Abstract
Abstract Combretastatins originally isolated from the South African willow tree Combretum cafrum are highly cytotoxic natural products, but their use is limited because of the cis/trans isomerization of the cis-stilbene moiety under physiological conditions. Herein we report the preparation of cis-restrained carbocyclic analogs of CA-4. The compounds, which differ by the size and hybridization of the carbocyclic ring have been evaluated for cytotoxic activity in vitro against a panel of human cancer and two non-tumor fibroblast cell lines and for their ability to inhibit tubulin polymerization. Biological data, supported by molecular docking studies, identified a cyclobutenyl derivative of the natural product as a promising drug candidate with selective nanomolar cytotoxic activity towards cancer cell lines, showing high potency against multidrug-resistant cells and inhibiting tubulin polymerization. This work was supported by Ministry of Health of the Czech Republic (15-31984A), internal grant of Palacky University (IGA_LF_2017_026) and by the Czech Ministry of Education, Youth and Sports LO1304, CZ-OPENSCREEN, (LM2015063) and EATRIS (LM2015064). Citation Format: Petr Dzubak, Jiři Rehulka, Sona Gurska, Uwe Riener, Marian Hajduch. Combretastatins as highly cytotoxic natural compounds [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2805.
Published Version
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