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.

3-Aroyl-1,4-diarylpyrroles inhibit chronic myeloid leukemia cell growth through an interaction with tubulin / LA REGINA, Giuseppe; Bai, R.; Coluccia, Antonio; Famiglini, Valeria; Passacantilli, Sara; Naccarato, Valentina; Ortar, Giorgio; Mazzoccoli, Carmela; Ruggieri, V.; Agriesti, F.; Piccoli, C.; Tataranni, T.; Nalli, Marianna; Brancale, A.; Vultaggio, S.; Mercurio, C.; Varasi, M.; Saponaro, C.; Sergio, S.; Maffia, M.; Coluccia, A. M. L.; Hamel, E.; Silvestri, Romano. - In: ACS MEDICINAL CHEMISTRY LETTERS. - ISSN 1948-5875. - STAMPA. - 8:5(2017), pp. 521-526. [10.1021/acsmedchemlett.7b00022]

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

LA REGINA, GIUSEPPE;COLUCCIA, Antonio;FAMIGLINI, VALERIA;PASSACANTILLI, SARA;NACCARATO, VALENTINA;ORTAR, Giorgio;MAZZOCCOLI, CARMELA;NALLI, Marianna;SILVESTRI, Romano
2017

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.
2017
3-aroyl-1,4-diarylpyrrole; cancer; chronic myeloid leukemia; synthesis; tubulin
01 Pubblicazione su rivista::01a Articolo in rivista
3-Aroyl-1,4-diarylpyrroles inhibit chronic myeloid leukemia cell growth through an interaction with tubulin / LA REGINA, Giuseppe; Bai, R.; Coluccia, Antonio; Famiglini, Valeria; Passacantilli, Sara; Naccarato, Valentina; Ortar, Giorgio; Mazzoccoli, Carmela; Ruggieri, V.; Agriesti, F.; Piccoli, C.; Tataranni, T.; Nalli, Marianna; Brancale, A.; Vultaggio, S.; Mercurio, C.; Varasi, M.; Saponaro, C.; Sergio, S.; Maffia, M.; Coluccia, A. M. L.; Hamel, E.; Silvestri, Romano. - In: ACS MEDICINAL CHEMISTRY LETTERS. - ISSN 1948-5875. - STAMPA. - 8:5(2017), pp. 521-526. [10.1021/acsmedchemlett.7b00022]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/954246
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