A convergent synthesis of alkyne-azide cycloaddition derivatives of 4-α,β-2-propyne podophyllotoxin depicting potent cytotoxic activity

A facile synthetic approach to construct the O-propargyl derivatives of 4 alpha and 4 beta-(1,2,3-triazol-4-yl)-podophyllotoxin (9a-k & 10a-k) and 4 '-Demethy1-4 '-4 beta-(1,2,3-triazol-4-yl)-epipodophyllotoxin (12a-d) were synthesized by means of click chemistry. The chemical structures were confirmed by H-1, C-13, 2D NMR and HRMS spectral analysis and their cytotoxicities were measured against diverse human cancer cell lines viz. PC-3, PANC-1, COLO-205 and A-549 by MU assay. Some of the compounds were found more potent than the parent molecule Podophyllotoxin, like; 9a & 10a, 9h & 10h, 9k & 10k, 10d, 8 and 12a. The most potent molecule discovered was compound 9k that exhibited the highest cytotoxicity on all the four cancer cell lines with IC50 values of 3.8-22 nM. The compound further found to induce apoptosis and strongly hindered the motility of aggressive prostate cancer PC-3 cells. (C) 2014 Elsevier Masson SAS. All rights reserved.