期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 11, 期 6, 页码 1125-1129出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.9b00526
关键词
gamma-Tubulin; structure-activity relationships; microtubule nucleation; spindle
资金
- JSPS KAKENHI [JP16K07710, JP17K01949]
- Okayama Foundation for Science and Technology
Gatastatin (O-7-benzyl glaziovianin A) is a gamma-tubulin-specific inhibitor that is used to investigate gamma-tubulin function in cells. We have previously reported that the unsubstituted phenyl ring of the O-7-benzyl group in gatastatin is important for gamma-tubulin inhibition. To obtain further structural information regarding gamma-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 alpha/beta-tubulin inhibitor; thus, these new results suggest that the O-6-position restricts affinity for alpha/beta- and gamma-tubulin. Considering that an O-7-benzyl group increases specificity for gamma-tubulin, more potent and specific gamma-tubulin inhibitors can be generated through O-6-modifications of gatastatin.
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