Structure Optimization of Gatastatin for the Development of γ-Tubulin-Specific Inhibitor
- Kana ShintaniKana ShintaniGraduate School, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8571, JapanMore by Kana Shintani,
- Haruna EbisuHaruna EbisuGraduate School, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8571, JapanMore by Haruna Ebisu,
- Minagi MukaiyamaMinagi MukaiyamaGraduate School, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8571, JapanMore by Minagi Mukaiyama,
- Taisei HatanakaTaisei HatanakaDivision of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, JapanMore by Taisei Hatanaka,
- Takumi ChinenTakumi ChinenGraduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo, Tokyo 113-0033, JapanMore by Takumi Chinen,
- Daisuke TakaoDaisuke TakaoGraduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo, Tokyo 113-0033, JapanMore by Daisuke Takao,
- Yoko NagumoYoko NagumoFaculty of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8571, JapanMore by Yoko Nagumo,
- Akira SakakuraAkira SakakuraDivision of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, JapanMore by Akira Sakakura,
- Ichiro Hayakawa*Ichiro Hayakawa*Phone +81 3 5317 9363. Email: [email protected] (Chemistry).Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, JapanMore by Ichiro Hayakawa, and
- Takeo Usui*Takeo Usui*Phone +81 29 853 6629. Email: [email protected] (Biology).Faculty of Life and Environmental Sciences, Microbiology Research Center for Sustainability, , University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8571, JapanMore by Takeo Usui
Abstract
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.
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- Haruna Ebisu, Kana Shintani, Takumi Chinen, Yoko Nagumo, Shuya Shioda, Taisei Hatanaka, Akira Sakakura, Ichiro Hayakawa, Hideo Kigoshi, Takeo Usui. Dual Inhibition of γ-Tubulin and Plk1 Induces Mitotic Cell Death. Frontiers in Pharmacology 2021, 11 https://doi.org/10.3389/fphar.2020.620185