Synthesis and biological evaluation of pyrimidine bridged combretastatin derivatives as potential anticancer agents and mechanistic studies |
| |
| Affiliation: | 1. Laboratory of Organic and Medicinal Chemistry, Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda, Punjab 151001, India;2. Laboratory of Molecular Medicine, Department of Human Genetics and Molecular Medicines, Central University of Punjab, Bathinda, Punjab 151001, India;3. Department of Experimental Medicine and Biotechnology, PGIMER, Chandigarh 160012, India;1. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt;2. Department of Pharmaceutical Chemistry, College of Pharmacy, Aljouf University, Aljouf 2014, Saudi Arabia;3. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt;1. Department of Toxicology, School of Public Health, Hebei Medical University, Shijiazhuang 050017, China;2. Department of Medicinal Chemistry, School of Pharmacy, Hebei Medical University, Shijiazhuang 050017, China;3. Institute of Chinese Integrative Medicine, Hebei Medical University, Shijiazhuang 050017, China;1. Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, 11561, Cairo, Egypt;2. Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), Giza, Egypt;3. Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy and Drug Manufacturing, Misr University for Science and Technology, Giza, Egypt;1. Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Science, Southern Medical University, Guangzhou 510515, PR China;2. Department of Medicinal Chemistry, Institute for Therapeutics Discovery and Development, College of Pharmacy, University of Minnesota, Minneapolis 55414, United States |
| |
| Abstract: | A number of pyrimidine bridged combretastatin derivatives were designed, synthesized and evaluated for anticancer activities against breast cancer (MCF-7) and lung cancer (A549) cell lines using MTT assays. Most of the synthesized compounds displayed good anticancer activity with IC50 values in low micro-molar range. Compounds 4a and 4p were found most potent in the series with IC50 values of 4.67 µM & 3.38 µM and 4.63 µM & 3.71 µM against MCF7 and A549 cancer cell lines, respectively. Biological evaluation of these compounds showed that selective cancer cell toxicity (in vitro using human lung and breast cancer cell lines) might be due to the inhibition of antioxidant enzymes instigating elevated ROS levels which triggers intrinsic apoptotic pathways. These compounds were found nontoxic to the normal human primary cells. Compound 4a, was found to be competitive inhibitor of colchicine and in the tubulin binding assay it showed tubulin polymerization inhibition potential comparable to colchicine. The molecular modeling studies also showed that the synthesized compounds fit well in the colchicine-binding pocket. |
| |
| Keywords: | Pyrimidine Combretastatin derivatives Apoptosis Tubulin inhibitors Colchicine binding site Anticancer |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
