2. Academic Validation
  3. Synthesis and biological evaluation of cis-restrained carbocyclic combretastatin A-4 analogs: Influence of the ring size and saturation on cytotoxic properties

Synthesis and biological evaluation of cis-restrained carbocyclic combretastatin A-4 analogs: Influence of the ring size and saturation on cytotoxic properties

  • Bioorg Med Chem. 2019 Oct 1;27(19):115032. doi: 10.1016/j.bmc.2019.07.048.
Christina Nowikow 1,  Rita Fuerst 2,  Maria Kauderer 1,  Christian Dank 1,  Walther Schmid 1,  Marian Hajduch 3,  Jiri Rehulka 3,  Sona Gurska 3,  Olena Mokshyna 3,  Pavel Polishchuk 3,  István Zupkó 4,  Petr Dzubak 5,  Uwe Rinner 6
Affiliations

Affiliations

  • 1 Institute of Organic Chemistry, University of Vienna, Währinger Straße 38, 1090 Vienna, Austria.
  • 2 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.
  • 3 Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University in Olomouc, Hnevotinska 5, Olomouc, Czech Republic.
  • 4 Department of Pharmacodynamics and Biopharmacy, University of Szeged, Eötvö u 6, 6720 Szeged, Hungary.
  • 5 Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University in Olomouc, Hnevotinska 5, Olomouc, Czech Republic. Electronic address: petr.dzubak@upol.cz.
  • 6 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. Electronic address: uwe.rinner@fh-krems.ac.at.
PMID: 31401010 DOI: 10.1016/j.bmc.2019.07.048
Abstract

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.

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