Design,synthesis and biological evaluation of novel 1,3,4-trisubstituted pyrazole derivatives as potential chemotherapeutic agents for hepatocellular carcinoma |
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| Institution: | 1. Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt;2. Pharmaceutical Sciences Department, Ibn Sina National College for Medical Studies, Jeddah 21418, Saudi Arabia;3. Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Assiut 71524, Egypt;4. Biochemistry Department, Cairo General Hospital, Cairo, Egypt;5. Pharmacology Department, Faculty of Veterinary, Cairo University, Cairo, Egypt;1. Drug Design and Medicinal Chemistry Lab, Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research (Formerly Faculty of Pharmacy), Jamia Hamdard, New Delhi 110062, India;2. Cancer Pharmacology Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu 180001, India;3. Natural Product Chemistry Division, Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India;4. Department of Flow Chemistry GP&T, R&D II, Sun Pharmaceutical Industries Ltd., Gurugram, Haryana, India;1. Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India;2. IICT – RMIT Research Centre, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India;3. Ian Potter NanoBioSensing Facility, NanoBiotechnology Research Laboratory, School of Applied Sciences, RMIT University, Melbourne 3000, Australia;4. Health Innovations Research Institute, RMIT University, Melbourne 3083, Australia;5. Centre for Advanced Materials and Industrial Chemistry, RMIT University, Melbourne 3000, Australia;1. Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 007, India;2. IICT-RMIT Research Centre, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 007, India;3. Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, 500 037, India;4. Catalytic Chemistry Research Chair, Chemistry Department, College of Science, King Saud University, Riyadh, 11451, Saudi Arabia;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, Istanbul, Turkey;2. Department of Biochemistry, School of Medicine, Aydin Adnan Menderes University, Ayd?n, Turkey |
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| Abstract: | A series of novel 1,3,4-trisubstituted pyrazole derivatives were synthesized and evaluated for their cytotoxic activity against three different cancer cell lines namely HCT116, UO-31 and HepG2. Compounds 3b, 3d, 7b and 9 showed excellent anticancer activity against all the tested cancer cell lines and had better cytotoxic activities than the reference drug, Sorafenib. Therefore, these compounds were chosen to be further evaluated in a panel of HCC cell lines. Among them, 3b and 7b were the most active compounds against HCC cells used here. Further studies on the mechanism demonstrated that 3b and 7b induced apoptosis in addition to induction of cell cycle arrest at G2/M phase in HepG2 and Huh7 cells. Consistent with these results, caspase-3 assay was done and the results revealed that the pro-apoptotic activity of the target compounds could be due to the stimulation of caspases-3. In addition, CDK1 inhibition assay was done and it was found that compounds 3b and 7b inhibited CDK1 activities with IC50 values of 2.38 and 1.52 µM, respectively. Finally, pyrazole derivatives 3b and 7b showed potent bioactivities, indicating that these compounds could be potent anticancer drugs in the future. |
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| Keywords: | Pyrazoles Synthesis Hepatocellular carcinoma Cell cycle Apoptosis CDK1 inhibition |
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