title: Quantum chemistry calculation-aided structural optimization of combretastatin A-4-like tubulin polymerization inhibitors: improved stability and biological activity.
abstract: A potent combretastatin A-4 (CA-4) like tubulin polymerization inhibitor 22b was found with strong antitumor activity previously. However, it easily undergoes cis-trans isomerization under natural light, and the resulting decrease in activity limits its further applications. In this study, we used quantum chemistry calculations to explore the molecular basis of its instability. Aided by the calculations, two rounds of structural optimization of 22b were conducted. Accelerated quantitative light stability testing confirmed that the stability of these designed compounds was significantly improved as predicted. Among them, compounds 1 and 3b displayed more potent inhibitory activity on tumor cell growth than 22b. In addition, the potent in vivo antitumor activity of compound 1 was confirmed. Quantum chemistry calculations were used in the optimization of stilbene-like molecules, providing new insight into stilbenoid optimization and important implications for the future development of novel CA-4-like tubulin polymerization inhibitors.
authors.affiliation: School of Pharmacy, Second Military Medical University , Shanghai 200433, China.
authors.forename: Junhang
authors.initials: J
authors.lastname: Jiang
authors.forename: Canhui
authors.initials: C
authors.lastname: Zheng
authors.forename: Kongkai
authors.initials: K
authors.lastname: Zhu
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.forename: Nannan
authors.initials: N
authors.lastname: Sun
authors.forename: Chongqing
authors.initials: C
authors.lastname: Wang
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.forename: Ju
authors.initials: J
authors.lastname: Zhu
authors.forename: Cheng
authors.initials: C
authors.lastname: Luo
authors.forename: Youjun
authors.initials: Y
authors.lastname: Zhou
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011789:Quantum Theory; D013267:Stilbenes / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000737:chemistry* / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D013267:Stilbenes; D014404:Tubulin; D050257:Tubulin Modulators; C058728:fosbretabulin