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

Michela Puxeddu, Hongliang Shen, Ruoli Bai, Antonio Coluccia, Marianna Nalli, Carmela Mazzoccoli, Eleonora Da Pozzo, Chiara Cavallini, Claudia Martini, Viviana Orlando, Stefano Biagioni, Cristina Mazzoni, Addolorata Maria Luce Coluccia, Ernest Hamel, Te Liu, Romano Silvestri, Giuseppe La Regina

Research output: Contribution to journalArticle

Abstract

Novel 3-aroyl-1,4-diarylpyrrole derivatives were synthesized to explore structure-activity relationships at the phenyls at positions 1 and 4 of the pyrrole. The presence of amino phenyl rings at positions 1 and 4 of the pyrrole ring were found to be a crucial requirement for potent antitumor activity. Several compounds strongly inhibited tubulin assembly through binding to the colchicine site. Compounds 42, 44, 48, 62 and 69 showed antitumor activity with low nanomolar IC50 values in several cancer cell lines. Compound 48 was generally more effective as an inhibitor of glioblastoma, colorectal and urinary bladder cancer cell lines; 69 consistently inhibited CML cell lines and demonstrated superiority in nilotinib and imatinib resistant LAMA84-R and KBM5-T315I cells. In animal models, compound 48 exhibited significant inhibition of the growth of T24 bladder carcinoma and ES-2 ovarian clear cell carcinoma tumors. Compounds 48 and 69 represent robust lead compounds for the design of new broad-spectrum anticancer agents active in different types of solid and hematological tumors.

Original languageEnglish
Pages (from-to)111828
JournalEuropean Journal of Medicinal Chemistry
DOIs
Publication statusE-pub ahead of print - Nov 2 2019

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    Puxeddu, M., Shen, H., Bai, R., Coluccia, A., Nalli, M., Mazzoccoli, C., Da Pozzo, E., Cavallini, C., Martini, C., Orlando, V., Biagioni, S., Mazzoni, C., Coluccia, A. M. L., Hamel, E., Liu, T., Silvestri, R., & La Regina, G. (2019). 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. European Journal of Medicinal Chemistry, 111828. https://doi.org/10.1016/j.ejmech.2019.111828