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Synthesis and biological evaluation of cis-restrained carbocyclic combretastatin A-4 analogs: Influence of the ring size and saturation on cytotoxic properties
C. Nowikow, R. Fuerst, M. Kauderer, C. Dank, W. Schmid, M. Hajduch, J. Rehulka, S. Gurska, O. Mokshyna, P. Polishchuk, I. Zupkó, P. Dzubak, U. Rinner,
Language English Country Great Britain
Document type Journal Article, Research Support, Non-U.S. Gov't
Grant support
NV15-31984A
MZ0
CEP Register
- MeSH
- G2 Phase Cell Cycle Checkpoints drug effects MeSH
- Humans MeSH
- Tubulin Modulators chemical synthesis metabolism pharmacology MeSH
- Molecular Structure MeSH
- Cell Line, Tumor MeSH
- Antineoplastic Agents chemical synthesis metabolism pharmacology MeSH
- Drug Screening Assays, Antitumor MeSH
- Molecular Docking Simulation MeSH
- Stilbenes chemical synthesis metabolism pharmacology MeSH
- Tubulin metabolism MeSH
- Protein Binding MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
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 Life Sciences University of Applied Sciences Krems Piaristengasse 1 3500 Krems Austria
Department of Pharmacodynamics and Biopharmacy University of Szeged Eötvö u 6 6720 Szeged Hungary
Institute of Organic Chemistry Graz University of Technology Stremayrgasse 9 8010 Graz Austria
Institute of Organic Chemistry University of Vienna Währinger Straße 38 1090 Vienna Austria
References provided by Crossref.org
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- $a 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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