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

被引：21

作者：

Nowikow, Christina ^{[1
]}

Fuerst, Rita ^{[1
,2
]}

Kauderer, Maria ^{[1
]}

Dank, Christian ^{[1
]}

Schmid, Walther ^{[1
]}

Hajduch, Marian ^{[3
]}

Rehulka, Jiri ^{[3
]}

Gurska, Sona ^{[3
]}

Mokshyna, Olena ^{[3
]}

Polishchuk, Pavel ^{[3
]}

Zupko, Istvan ^{[4
]}

Dzubak, Petr ^{[3
]}

Rinner, Uwe ^{[1
,5
]}

机构：

[1] Univ Vienna, Inst Organ Chem, Wahringer Str 38, A-1090 Vienna, Austria

[2] Graz Univ Technol, Inst Organ Chem, Stremayrgasse 9, A-8010 Graz, Austria

[3] Palacky Univ Olomouc, Inst Mol & Translat Med, Fac Med & Dent, Hnevotinska 5, Olomouc, Czech Republic

[4] Univ Szeged, Dept Pharmacodynam & Biopharm, Eotvo U 6, H-6720 Szeged, Hungary

[5] Univ Appl Sci Krems, Dept Life Sci, Piaristengasse 1, A-3500 Krems, Austria

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2019年 / 27卷 / 19期

关键词：

VASCULAR DISRUPTING AGENTS; ANTINEOPLASTIC AGENTS; CELL-GROWTH; TUBULIN; DERIVATIVES; BINDING; INHIBITORS; POTENT; STILBENE; PRODRUGS;

D O I：

10.1016/j.bmc.2019.07.048

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页数：13

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