SAR analysis and biological studies of synthesized podophyllum derivates obtained by N linkage modification at C-4 position

The SAR analysis suggests that compounds with imidogen exposed on the pyridine, rather than pyrimidine, exhibited significantly elevated potency. Moreover, the presence of a chlorine atom in the heterocyclic ring enhanced cytotoxicity, with the order 3-position > 4-position > 5-position > 6-position. Specifically, two compounds, 3g and 3h, were shown to have the most potent HeLa cells cytotoxicity. The compound 3g was shown to inhibit microtubule polymerization and compound 3h affected topoisomerase II catalytic activity. Both compounds resulted in G2/M phase arrest and apoptosis, purportedly by increasing the expression of P53, followed by Bax up-regulation, Bcl-2 down-regulation, and caspase-3 activation.