TY - JOUR
T1 - Synthesis and biological evaluation of cis-restrained carbocyclic combretastatin A-4 analogs
T2 - Influence of the ring size and saturation on cytotoxic properties
AU - Nowikow, Christina
AU - Fuerst, 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 - Zupkó, István
AU - Dzubak, Petr
AU - Rinner, Uwe
N1 - Funding Information:
This work was supported by Technology Agency of the Czech Republic TE01020028 , Ministry of Health of the Czech Republic ( 15-31984A ), internal grant of Palacky University ( IGA_LF_2019_018 ) and by the Czech Ministry of Education, Youth and Sports (LO1304, CZ-OPENSCREEN-LM2015063, EATRIS-LM2015064, IT4Innovations National Supercomputing Center – LM2015070) and the European Regional Development Fund – Project ENOCH (No. CZ.02.1.01/0.0/0.0/16_019/0000868).
Publisher Copyright:
© 2019 Elsevier Ltd
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.
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U2 - 10.1016/j.bmc.2019.07.048
DO - 10.1016/j.bmc.2019.07.048
M3 - Article
C2 - 31401010
AN - SCOPUS:85070237715
SN - 0968-0896
VL - 27
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 19
M1 - 115032
ER -