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^*

^*Corresponding author for this work

Institute of Organic Chemistry (6410)

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

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 & Medicinal Chemistry
Volume	27
Issue number	19
DOIs	https://doi.org/10.1016/j.bmc.2019.07.048
Publication status	Published - 1 Oct 2019

Access to Document

10.1016/j.bmc.2019.07.048

Cite this

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), [115032]. https://doi.org/10.1016/j.bmc.2019.07.048

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, vol. 27, no. 19, 115032. https://doi.org/10.1016/j.bmc.2019.07.048

@article{d4e9c09351aa409193bd928bb76aaf21,

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

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.",

author = "Christina Nowikow and Rita F{\"u}rst and Maria Kauderer and Christian Dank and Walther Schmid and Marian Hajduch and Jiri Rehulka and Sona Gurska and Olena Mokshyna and Pavel Polishchuk and Istvan Zupko and Petr Dzubak and Uwe Rinner",

year = "2019",

month = oct,

day = "1",

doi = "10.1016/j.bmc.2019.07.048",

language = "English",

volume = "27",

journal = "Bioorganic & Medicinal Chemistry",

issn = "0968-0896",

publisher = "Elsevier B.V.",

number = "19",

}

TY - JOUR

T1 - Synthesis and biological evaluation of cis-restrained carbocyclic combretastatin A-4 analogs: Influence of the ring size and saturation on cytotoxic properties

AU - Nowikow, Christina

AU - Fürst, Rita

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 - Zupko, Istvan

AU - Dzubak, Petr

AU - Rinner, Uwe

PY - 2019/10/1

Y1 - 2019/10/1

N2 - 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.

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.

U2 - 10.1016/j.bmc.2019.07.048

DO - 10.1016/j.bmc.2019.07.048

M3 - Article

VL - 27

JO - Bioorganic & Medicinal Chemistry

JF - Bioorganic & Medicinal Chemistry

SN - 0968-0896

IS - 19

M1 - 115032

ER -

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

Abstract

Access to Document

Fingerprint

Cite this