Discovery of O6-benzyl glaziovianin A, a potent cytotoxic substance and a potent inhibitor of α,β-tubulin polymerization

  • Bioorg Med Chem. 2016 Nov 1;24(21):5639-5645. doi: 10.1016/j.bmc.2016.09.026.
Ichiro Hayakawa  1 ,  Shuya Shioda  2 ,  Takumi Chinen  3 ,  Taisei Hatanaka  4 ,  Haruna Ebisu  3 ,  Akira Sakakura  4 ,  Takeo Usui  5 ,  Hideo Kigoshi  6
Affiliations
  • 1. Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan. Electronic address: [email protected].
  • 2. Department of Chemistry, Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8571, Japan.
  • 3. Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8572, Japan.
  • 4. Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan.
  • 5. Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8572, Japan. Electronic address: [email protected].
  • 6. Department of Chemistry, Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8571, Japan. Electronic address: [email protected].
PMID: 27665177 DOI: 10.1016/j.bmc.2016.09.026
Abstract

We have discovered O6-benzyl glaziovianin A, which showed stronger inhibition of microtubule polymerization (IC50=2.1μM) than known α,β-tubulin inhibitors, such as colchicine and glaziovianin A. Also, we performed competition binding experiments of O6-benzyl glaziovianin A and revealed that O6-benzyl glaziovianin A binds to the colchicine binding site with high affinity. It is interesting that glaziovianin A derivatives change their mode of action in benzylation at the O6 (α,β-tubulin inhibitor) or O7 (γ-tubulin-specific inhibitor) position.

Keywords
Cytotoxicity; O(6)-Benzyl glaziovianin A; Structure–activity relationship study; α,β-Tubulin inhibitor.