In vitro and in vivo biological evaluation of new 4,5-disubstituted 1,2,3-triazoles as cis-constrained analogs of combretastatin A4.
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.
Institut Curie, Centre de Recherche, 26 rue d'Ulm, F-75005 Paris, France.
Núria
N
Mur Blanch
Guy G
GG
Chabot
Lionel
L
Quentin
Daniel
D
Scherman
Stéphane
S
Bourg
Daniel
D
Dauzonne
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D042783:Endothelial Cells / Q000187:drug effects; D005260:Female; D006801:Humans; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D062105:Molecular Docking Simulation; D055503:Protein Multimerization / Q000187:drug effects; D020836:Protein Structure, Quaternary; D013237:Stereoisomerism; D013267:Stilbenes / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D014404:Tubulin / Q000737:chemistry*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D013267:Stilbenes; D014230:Triazoles; D014404:Tubulin; C058728:fosbretabulin