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Paper | Special issue | Vol 99, No. 1, 2019, pp.238-247
Published online, 20th July, 2018
DOI: 10.3987/COM-18-S(F)16
Structure–Activity Relationship Study of Gatastatin Based on the Topliss Tree Approach

Ichiro Hayakawa,* Shuya Shioda, Takumi Chinen, Takeo Usui, and Hideo Kigoshi*

*Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima-naka, Okayama 700-8530, Japan


Various analogues of gatastatin, a γ-tubulin-specific inhibitor, were designed and synthesized by systematically optimizing the aromatic ring at the O7-benzyl group in accordance with an operational Topliss tree, and their biological activities were evaluated. Some derivatives showed stronger cytotoxicity against HeLa cells than gatastatin. Especially, the cytotoxicity of the meta-chloro derivative was about 18-fold stronger than that of gatastatin. However, these derivatives did not exhibit binding ability to the yeast γ-tubulin small complex or inhibitory activity against α,β-tubulin polymerization. These results suggested that γ-tubulin strongly recognized the unsubstituted phenyl ring of the O7-benzyl group in gatastatin.