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

Christina Nowikow; Rita Fuerst; Maria Kauderer; Christian Dank; Walther Schmid; Marian Hajduch; Jiri Rehulka; Sona Gurska; Olena Mokshyna; Pavel Polishchuk; István Zupkó; Petr Dzubak; Uwe Rinner

doi:10.1016/j.bmc.2019.07.048

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

Christina Nowikow, Rita Fuerst, Maria Kauderer, Christian Dank, Walther Schmid, Marian Hajduch, Jiri Rehulka, Sona Gurska, Olena Mokshyna, Pavel Polishchuk, István Zupkó, Petr Dzubak^*, Uwe Rinner

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

13 Citations (Scopus)

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.

Original language	English
Article number	115032
Journal	Bioorganic and Medicinal Chemistry
Volume	27
Issue number	19
DOIs	https://doi.org/10.1016/j.bmc.2019.07.048
Publication status	Published - Oct 1 2019
Externally published	Yes

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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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., & Rinner, U. (2019). Synthesis and biological evaluation of cis-restrained carbocyclic combretastatin A-4 analogs: Influence of the ring size and saturation on cytotoxic properties. Bioorganic and Medicinal Chemistry, 27(19), Article 115032. https://doi.org/10.1016/j.bmc.2019.07.048

Nowikow, C, Fuerst, R, Kauderer, M, Dank, C, Schmid, W, Hajduch, M, Rehulka, J, Gurska, S, Mokshyna, O, Polishchuk, P, Zupkó, I, Dzubak, P & Rinner, U 2019, 'Synthesis and biological evaluation of cis-restrained carbocyclic combretastatin A-4 analogs: Influence of the ring size and saturation on cytotoxic properties', Bioorganic and Medicinal Chemistry, vol. 27, no. 19, 115032. https://doi.org/10.1016/j.bmc.2019.07.048

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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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AU - Kauderer, Maria

AU - Dank, Christian

AU - Schmid, Walther

AU - Hajduch, Marian

AU - Rehulka, Jiri

AU - Gurska, Sona

AU - Mokshyna, Olena

AU - Polishchuk, Pavel

AU - Zupkó, István

AU - Dzubak, Petr

AU - Rinner, Uwe

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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

Abstract

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