Structure Optimization of Gatastatin for the Development of γ-Tubulin-Specific Inhibitor

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.