Design,synthesis, anticancer evaluation and docking studies of new pyrimidine derivatives as potent thymidylate synthase inhibitors |
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| Institution: | 1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy (girls), Al-Azhar University, Nasr City, Cairo, Egypt;2. Department of Organic Chemistry, Faculty of Science, Ain Shams University, Abbassia, 11566 Cairo, Egypt;1. Department of Pharmaceutical Chemistry, L. M. College of Pharmacy, Navrangpura, Ahmedabad, 380009 Gujarat, India;2. Department of Pharmacy, Dharmsinh Desai University, Nadiad, 387001 Gujarat, India;3. Division of Biological and Life Sciences, Ahmedabad University, Ahmedabad, 380009 Gujarat, India;4. Department of Pharmaceutical Chemistry, L. J. Institute of Pharmacy, Ahmedabad, 382210 Gujarat, India;1. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr Elini St., Cairo 11562, Egypt;2. Pharmaceutical Chemistry Department, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), Giza, Egypt;3. Biochemistry Department, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), Giza, Egypt;4. Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, 12578 Cairo, Egypt;1. Chemistry Department, Faculty of Science, Ain Shams University, Abbassia, Cairo 11566, Egypt;2. Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia;2. Department of Medicinal Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt;3. Sharjah Institute for Medical Research and College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates;4. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt;5. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia;6. Department of Pharmacology, Medicinal and Aromatic Plants Research Institute, National Center for Research, Khartoum 2404, Sudan;7. Department of Pharmaceutics, Faculty of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia;8. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Helwan University, Cairo, Egypt;9. Rangel College of Pharmacy, Health Science Center, Texas A&M University, Kingsville, TX 78363, United States |
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| Abstract: | Cancer is a perplexing and challenging problem for researchers. In this study, a series of 6-aryl-5-cyano-pyrimidine derivatives were designed, synthesized and evaluated for their anticancer activity against HePG-2, MCF-7 and HCT-116 cell lines. Compounds 2, 3d, 4a-c, 5, 8 and 12 displayed high anticancer activity, comparable to that of 5-fluorouracil. Additionally, those compounds with effective anticancer activity were further assessed for their ability to inhibit thymidylate synthase (TS) enzyme. All the tested compounds demonstrated a marked TS inhibitory activity (33.66–74.98%), with IC50 ranging from 3.89 to 15.74 nM. Moreover, apoptosis studies were conducted on the most potent compound 8, to evaluate its proapoptotic potential. Interestingly, compound 8 induced the level of active caspase 3, and elevated the Bax/Bcl2 ratio 44 folds in comparison to the control. Finally, a molecular docking study was conducted to detect the probable interaction between the active compounds and the thymidylate synthase active site. |
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| Keywords: | Anticancer Thymidylate synthase Pyrimidine Docking Apoptosis |
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