In a continuing search of dual P-gp and hCA XII inhibitors, we synthesized and studied new N,N-bis(alkanol)amine aryl diester derivatives characterized by the presence of a coumarin group. These hybrids contain both P-gp and hCA XII binding groups to synergistically overcome the P-gp-mediated multidrug resistance (MDR) in cancer cells expressing both P-gp and hCA XII. Indeed, hCA XII modulates the efflux activity of P-gp and the inhibition of hCA XII reduces the intracellular pH, thereby decreasing the ATPase activity of P-gp. All compounds showed inhibitory activities on P-gp and hCA XII proteins taken individually, and many of them displayed a synergistic effect in HT29/DOX and A549/DOX cells that overexpress both P-gp and hCA XII, being more potent than in K562/DOX cells overexpressing only P-gp. Compounds 5 and 14 were identified as promising chemosensitizer agents for selective inhibition in MDR cancer cells overexpressing both P-gp and hCA XII.

New dual P-Glycoprotein (P-gp) and human carbonic anhydrase XII (hCA XII) inhibitors as Multidrug Resistance (MDR) reversers in cancer cells / Braconi, Laura; Teodori, Elisabetta; Riganti, Chiara; Coronnello, Marcella; Nocentini, Alessio; Bartolucci, Gian Luca; Pallecchi, Marco; Contino, Marialessandra; Manetti, Dina; Romanelli, Maria Novella; Supuran, Claudiu T; Dei, Silvia. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - ELETTRONICO. - (2022), pp. 0-0. [10.1021/acs.jmedchem.2c01175]

New dual P-Glycoprotein (P-gp) and human carbonic anhydrase XII (hCA XII) inhibitors as Multidrug Resistance (MDR) reversers in cancer cells

Braconi, Laura;Teodori, Elisabetta;Coronnello, Marcella;Nocentini, Alessio;Bartolucci, Gian Luca;Pallecchi, Marco;Manetti, Dina;Romanelli, Maria Novella;Supuran, Claudiu T;Dei, Silvia
2022

Abstract

In a continuing search of dual P-gp and hCA XII inhibitors, we synthesized and studied new N,N-bis(alkanol)amine aryl diester derivatives characterized by the presence of a coumarin group. These hybrids contain both P-gp and hCA XII binding groups to synergistically overcome the P-gp-mediated multidrug resistance (MDR) in cancer cells expressing both P-gp and hCA XII. Indeed, hCA XII modulates the efflux activity of P-gp and the inhibition of hCA XII reduces the intracellular pH, thereby decreasing the ATPase activity of P-gp. All compounds showed inhibitory activities on P-gp and hCA XII proteins taken individually, and many of them displayed a synergistic effect in HT29/DOX and A549/DOX cells that overexpress both P-gp and hCA XII, being more potent than in K562/DOX cells overexpressing only P-gp. Compounds 5 and 14 were identified as promising chemosensitizer agents for selective inhibition in MDR cancer cells overexpressing both P-gp and hCA XII.
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Goal 3: Good health and well-being
Braconi, Laura; Teodori, Elisabetta; Riganti, Chiara; Coronnello, Marcella; Nocentini, Alessio; Bartolucci, Gian Luca; Pallecchi, Marco; Contino, Marialessandra; Manetti, Dina; Romanelli, Maria Novella; Supuran, Claudiu T; Dei, Silvia
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2158/1285647
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