Novel 3-aroyl-1,4-diarylpyrroles against solid tumors and hematological malignancies

Microtubules (MTs) are an attractive target for development of efficient anticancer agents. Evidence has accumulated correlating inhibition of tubulin polymerization and leukemic cell proliferation.[1] The activity of colchicine site agents in chronic myeloid leukemia (CML) has not been adequately explored yet.[2] Recently, starting from previously reported aroylindoles and aroilpyrroles, we developed novel 3-aroyl-1,4-diarylpyrrole (ARDAP) derivatives to explore structure-activity relationships at the phenyls at the position 1 and 4 of the pyrrole.[3] Several compounds strongly inhibited tubulin assembly through binding to the colchicine site, the bests derivatives present the amino group in both phenyls. In particular, compound 1 was generally more effective as an inhibitor of the glioblastoma, colorectal and urinary bladder cancer cells, whereas 2 consistently was more active as an inhibitor of the CML cell lines. In animal models, this promising compound exhibited significant inhibition of the growth of T24 bladder carcinoma and ES-2 ovarian clear cell carcinoma tumors. These derivatives represent robust lead compounds for the design of new anticancer agents active in different types of solid and haematological tumors. References. [1] Mollinedo, F.; Gajate, C. Microtubules, microtubule-interfering agents and apoptosis, Apoptosis 2003, 8, 413-450. [2] I. Pasic, J.H. Lipton, Current approach to the treatment of chronic myeloid leukaemia. Leuk. Res. 2017, 55, 65-78. [3] M. Puxeddu et al. Structure-activity relationship studies and in vitro and in vivo anticancer activity of novel 3-aroyl-1,4-diarylpyrroles against solid tumors and hematological malignancies. Eur. J. Med. Chem. 2020, 185, e11182824.