Design, Synthesis and Cytotoxicity Evaluation of New 3, 5-Disubstituted-2-Thioxoimidazolidinones

作者：Abdellatif Khaled R A; Elbadawi Mostafa M; Elsaady Mohammed T; Abd El Hafeez Amer A; Fujimura Takashi; Kawamoto Seiji; Khodair Ahmed I

来源：Anti-Cancer Agents in Medicinal Chemistry, 2018, 18(4): 573-582.

DOI：10.2174/1871520618666171129213838

• 2-Thioxoimidazolidinone
• mannich reaction
• prostate cancer
• breast cancer
• topoisomerase I
• synthesis

Background: Some 2-thioxoimidazolidinones have been reported as anti-prostate and anti-breast cancer agents through their inhibitory activity on topoisomerase I that is considered as a potential chemotherapeutic target.
Objective: A new series of 3,5-disubstituted-2-thioxoimidazolidinone derivatives 10a-f and their S-methyl analogs 11a-f were designed, synthesized and evaluated for cytotoxicity against human prostate cancer cell line (PC-3), human breast cancer cell line (MCF-7) and non-cancerous human lung fibroblast cell line (WI-38).
Results and Method: While compounds 10a-f showed a broad range of activities against PC-3 and MCF-7 cell lines (IC50 = 34.0 - 186.9 and 24.6 - 147.5 mu M respectively), the S-methyl analogs 11a-f showed (IC50 = 22.7 - 198.5 and 16.9 - 188.2 mu M respectively) in comparison with 5-fluorouracil (IC50 = 60.7 and 40.7 mu M respectively). 11c (IC50 = 22.7 and 29.2 mu M) and 11f (IC50 = 28.7 and 16.9 mu M) were the most potent among all compounds against both PC-3 and MCF-7 respectively with no cytotoxicity against WI-38.
Conclusion: The newly synthesized compounds showed good activity against PC-3 and MCF-7 cell lines in comparison with 5-fluorouracil. Compounds 11c and 11f bound with human topoisomerase I similar to its known inhibitors and significantly inhibited its DNA relaxation activity in a dose dependent manner which may rationalize their molecular mechanism as cytotoxic agents.

• 出版日期2018