Design, synthesis and biological evaluation of 3,5-diaryl-isoxazoline/isoxazole-pyrrolobenzodiazepine conjugates as potential anticancer agents

A series of 3,5-diaryl-isoxazoline/isoxazole linked pyrrolo[2,1-c][1,4]benzodiazepine (PBD) conjugates were prepared. These conjugates showed potent anticancer activity with GI50 values in the range of <0.1–3.6 μM. Some of these PBD conjugates (6a–c) with promising anticancer activity were further investigated on the cell cycle distribution. Moreover, these PBD conjugates exhibited G0/G1 arrest, enhancement in the levels of p53 protein as well as mitochondrial-mediated intrinsic pathway, leading to release of cytochrome c, activation of caspase-3, cleavage of PARP and subsequent apoptotic cell death. Hence these PBD conjugates with 6a being the most potent one could be be taken up for preclinical studies either alone or in combination with existing therapies.

Graphical abstractNew class of 3,5-diaryl-isoxazoline/isoxazole-pyrrolobenzodiazepine conjugates were prepared and evaluated for their anticancer activity. Further, some of the biological assays related to mechanism aspects were also carried out.Figure optionsDownload full-size imageDownload as PowerPoint slide