Open AccessStructure Optimization of Gatastatin for the Development of γ-Tubulin-Specific Inhibitor
Author(s) -
Kana Shintani,
Haruna Ebisu,
Minagi Mukaiyama,
Taisei Hatanaka,
Takumi Chinen,
Daisuke Takao,
Yoko Nagumo,
Akira Sakakura,
Ichiro Hayakawa,
Takeo Usui
Publication year - 2020
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.9b00526
Subject(s) - tubulin , moiety , cytotoxicity , stereochemistry , microtubule , chemistry , ring (chemistry) , biochemistry , biology , microbiology and biotechnology , in vitro , organic chemistry
Gatastatin ( O 7 -benzyl glaziovianin A) is a γ-tubulin-specific inhibitor that is used to investigate γ-tubulin function in cells. We have previously reported that the unsubstituted phenyl ring of the O 7 -benzyl group in gatastatin is important for γ-tubulin inhibition. To obtain further structural information regarding γ-tubulin inhibition, we synthesized several gatastatin derivatives containing a fixed O 7 -benzyl moiety. Modifications of the B-ring resulted in drastic decrease in cytotoxicity, abnormal spindle formation activity, and inhibition of microtubule (MT) nucleation. In contrast, various O 6 -alkylated gatastatin derivatives showed potent cytotoxicity, induced abnormal spindle formation, and inhibited MT nucleation. We had previously reported that O 6 -benzyl glaziovianin A is a potent α/β-tubulin inhibitor; thus, these new results suggest that the O 6 -position restricts affinity for α/β- and γ-tubulin. Considering that an O 7 -benzyl group increases specificity for γ-tubulin, more potent and specific γ-tubulin inhibitors can be generated through O 6 -modifications of gatastatin.