMR0000-0001-7018-6654Department of Chemistry, Faculty of Science, Taibah University, Al-Madinah Al-Munawarah 30002, Saudi Arabia.HagarMohamedM0000-0003-0169-7738Chemistry Department, Faculty of Science, Alexandria University, Alexandria 21321, Egypt.RezkiNadjetN0000-0001-8330-1738Department of Chemistry, Faculty of Science, Taibah University, Al-Madinah Al-Munawarah 30002, Saudi Arabia.engJournal Article20210925
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1090-2120962020MarBioorganic chemistryBioorg ChemStructure-based design and optimization of pyrimidine- and 1,2,4-triazolo[4,3-a]pyrimidine-based matrix metalloproteinase-10/13 inhibitors via Dimroth rearrangement towards targeted polypharmacology.10361610361610.1016/j.bioorg.2020.103616S0045-2068(19)31828-0Recently, interest in matrix metalloproteinases (MMPs) -10 and -13 has been revitalized with the growing knowledge on their relevance within the MMPs network and significance of their inhibition for treatment of various diseases like arthritis, cancer, atherosclerosis and Alzheimer. Within this approach, dual MMP-10/13 inhibition was disclosed as new approach for targeted polypharmacology. While several efficient MMP-13 inhibitors are known, very few potent and selective MMP-10 inhibitors were reported. This study describes the design, synthesis and optimization of novel MMP-10/13 inhibitors with enhanced MMP-10 potency and selectivity towards polypharmacology. Starting with a lead fused pyrimidine-based MMP-13 inhibitor with weak MMP-10 inhibition, a structure-based design of pyrimidine and fused pyrimidine scaffolds was rationalized to enhance activity against MMP-10 in parallel with MMP-13. Firstly, a series of 6-methyl pyrimidin-4-one hydrazones 6-10 was synthesized via conventional and ultrasonic-assisted methods, then evaluated for MMP-10/13 inhibition. The most active derivative 9 exhibited acceptable dual potency with 7-fold selectivity for MMP-10 (IC50 = 53 nM) over MMP-13. Such hydrazones were then cyclized to the corresponding isomeric 1,2,4-triazolo[4,3-a]pyrimidines 12-19. Their MMP-10/13 inhibition assay revealed, in most cases, superior dual activities with general MMP-10 selectivity compared to the corresponding precursors 6-10. In addition, a clear structure activity relationship trend was deduced within the identified regioisomers, where the 5-oxo-1,2,4-triazolo[4,3-a]pyrimidine derivatives 15 and 16 were far more active against MMP-10/13 than their regioisomers 12 and 13. Remarkably, the p-bromophenyl derivative 16 exhibited the highest MMP-10 inhibition (IC50 = 24 nM), whereas the p-methoxy derivative 18 was the most potent MMP-13 inhibitor (IC50 = 294 nM). Moreover, 16 exhibited 19-fold selectivity for MMP-10 over MMP-13, 10-fold over MMP-9, and 29-fold over MMP-7. Docking studies were performed to provide reasonable explanation for structure-activity relationships and isoform selectivity. 16 and 18 were then evaluated for their anticancer activities against three human cancers to assess their therapeutic potential at cellular level via MTT assay. Both compounds exhibited superior anticancer activities compared to quercetin. Their in silico ligand efficiency metrics, physicochemical properties and ADME parameters were drug-like. Guided by such findings that point to 16 as the most promising compound in this study, further structure optimization was carried out via photoirradiation-mediated Dimroth rearrangement of the inactive triazolopyrimidine 13 to its potent regioisomer 16.Copyright © 2020 Elsevier Inc. All rights reserved.El AshryEl Sayed HelmyESHChemistry Department, Faculty of Science, Alexandria University, Alexandria 21321, Egypt. Electronic address: eelashry60@hotmail.com.AwadLaila FathyLFChemistry Department, Faculty of Science, Alexandria University, Alexandria 21321, Egypt.TelebMohamedMDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt.IbrahimNihal AhmedNAChemistry Department, Faculty of Science, Alexandria University, Alexandria 21321, Egypt.Abu-SerieMarwa MMMMedical Biotechnology Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications (SRTA-City), Egypt.Abd Al MoatyMohamed NabilMNChemistry Department, Faculty of Science, Alexandria University, Alexandria 21321, Egypt. Electronic address: mohamednabil_sc_chem@yahoo.com.engJournal Article20200125
United StatesBioorg Chem13037030045-206801,2,4-triazolo(3,4-a)pyridine0Matrix Metalloproteinase Inhibitors0Pyridines0TriazolesEC 3.4.24.-MMP13 protein, humanEC 3.4.24.-Matrix Metalloproteinase 13EC 3.4.24.22MMP10 protein, humanEC 3.4.24.22Matrix Metalloproteinase 10IMCell Line, TumorDrug DesignDrug Screening Assays, AntitumorHumansMatrix Metalloproteinase 10metabolismMatrix Metalloproteinase 13metabolismMatrix Metalloproteinase InhibitorschemistrypharmacologyMolecular Docking SimulationNeoplasmsdrug therapymetabolismPolypharmacologyPyridineschemistrypharmacologyStructure-Activity RelationshipTriazoleschemistrypharmacologyAnticancerDimroth rearrangementMMP-10/13PolypharmacologyPyrimidineTriazolopyrimidine20191028202012020201222020286020212256020202860ppublish3203284710.1016/j.bioorg.2020.103616S0045-2068(19)31828-0trying2...
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Harnessing ROS-Induced Oxidative Stress for Halting Colorectal Cancer Thiazolidinedione-Based SOD Inhibitors.
Mohamed Nabil Abd Al Moaty El Sayed H El Ashry Laila Fathy Awad Asmaa Mostafa Marwa M Abu-Serie

ACS Omega

June 2022

Based on the "canonical" view of reactive oxygen species' (ROS) contribution to carcinogenesis, ROS induce oxidative stress and promote various tumor progression events. However, tumor cells also need to defend themselves against oxidative damage. This "heresy" was supported by several recent studies underlining the role of cellular antioxidant capacity in promoting metastasis and resistance to chemotherapy.

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Enhancing the Anticancer Potential of Targeting Tumor-Associated Metalloenzymes via VEGFR Inhibition by New Triazolo[4,3-]pyrimidinone Acyclo C-Nucleosides Multitarget Agents.
Mohamed Nabil Abd Al Moaty El Sayed Helmy El Ashry Laila Fathy Awad Nihal Ahmed Ibrahim Marwa Muhammad Abu-Serie

Molecules

April 2022

The role of metalloenzymes in tumor progression had broadened their application in cancer therapy. Of these, MMPs and CAs are validated druggable targets that share some pivotal signaling pathways. The majority of MMPs or CAs inhibitors are designed as single-target agents.

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Halting Tumor Progression via Novel Non-Hydroxamate Triazole-Based Mannich Bases MMP-2/9 Inhibitors; Design, Microwave-Assisted Synthesis, and Biological Evaluation.
Fawzia Faleh Albelwi Mohamed Teleb Marwa M Abu-Serie Mohamed Nabil Abd Al Moaty Mai S Alsubaie

Int J Mol Sci

September 2021

Matrix metalloproteinases (MMPs) are key signaling modulators in the tumor microenvironment. Among MMPs, MMP-2 and MMP-9 are receiving renewed interest as validated druggable targets for halting different tumor progression events. Over the last decades, a diverse range of MMP-2/9 inhibitors has been identified starting from the early hydroxamic acid-based peptidomimetics to the next generation non-hydroxamates.

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Structure-based design and optimization of pyrimidine- and 1,2,4-triazolo[4,3-a]pyrimidine-based matrix metalloproteinase-10/13 inhibitors via Dimroth rearrangement towards targeted polypharmacology.
El Sayed Helmy El Ashry Laila Fathy Awad Mohamed Teleb Nihal Ahmed Ibrahim Marwa M Abu-Serie Mohamed Nabil Abd Al Moaty

Bioorg Chem

March 2020

Recently, interest in matrix metalloproteinases (MMPs) -10 and -13 has been revitalized with the growing knowledge on their relevance within the MMPs network and significance of their inhibition for treatment of various diseases like arthritis, cancer, atherosclerosis and Alzheimer. Within this approach, dual MMP-10/13 inhibition was disclosed as new approach for targeted polypharmacology. While several efficient MMP-13 inhibitors are known, very few potent and selective MMP-10 inhibitors were reported.

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