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

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

  • Bioorg Med Chem Lett. 2014 Aug 15;24(16):3961-3. doi: 10.1016/j.bmcl.2014.06.034.
Junichiro Yamamoto 1,  Nobuyoshi Amishiro 2,  Kazuhiko Kato 2,  Yoshihisa Ohta 2,  Yoji Ino 2,  Mitsuharu Araki 2,  Tetsuya Tsujita 2,  Seiho Okamoto 2,  Takeshi Takahashi 2,  Hideaki Kusaka 2,  Shiro Akinaga 2,  Yoshinori Yamashita 2,  Ryuichiro Nakai 2,  Chikara Murakata 2
Affiliations

Affiliations

  • 1 Fuji Research Park, Research Division, Kyowa Hakko Kirin Co., Ltd, 1188 Shimotogari, Nagaizumi-cho, Suntou-gun, Shizuoka 411-8731, Japan. Electronic address: junichiro.yamamoto@kyowa-kirin.co.jp.
  • 2 Fuji Research Park, Research Division, Kyowa Hakko Kirin Co., Ltd, 1188 Shimotogari, Nagaizumi-cho, Suntou-gun, Shizuoka 411-8731, Japan.
PMID: 25001485 DOI: 10.1016/j.bmcl.2014.06.034
Abstract

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.

Keywords

Mitotic kinesin Eg5 inhibitor; Thiadiazoline derivatives.

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