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 Fürst; Maria Kauderer; Christian Dank; Walther Schmid; Marian Hajduch; Jiri Rehulka; Sona Gurska; Olena Mokshyna; Pavel Polishchuk; Istvan Zupko; 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 Fürst, Maria Kauderer, Christian Dank, Walther Schmid, Marian Hajduch, Jiri Rehulka, Sona Gurska, Olena Mokshyna, Pavel Polishchuk, Istvan Zupko, Petr Dzubak^*, Uwe Rinner^*

^*Korrespondierende/r Autor/-in für diese Arbeit

Institut für Organische Chemie (6410)

Publikation: Beitrag in einer Fachzeitschrift › Artikel › Begutachtung

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.

Originalsprache	englisch
Aufsatznummer	115032
Fachzeitschrift	Bioorganic & Medicinal Chemistry
Jahrgang	27
Ausgabenummer	19
DOIs	https://doi.org/10.1016/j.bmc.2019.07.048
Publikationsstatus	Veröffentlicht - 1 Okt. 2019

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10.1016/j.bmc.2019.07.048

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Nowikow, C., Fürst, R., Kauderer, M., Dank, C., Schmid, W., Hajduch, M., Rehulka, J., Gurska, S., Mokshyna, O., Polishchuk, P., Zupko, 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 & Medicinal Chemistry, 27(19), Artikel 115032. https://doi.org/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. / Nowikow, Christina; Fürst, Rita; Kauderer, Maria et al.
in: Bioorganic & Medicinal Chemistry, Jahrgang 27, Nr. 19, 115032, 01.10.2019.

Publikation: Beitrag in einer Fachzeitschrift › Artikel › Begutachtung

Nowikow, C, Fürst, R, Kauderer, M, Dank, C, Schmid, W, Hajduch, M, Rehulka, J, Gurska, S, Mokshyna, O, Polishchuk, P, Zupko, 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 & Medicinal Chemistry, Jg. 27, Nr. 19, 115032. https://doi.org/10.1016/j.bmc.2019.07.048

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AU - Fürst, Rita

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AU - Dank, Christian

AU - Schmid, Walther

AU - Hajduch, Marian

AU - Rehulka, Jiri

AU - Gurska, Sona

AU - Mokshyna, Olena

AU - Polishchuk, Pavel

AU - Zupko, Istvan

AU - Dzubak, Petr

AU - Rinner, Uwe

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AB - 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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DO - 10.1016/j.bmc.2019.07.048

M3 - Article

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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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