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3-Aroyl-1,4-diarylpyrroles inhibit chronic myeloid leukemia cell growth through an interaction with tubulin

La Regina, Giuseppe, Bai, Ruoli, Coluccia, Antonio, Famiglini, Valeria, Passacantilli, Sara, Naccarato, Valentina, Ortar, Giorgio, Mazzoccoli, Carmela, Ruggieri, Vitalba, Agriesti, Francesca, Piccoli, Claudia, Tataranni, Tiziana, Nalli, Marianna, Brancale, Andrea, Vultaggio, Stefania, Mercurio, Ciro, Varasi, Mario, Saponaro, Concetta, Sergio, Sara, Maffia, Michele, Coluccia, Addolorata Maria Luce, Hamel, Ernest and Silvestri, Romano 2017. 3-Aroyl-1,4-diarylpyrroles inhibit chronic myeloid leukemia cell growth through an interaction with tubulin. ACS Medicinal Chemistry Letters 8 (5) , pp. 521-526. 10.1021/acsmedchemlett.7b00022

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Abstract

We designed 3-aroyl-1,4-diarylpyrrole (ARDAP) derivatives as potential anticancer agents having different substituents at the 1- or 4-phenyl ring. ARDAP compounds exhibited potent inhibition of tubulin polymerization, binding of colchicine to tubulin, and cancer cell growth. ARDAP derivative 10 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. Compound 10 minimally affected the proliferation of normal blood cells, indicating that it may be a promising agent to overcome broad tyrosine kinase inhibitor resistance in relapsed/refractory CML patients. Compound 10 significantly decreased CML proliferation by inducing G2/M phase arrest and apoptosis via a mitochondria-dependent pathway. ARDAP 10 augmented the cytotoxic effects of IM in human CML cells. Compound 10 represents a robust lead compound to develop tubulin inhibitors with potential as novel treatments for CML.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Pharmacy
Subjects: R Medicine > RS Pharmacy and materia medica
Uncontrolled Keywords: Cancer, tubulin, chronic myeloid leukemia, synthesis, 3-aroyl-1,4-diarylpyrrole
Publisher: American Chemical Society
ISSN: 1948-5875
Date of First Compliant Deposit: 7 June 2017
Date of Acceptance: 26 April 2017
Last Modified: 27 Apr 2018 13:03
URI: http://orca.cf.ac.uk/id/eprint/101273

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