Isoxazole-type derivatives related to combretastatin A-4, synthesis and biological evaluation

Bioorganic & Medicinal Chemistry
Julia KaffyJean-Claude Florent

Abstract

Novel combretastatin analogues bearing various five-membered heterocycles with consecutive oxygen and nitrogen atoms, in place of the olefinic bridge of CA4, have been synthesized (isoxazole, isoxazoline, oxadiazole, etc). These compounds have been evaluated for cytotoxicity and their ability to inhibit the tubulin assembly. On the basis of the relative position of the aromatic A- and B-rings on the heterocyclic moiety, they could be split in two classes, the alpha,gamma- or alpha,beta-diaryl heterocyclic derivatives. In the first series, the 3,5-diaryloxadiazole 9a displayed comparable antitubulin activity to that of CA4, but was devoid of cytotoxic effects. Among the alpha,beta-diaryl heterocyclic derivatives, the 4,5-diarylisoxazole 35 exhibited greater antitubulin activity than that of CA4 (0.75 vs 1.2 microM), but modest antiproliferative activity. These data showed that minor alteration in the chemical structure of the heterocyclic ring and its relative orientation with regard to the two phenyl rings of CA4 could dramatically influence the tubulin binding properties.

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Citations

Feb 2, 2013·Bioorganic & Medicinal Chemistry·Nancy TyJean-Claude Florent
Jul 3, 2013·Bioorganic & Medicinal Chemistry Letters·Ganesh S JedheGangadhar J Sanjayan
May 28, 2013·European Journal of Medicinal Chemistry·Zong-Ying LiuDavid W Boykin
Jan 7, 2014·European Journal of Medicinal Chemistry·Dmitry V TsyganovVictor V Semenov
Apr 28, 2010·Journal of Medicinal Chemistry·Romeo RomagnoliGiampietro Viola
Mar 5, 2013·Organic and Medicinal Chemistry Letters·Sunil KumarKanaya L Dhar
Jul 19, 2016·Journal of Medicinal Chemistry·Virginia SpanòNadia Zaffaroni
Aug 24, 2012·ChemMedChem·Paola BarrajaGirolamo Cirrincione
Nov 19, 2015·Chemical Record : an Official Publication of the Chemical Society of Japan ... [et Al.]·Renta Jonathan Chew, Pak-Hing Leung
Sep 27, 2018·Journal of Enzyme Inhibition and Medicinal Chemistry·Burcu ÇalışkanErden Banoglu
Sep 12, 2015·The Journal of Pharmacology and Experimental Therapeutics·Lisa M GreeneDaniela M Zisterer
Sep 15, 2015·Magnetic Resonance in Chemistry : MRC·Lucia Ungvarská MaľučkáJán Imrich
Feb 23, 2021·European Journal of Medicinal Chemistry·Abdelfattah FaouziThierry Lomberget
Nov 6, 2010·Journal of Natural Products·Victor V SemenovMarina N Semenova

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