In vitro and in vivo biological evaluation of new 4,5-disubstituted 1,2,3-triazoles as cis-constrained analogs of combretastatin A4.

Núria Mur Blanch; Guy Chabot; Lionel Quentin; Daniel Scherman; Stéphane Bourg; Daniel Dauzonne

doi:10.1016/j.ejmech.2012.04.017

In vitro and in vivo biological evaluation of new 4,5-disubstituted 1,2,3-triazoles as cis-constrained analogs of combretastatin A4.

Núria Mur Blanch ¹ Guy Chabot ^{2, *} Lionel Quentin ² Daniel Scherman ² Stéphane Bourg ³ Daniel Dauzonne ¹

* Auteur correspondant

1 CSVB - Conception, synthèse et vectorisation de biomolécules.

2 UPCGI - UMR 8151 / UMR_S 1022 - Unité de pharmacologie chimique et génétique et d'imagerie

3 PCV - Physique et Chimie du Vivant

Abstract : To find new and better antivascular agents for cancer therapy, a series of combretastatin A4 (CA4) analogs were prepared from 1,3-diaryl-2-nitroprop-1-enes (6-12) obtained in a two-step synthesis from appropriate arylaldehydes and 2-aryl-1-nitroethanes (4 or 5). Treatment of these 1,3-diaryl-2-nitroprop-1-enes 6-12 by sodium azide in DMSO yielded the targeted compounds. The synthesized 1,2,3-triazoles disubstituted in 4- and 5-positions by one benzyl group and one aryl nucleus have also been tested for biological activities involved in antivascular action. It was found that several new compounds exhibited interesting biological activities in the nanomolar or low micromolar range, in terms of rounding up of endothelial cells, inhibition of tubulin polymerization, and cytotoxicity on B16 melanoma cancer cells. In silico docking studies of 11 and 19 within the active site of tubulin were also carried out in order to rationalize the inhibitory properties of these compounds and further understand their inhibition mechanism. In vivo evaluation of compounds 11 and 19 in mice bearing colon 26 carcinoma indicated modest anticancer activity.

keyword : Antivascular agents combretastatin analogs triazoles endothelial cells tubulin polymerization cytotoxicity

Type de document :

Article dans une revue

European Journal of Medicinal Chemistry, Elsevier, 2012, 54, pp.22-32. 〈10.1016/j.ejmech.2012.04.017〉

Domaine :

Sciences du Vivant [q-bio] / Cancer

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http://www.hal.inserm.fr/inserm-00709733
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In vitro and in vivo biological evaluation of new 4,5-disubstituted 1,2,3-triazoles as cis-constrained analogs of combretastatin A4.

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In vitro and in vivo biological evaluation of new 4,5-disubstituted 1,2,3-triazoles as cis-constrained analogs of combretastatin A4.

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