1. Synthesis and biological evaluation of cis-restrained carbocyclic combretastatin A-4 analogs: Influence of the ring size and saturation on cytotoxic properties.
- Author
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Nowikow C, Fuerst R, Kauderer M, Dank C, Schmid W, Hajduch M, Rehulka J, Gurska S, Mokshyna O, Polishchuk P, Zupkó I, Dzubak P, and Rinner U
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents metabolism, Cell Line, Tumor, Drug Screening Assays, Antitumor, G2 Phase Cell Cycle Checkpoints drug effects, Humans, Molecular Docking Simulation, Molecular Structure, Protein Binding, Stilbenes chemical synthesis, Stilbenes metabolism, Tubulin metabolism, Tubulin Modulators chemical synthesis, Tubulin Modulators metabolism, Tubulin Modulators pharmacology, Antineoplastic Agents pharmacology, Stilbenes pharmacology
- 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., (Copyright © 2019 Elsevier Ltd. All rights reserved.)
- Published
- 2019
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