Microtubules are an attractive target for the development of effective anti-leukemia agents.[1] Evidence has accumulated correlating inhibition of tubulin polymerization and leukemic cell proliferation.[2] The activity of colchicine site agents in chronic myeloid leukemia (CML) has not been adequately explored. Recently, starting from previously reported aroylindoles (ARI, 1)[3] we developed a class of 3-aroyl-1-arylpyrroles (ARAPs, 2) via benzocracking approach by shifting the indole benzene moiety to position 1 of the pyrrole ring.[4] ARAPs proved to be potent inhibitors of both tubulin assembly and cancer cells growth, by binding the colchicine binding site. Pursuing our studied on tubulin targeting agents, we designed 3-aroyl-1,4-diarylpyrroles (ARDAPs, 3-16) as potential anticancer agents bearing different substituents at the 1- or 4-phenyl ring (Chart 1). ARDAPs exhibited potent inhibition of tubulin polymerization, binding of colchicine to tubulin and cancer cell growth. (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 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. The same compound 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. New ARDAP significantly decreased CML proliferation by inducing G2/M phase arrest and apoptosis via a mitochondria-dependent pathway and increased the cytotoxic effects of IM in human CML cells. References. [1] de Bruin, E. C.; Medema, J. P. Cancer Treat. Rev. 2008, 34, 737-749. [2] Bates, D.; Feris, E. J.; Danilov, A. V. et al. Cancer Biol. Ther. 2016, 17, 291-299. [3] La Regina, G.; Sarkar, T.; Bai, R. et al. J. Med. Chem. 2009, 52, 7512-7527. [4] La Regina, G.; Bai, R.; Coluccia, A. et al. J. Med. Chem. 2014, 57, 6531-6552.
3-Aroyl-1,4-diarylpyrroles inhibit chronic myeloid leukemia cell growth through an interaction with tubulin / LA REGINA, Giuseppe; Naccarato, Valentina; Coluccia, Antonio; Maria Luce Coluccia, Addolorata; Hamel, Ernest; Silvestri, Romano. - ELETTRONICO. - (2017), pp. 153-153. (Intervento presentato al convegno 10th Joint Meeting on Medicinal Chemistry tenutosi a Dubrovnik, Croazia nel 25-28 giugno 2017).
3-Aroyl-1,4-diarylpyrroles inhibit chronic myeloid leukemia cell growth through an interaction with tubulin
Giuseppe La Regina
;Valentina Naccarato;Antonio Coluccia;Romano Silvestri
2017
Abstract
Microtubules are an attractive target for the development of effective anti-leukemia agents.[1] Evidence has accumulated correlating inhibition of tubulin polymerization and leukemic cell proliferation.[2] The activity of colchicine site agents in chronic myeloid leukemia (CML) has not been adequately explored. Recently, starting from previously reported aroylindoles (ARI, 1)[3] we developed a class of 3-aroyl-1-arylpyrroles (ARAPs, 2) via benzocracking approach by shifting the indole benzene moiety to position 1 of the pyrrole ring.[4] ARAPs proved to be potent inhibitors of both tubulin assembly and cancer cells growth, by binding the colchicine binding site. Pursuing our studied on tubulin targeting agents, we designed 3-aroyl-1,4-diarylpyrroles (ARDAPs, 3-16) as potential anticancer agents bearing different substituents at the 1- or 4-phenyl ring (Chart 1). ARDAPs exhibited potent inhibition of tubulin polymerization, binding of colchicine to tubulin and cancer cell growth. (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 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. The same compound 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. New ARDAP significantly decreased CML proliferation by inducing G2/M phase arrest and apoptosis via a mitochondria-dependent pathway and increased the cytotoxic effects of IM in human CML cells. References. [1] de Bruin, E. C.; Medema, J. P. Cancer Treat. Rev. 2008, 34, 737-749. [2] Bates, D.; Feris, E. J.; Danilov, A. V. et al. Cancer Biol. Ther. 2016, 17, 291-299. [3] La Regina, G.; Sarkar, T.; Bai, R. et al. J. Med. Chem. 2009, 52, 7512-7527. [4] La Regina, G.; Bai, R.; Coluccia, A. et al. J. Med. Chem. 2014, 57, 6531-6552.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
