Synthesis and Evaluation of Analogues of N-Phthaloyl-l-tryptophan (RG108) as Inhibitors of DNA Methyltransferase 1
详细信息 查看全文
- 作者：Saadia Asgatay ; Christine Champion ; Ga?l Marloie ; Thierry Drujon ; Catherine Senamaud-Beaufort ; Alexandre Ceccaldi ; Alexandre Erdmann ; Arumugam Rajavelu ; Philippe Schambel ; Albert Jeltsch ; Olivier Lequin ; Philippe Karoyan ; Paola B. Arimondo ; Dominique Guianvarc’h
- 刊名：Journal of Medicinal Chemistry
- 出版年：2014
- 出版时间：January 23, 2014
- 年：2014
- 卷：57
- 期：2
- 页码：421-434
- 全文大小：599K
- ISSN：1520-4804
文摘
DNA methyltransferases (DNMT) are promising drug targets in cancer provided that new, more specific, and chemically stable inhibitors are discovered. Among the non-nucleoside DNMT inhibitors, N-phthaloyl-l-tryptophan 1 (RG108) was first identified as inhibitor of DNMT1. Here, 1 analogues were synthesized to understand its interaction with DNMT. The indole, carboxylate, and phthalimide moieties were modified. Homologated and conformationally constrained analogues were prepared. The latter were synthesized from prolinohomotryptophan derivatives through a methodology based amino鈥搝inc鈥揺ne鈥揺nolate cyclization. All compounds were tested for their ability to inhibit DNMT1 in vitro. Among them, constrained compounds 16鈥?b>18 and NPys derivatives 10鈥?b>11 were found to be at least 10-fold more potent than the reference compound. The cytotoxicity on the tumor DU145 cell line of the most potent inhibitors was correlated to their inhibitory potency. Finally, docking studies were conducted in order to understand their binding mode. This study provides insights for the design of the next-generation of DNMT inhibitors.