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

Abstract A facile synthetic approach to construct the O-propargyl derivatives of 4α and 4β-(1,2,3-triazol-4-yl)-podophyllotoxin ( 9a–k & 10a–k ) and 4′-Demethyl-4′-4β-(1,2,3-triazol-4-yl)-epipodophyllotoxin ( 12a–d ) were synthesized by means of click chemistry. The chemical structures were confirmed by 1 H, 13 C, 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 MTT 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 IC 50 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.