Development of a New Benzophenone鈥揇iketopiperazine-Type Potent Antimicrotubule Agent Possessing a 2-Pyridine Structure

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• 作者：Yoshiki Hayashi ; Haruka Takeno ; Takumi Chinen ; Kyohei Muguruma ; Kohei Okuyama ; Akihiro Taguchi ; Kentaro Takayama ; Fumika Yakushiji ; Masahiko Miura ; Takeo Usui ; Yoshio Hayashi
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2014
• 出版时间：October 9, 2014
• 年：2014
• 卷：5
• 期：10
• 页码：1094-1098
• 全文大小：308K
• ISSN：1948-5875

文摘

A new benzophenone鈥揹iketopiperazine-type potent antimicrotubule agent was developed by modifying the structure of the clinical candidate plinabulin (1). Although the right-hand imidazole ring with a branched alkyl chain at the 5-position in 1 was critical for the potency of the antimicrotubule activity, we successfully substituted this moiety with a simpler 2-pyridyl structure by converting the left-hand ring from a phenyl to a benzophenone structure without decreasing the potency. The resultant compound 6b (KPU-300) exhibited a potent cytotoxicity, with an IC₅₀ value of 7.0 nM against HT-29 cells, by strongly binding to tubulin (K_d = 1.3 渭M) and inducing microtubule depolymerization.

Keywords:

Cyclic dipeptide; diketopiperazine; antimicrotubule agent; anticancer