4β-[(4-Alkyl)-1,2,3-triazol-1-yl] podophyllotoxins as anticancer compounds: Design, synthesis and biological evaluation

A series of 4β-[(4-alkyl)-1,2,3-triazol-1-yl] podophyllotoxin derivatives were designed in silico, synthesised by employing click chemistry approach, and evaluated for cytotoxicity against a panel of human cancer cell lines (SF-295, A-549, PC-3, Hep-2, HCT-15 and MCF-7). Majority of the compounds proved to be more potent than etoposide and select compounds exhibited significant anticancer activity with IC50 values in the range of 0.001–1 μM. DNA fragmentation and flow-cytometric results reveals that 4β-[(4-alkyl)-1,2,3-triazol-1-yl] podophyllotoxin derivatives induce dose dependent apoptosis. Docking experiments showed a good correlation between their calculated interaction energies with the topoisomerase-II and the observed IC50 values of all these compounds. A series of 4β-[(4-alkyl)-1,2,3-triazol-1-yl] podophyllotoxin derivatives were designed, synthesised and evaluated for cytotoxicity. Most of the compounds exhibited better cytotoxicity than etoposide. DNA fragmentation and flow-cytometric results reveal dose dependent apoptosis. [Display omitted] ► The work presented in this manuscript highlights the design, synthesis and screening of a series of novel 4β-[(4-alkyl)-1,2,3-triazol-1-yl] podophyllotoxin derivatives as anticancer compounds. The semi synthetic modification of podophyllotoxin was taken up after due consideration of the SAR of the natural product and structural modifications were guided by in silico docking studies. ► In vitro screening for their cytotoxicity has been carried out against a panel of human cancer cell lines (SF-295, A-549, PC-3, Hep-2, HCT-15 and MCF-7). Majority of the compounds proved to be more potent than etoposide and select compounds exhibited significant anticancer activity with IC50 values in the range of 0.001-1 mM. DNA fragmentation and flow-cytometric results reveals that 4β-[(4-alkyl)-1,2,3-triazol-1-yl] podophyllotoxin derivatives induce dose dependent apoptosis. ► Docking experiments showed a good correlation between their calculated interaction energies with the Topoisomerase-II and the observed IC50 values of all these compounds.