Synthetic studies on mitotic kinesin Eg5 inhibitors: Synthesis and structure-activity relationships of novel 2,4,5-substituted-1,3,4-thiadiazoline derivatives

被引：8

作者：

Yamamoto, Junichiro ^{[1
]}

Amishiro, Nobuyoshi ^{[1
]}

Kato, Kazuhiko ^{[1
]}

Ohta, Yoshihisa ^{[1
]}

Ino, Yoji ^{[1
]}

Araki, Mitsuharu ^{[1
]}

Tsujita, Tetsuya ^{[1
]}

Okamoto, Seiho ^{[1
]}

Takahashi, Takeshi ^{[1
]}

Kusaka, Hideaki ^{[1
]}

Akinaga, Shiro ^{[1
]}

Yamashita, Yoshinori ^{[1
]}

Nakai, Ryuichiro ^{[1
]}

Murakata, Chikara ^{[1
]}

机构：

[1] Kyowa Hakko Kirin Co Ltd, Div Res, Nagaizumi, Shizuoka 4118731, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2014年 / 24卷 / 16期

关键词：

Mitotic kinesin Eg5 inhibitor; Thiadiazoline derivatives;

D O I：

10.1016/j.bmcl.2014.06.034

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The 2,4,5-substituted-1,3,4-thiadiazoline derivative 1a has been identified as a new class of mitotic kinesin Eg5 inhibitor. With the aim of enhancement of the mitotic phase accumulation activity, structure optimization of side chains at the 2-, 4-, and 5-positions of the 1,3,4-thiadiazoline ring of 1a was performed. The introduction of sulfonylamino group at the side chain at the 5-position and bulky acyl group at the 2- and 4-position contributed to a significant increase in the mitotic phase accumulation activity and Eg5 inhibitory activity. As a result, a series of optically active compounds exhibited an increased antitumor activity in a human ovarian cancer xenograft mouse model that was induced by oral administration. (C) 2014 Elsevier Ltd. All rights reserved.

引用

页码：3961 / 3963

页数：3