Combretastatin A-4 (CA-4) is a highly cytotoxic natural product and several derivatives have been prepared which underwent clinical trial. These investigations revealed that the cis-stilbene moiety of the natural product is prone to undergo cis/trans isomerization under physiological conditions, reducing the overall activity of the drug candidates. 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 their cytotoxic properties and their ability to inhibit tubulin polymerization. Biological data, supported by molecular docking studies, identified cyclobutenyl and cyclobutyl derivatives of the natural product as highly promising drug candidates.

Department of Pharmacodynamics and Biopharmacy University of Szeged Eötvö u 6 6720 Szeged Hungary

Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry Palacky University in Olomouc Hnevotinska 5 Olomouc Czech Republic

Institute of Organic Chemistry University of Vienna Währinger Straße 38 1090 Vienna Austria

Institute of Organic Chemistry University of Vienna Währinger Straße 38 1090 Vienna Austria; Department of Life Sciences University of Applied Sciences Krems Piaristengasse 1 3500 Krems Austria

Institute of Organic Chemistry University of Vienna Währinger Straße 38 1090 Vienna Austria; Institute of Organic Chemistry Graz University of Technology Stremayrgasse 9 8010 Graz Austria

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