Novel [1,2,4]triazolo[1,5-a]pyrimidine derivatives as potent antitubulin agents: Design,multicomponent synthesis and antiproliferative activities |
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| Institution: | 1. Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Science, Southern Medical University, Guangzhou 510515, PR China;2. Department of Microbiology, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou 510515, PR China;1. M. I. Platov South-Russian State Polytechnic University, 346428 Novocherkassk, Russian Federation;2. A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 119991 Moscow, Russian Federation;1. Department of Biology, Faculty of Science, University of Guilan, Rasht, Iran;2. Department of Chemistry, Faculty of Science, Imam Khomeini International University, Qazvin, Iran;1. School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China;2. State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, 210023, Jiangsu, China;3. Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Zhengzhou, 450001, China;4. Co-Innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University, Zhengzhou, 450001, China;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 and Institute for Therapeutics Discovery and Development, College of Pharmacy, University of Minnesota, Minneapolis 55414, United States;1. Pharmaceutical Sciences Research Center, Student Research Committee, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran;2. Department of Toxicology and Pharmacology, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran;3. Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences (SBMU), Tehran, Iran;4. Department of Medicinal Chemistry and Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran |
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| Abstract: | As restricted CA-4 analogues, a novel series of 1,2,4]triazolo1,5-a]pyrimidines possessing 3,4,5-trimethoxylphenyl groups has been achieved successfully via an efficient one-pot three-component reaction of 3-(3,4,5-trimethoxyphenyl)-1H-1,2,4-triazol-5-amine, 1,3-dicarbonyl compounds and aldehydes. Initial biological evaluation demonstrated some of target compounds displayed potent antitumor activity in vitro against three cancer cell lines. Among them, the most highly active analogue 26 inhibited the growth of HeLa, and A549 cell lines with IC50 values at 0.75, and 1.02 μM, respectively, indicating excellent selectivity over non-tumoural cell line HEK-293 (IC50 = 29.94 μM) which suggested that the target compounds might possess a high safety index. Moreover, cell cycle analysis illustrated that the analogue 26 significantly induced HeLa cells arrest in G2/M phase, meanwhile the compound could dramatically affect cell morphology and microtubule networks. In addition, compound 28 exhibited potent anti-tubulin activity with IC50 values of 9.90 μM, and molecular docking studies revealed the analogue occupied the colchicine-binding site of tubulin. These observations suggest that 1,2,4]triazolo1,5-a]pyrimidines represent a new class of tubulin polymerization inhibitors and well worth further investigation aiming to generate potential anticancer agents. |
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| Keywords: | Microtubules Antiproliferative activity Tubulin polymerization |
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