Dual Inhibitors of P-gp and Carbonic Anhydrase XII (hCA XII) against Tumor Multidrug Resistance with Piperazine Scaffold
Articolo
Data di Pubblicazione:
2024
Abstract:
A new series of piperazine derivatives were synthesized and studied with the aim of obtaining dual inhibitors of P-glycoprotein (P-gp) and carbonic anhydrase XII (hCA XII) to synergistically overcome the P-gp-mediated multidrug resistance (MDR) in cancer cells expressing the two proteins, P-gp and hCA XII. Indeed, these hybrid compounds contain both P-gp and hCA XII binding groups on the two nitrogen atoms of the heterocyclic ring. All compounds showed good inhibitory activity on each protein (P-gp and hCA XII) studied individually, and many of them showed a synergistic effect in the resistant HT29/DOX and A549/DOX cell lines which overexpress both the target proteins. In particular, compound 33 displayed the best activity by enhancing the cytotoxicity and intracellular accumulation of doxorubicin in HT29/DOX and A549/DOX cells, thus resulting as promising P-gp-mediated MDR reverser with a synergistic mechanism. Furthermore, compounds 13, 27 and 32 induced collateral sensitivity (CS) in MDR cells, as they were more cytotoxic in resistant cells than in the sensitive ones; their CS mechanisms were extensively investigated.
Tipologia CRIS:
03A-Articolo su Rivista
Keywords:
A549/DOX; CA XII inhibitors; HT29/DOX; K562/DOX; MDR reversers; P-gp modulators; dual P-gp/CA XII inhibitory activity; hybrid compounds; multitarget ligands; selective chemosensitizers
Elenco autori:
Braconi, Laura; Riganti, Chiara; Parenti, Astrid; Cecchi, Marta; Nocentini, Alessio; Bartolucci, Gianluca; Menicatti, Marta; Contino, Marialessandra; Colabufo, Nicola Antonio; Manetti, Dina; Romanelli, Maria Novella; Supuran, Claudiu T; Teodori, Elisabetta
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