Dual Inhibitors of P-gp and Carbonic Anhydrase XII (hCA XII) against Tumor Multidrug Resistance with Piperazine Scaffold

• Published in: Molecules (Basel, Switzerland) Vol. 29; no. 14; p. 3290
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 11.07.2024
• Subjects: A549 Cells; A549/DOX; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; ATP Binding Cassette Transporter, Subfamily B, Member 1 - antagonists & inhibitors; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism; CA XII inhibitors; Cancer; Carbonic Anhydrase Inhibitors - chemical synthesis; Carbonic Anhydrase Inhibitors - chemistry; Carbonic Anhydrase Inhibitors - pharmacology; Carbonic Anhydrases - metabolism; Cell Line, Tumor; Cytotoxicity; Doxorubicin - chemistry; Doxorubicin - pharmacology; Drug Resistance, Multiple - drug effects; Drug Resistance, Neoplasm - drug effects; Glycoproteins; HT29 Cells; HT29/DOX; Humans; K562/DOX; MDR reversers; Molecular Structure; Nitrogen; P-gp modulators; Piperazine - chemistry; Piperazine - pharmacology; Piperazines - chemical synthesis; Piperazines - chemistry; Piperazines - pharmacology; Proteins; Structure-Activity Relationship; Toxicity; Tumors; selective chemosensitizers; P-gp modulators; MDR reversers; multitarget ligands; dual P-gp/CA XII inhibitory activity; A549/DOX; K562/DOX; HT29/DOX; hybrid compounds; CA XII inhibitors
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules29143290

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 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 , and 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.