Design, synthesis and biological evaluation of imidazo[1,5-a]pyridine-PBD conjugates as potential DNA-directed alkylating agentsElectronic supplementary information (ESI) available. See DOI: 10.1039/c2md20219k

A series of novel imidazo[1,5- a ]pyridine-PBD conjugates were synthesized and evaluated for their antitumor activity in breast cancer cell line (MCF-7). Interestingly, all the compounds showed enhanced DNA binding ability. These conjugates showed significant antitumor activity as deduced by MTT cell proliferation assay and amongst them, compounds 13f and 13g exhibit promising antitumor activity. G2/M phase cell cycle arrest was observed on the treatment of breast cancer cells (MCF-7) with 2 μM concentration of these compounds. Moreover, accumulation of cells in the G0 (apoptotic) phase was observed upon increase of their concentration to 4 μM. These compounds also induced the expression of proteins involved in apoptosis and DNA damage such as p53, p21 and γ-H2AX. In silico binding studies of compound 13g with DNA was performed to understand the mode of interactions and we observed that compound 13g binds well with the minor groove of DNA. A series of imidazo[1,5- a ]pyridine-PBD conjugates 13a-l have been prepared and evaluated for their anticancer activity.