TY - JOUR
T1 - Structure Optimization of Gatastatin for the Development of γ-Tubulin-Specific Inhibitor
AU - Shintani, Kana
AU - Ebisu, Haruna
AU - Mukaiyama, Minagi
AU - Hatanaka, Taisei
AU - Chinen, Takumi
AU - Takao, Daisuke
AU - Nagumo, Yoko
AU - Sakakura, Akira
AU - Hayakawa, Ichiro
AU - Usui, Takeo
AU - Usui, Takeo
PY - 2020/6/11
Y1 - 2020/6/11
N2 - Gatastatin (O7-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 O7-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 O7-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 O6-alkylated gatastatin derivatives showed potent cytotoxicity, induced abnormal spindle formation, and inhibited MT nucleation. We had previously reported that O6-benzyl glaziovianin A is a potent α/β-tubulin inhibitor; thus, these new results suggest that the O6-position restricts affinity for α/β- and γ-tubulin. Considering that an O7-benzyl group increases specificity for γ-tubulin, more potent and specific γ-tubulin inhibitors can be generated through O6-modifications of gatastatin.
AB - Gatastatin (O7-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 O7-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 O7-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 O6-alkylated gatastatin derivatives showed potent cytotoxicity, induced abnormal spindle formation, and inhibited MT nucleation. We had previously reported that O6-benzyl glaziovianin A is a potent α/β-tubulin inhibitor; thus, these new results suggest that the O6-position restricts affinity for α/β- and γ-tubulin. Considering that an O7-benzyl group increases specificity for γ-tubulin, more potent and specific γ-tubulin inhibitors can be generated through O6-modifications of gatastatin.
KW - microtubule nucleation
KW - spindle
KW - structure-activity relationships
KW - γ-Tubulin
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U2 - 10.1021/acsmedchemlett.9b00526
DO - 10.1021/acsmedchemlett.9b00526
M3 - Article
AN - SCOPUS:85087152705
VL - 11
SP - 1125
EP - 1129
JO - ACS Medicinal Chemistry Letters
JF - ACS Medicinal Chemistry Letters
SN - 1948-5875
IS - 6
ER -