Ricerc@Sapienza

3-Aroyl-1,4-diarylpyrrole (ARDAP) derivatives are a new class of potential anticancer agents. ARDAP compounds exhibit potent inhibition of tubulin polymerization, binding of colchicine to tubulin, and cancer cell growth. In particular, (4-(4-aminophenyl)-1-phenyl-1H-pyrrol-3-yl)(3,4,5-trimethoxyphenyl)methanone inhibited the proliferation of BCR/ABL-expressing KU812 and LAMA84 cells from chronic myeloid leukemia (CML) patients in blast crisis and of hematopoietic cells ectopically expressing the imatinib mesylate (IM)-sensitive KBM5-WT or its IM-resistant KBM5-T315I mutation. This compound has proven to overcome broad tyrosine kinase inhibitor resistance in relapsed/refractory CML patients, and represents a robust lead compound to develop tubulin inhibitors with potential as novel treatments for CML. In this research project we aim to design new ARDAPs having different substituents at the 1- and/or 4-phenyl ring(s) with guidance from computational and structure-activity relationships studies. The new ARDAP derivatives are synthesized starting from chalcones, which are converted to the corresponding 3-aroyl-4-arylpyrrole derivatives with p-toluenesulfonylmethyl isocyanide (TosMIC). Introduction of the 1-aryl or heteroaryl substituent is performed with the appropriate boronic acid. The new compounds are investigated for inhibition of tubulin polymerisation, cancer cell growth, and binding to colchicine site on tubulin. Highly potent ARDAP derivatives are investigated for efficacy with BCR/ABL-expressing cells established in vitro from CML patients in blast crisis (KU812 and LAMA 84), viability of Imatinib-sensitive KBM5 and Imatinib-resistant KBM5-T315I cells, and the ability to augment the cytotoxic effects of Imatinib in human CML cells.