Synthesis and biological evaluation of novel 4,5-disubstituted 2H-1,2,3-triazoles as cis-constrained analogues of combretastatin A-4

Abstract

A series of combretastatin A-4 (CA-4) analogues have been prepared from (Z)-substituted diarylacrylonitriles (1a–1p) obtained in a two-step synthesis from appropriate arylaldehydes and acrylonitriles. The resulting 4,5-disubstituted 2H-1,2,3-triazoles were evaluated for their anti-cancer activities against a panel of 60 human cancer cell lines. The diarylacrylonitrile analogue 2l exhibited the most potent anti-cancer activity in the screening studies, with GI50 values of <10 nM against almost all the cell lines in the human cancer cell panel and TGI values of <10nM against cancer cell lines SF-539, MDA-MB-435, OVCAR-3 and A498. Furthermore, in silico docking studies of compounds 2l, 2e and 2h within the active site of tubulin were carried out in order to rationalize the mechanism of anti-cancer properties of these compounds. From the in silico studies, compound 2e was predicted to have better affinity for the colchicine binding site on tubulin compared to compounds 2l and 2h. Analogue 2e was also evaluated for its anti-cancer activity by colony formation assay against 9LSF rat gliosarcoma cells and afforded an LD50 of 7.5 nM. A cell cycle redistribution assay using analogue 2e was conducted to further understand the mechanism of action of these CA-4 analogues. From this study, analogues 2e and 2l were the most potent anti-cancer agents in this structural class, and were considered lead compounds for further development as anti-cancer drugs.

Synthesis and biological activity of pyrrole analogues of combretastatin A-4

“…These cell lines were chosen as they have shown previous susceptibility to CA-4. 2,6,12,21,22 The results show that 2,3-diaryl pyrroles 34 and 35 were more active than the prepared1,2-diaryl pyrroles. The most active compound 35 had IC 50 values of 0.21 lM and 0.07 lM against K-562 and MDA-MB-231 cell lines respectively.…”

“…[1][2][3][4][5][6][7][8][9][10][11][12][13] Combretastatin A-4 binds to the colchicine (1) domain of tubulin and inhibits microtubule polymerisation, resulting in destabilisation of the microtubule cytoskeleton and inhibition of mitosis. The structural simplicity and potent cytotoxicity of CA-4 has led to the development of analogues of CA-4 as new anticancer agents (Fig.…”

“…1). 2,3,[11][12][13] Structure-activity-relationship (SAR) studies with CA-4 have indicated that the cis-configuration of the olefinic bridge between the two aromatic rings A and B is essential. The 3,4,5-trimethoxy group on ring A affects cytotoxic activity and 3-hydroxy-4-methoxy groups on ring B affects binding to tubulin.…”

“…This cis-trans isomerisation results in a loss of antimitotic activity and cytotoxicity. 1,2,5,7,9,14 The low water-solubility of CA-4 results in its low efficacy in vivo and therefore the water-soluble sodium phosphate prodrug of CA-4, fosbretabulin (CA-4P), was designed and is currently in phase II/III clinical trials. [5][6][7][8][9][10][11] Efforts to remove the possibility of cis-trans isomerisation have been attempted by replacing the cis-olefin with a five-membered heterocycle which result in a cis-like constrained configuration.…”

“…CA-4 analogues having five-membered heterocyclic rings such as oxazoles, imidazoles and triazoles have been reported to have increased potency and bioactivity. 2,3,13,14 Pyrrole-linked heterocyclic analogues have also been previously synthesised and their antimitotic activity evaluated with 3,4-diaryl-1H-pyrrole-2-carboxylates, 15 4,5-diaryl-1H-pyrrole-2-carboxylates, 7 3,5-diaryl-1H-pyrrole-2-carboxylates 16 and 1,2-diaryl-1H-pyrroles 10 being reported.…”