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

被引：39

作者：

Hayashi, Yoshiki ^{[1
]}

Takeno, Haruka ^{[1
]}

Chinen, Takumi ^{[2
]}

Muguruma, Kyohei ^{[1
]}

Okuyama, Kohei ^{[3
,4
]}

Taguchi, Akihiro ^{[1
]}

Takayama, Kentaro ^{[1
]}

Yakushiji, Fumika ^{[1
]}

Miura, Masahiko ^{[3
]}

Usui, Takeo ^{[2
]}

Hayashi, Yoshio ^{[1
]}

机构：

[1] Tokyo Univ Pharm & Life Sci, Dept Med Chem, Hachioji, Tokyo 1920392, Japan

[2] Univ Tsukuba, Grad Sch Life & Environm Sci, Tsukuba, Ibaraki 3058572, Japan

[3] Tokyo Med & Dent Univ, Grad Sch Med & Dent Sci, Dept Oral Hlth Sci, Sect Oral Radiat Oncol,Bunkyo Ku, Tokyo 1138549, Japan

[4] Tokyo Med & Dent Univ, Grad Sch Med & Dent Sci, Dept Maxillofacial & Neck Reconstruct, Sect Maxillofacial Surg,Bunkyo Ku, Tokyo 1138549, Japan

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2014年 / 5卷 / 10期

基金：

日本学术振兴会;

关键词：

Cyclic dipeptide; diketopiperazine; antimicrotubule agent; anticancer; PHENYLAHISTIN DERIVATIVES; BINDING; TUBULIN; (-)-PHENYLAHISTIN; COLCHICINE;

D O I：

10.1021/ml5001883

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A new benzophenone-diketopiperazine-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 mu M) and inducing microtubule depolymerization.

引用

页码：1094 / 1098

页数：5

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