Dual Inhibitors of P-gp and Carbonic Anhydrase XII (hCA XII) against Tumor Multidrug Resistance with Piperazine Scaffold
Laura Braconi,
Chiara Riganti,
Astrid Parenti,
Marta Cecchi,
Alessio Nocentini,
Gianluca Bartolucci,
Marta Menicatti,
Marialessandra Contino,
Nicola Antonio Colabufo,
Dina Manetti,
Maria Novella Romanelli,
Claudiu T. Supuran,
Elisabetta Teodori
Affiliations
Laura Braconi
Section of Pharmaceutical and Nutraceutical Sciences, Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy
Chiara Riganti
Oncological Pharmacology Laboratory and Molecular Biotechnology Center “Guido Tarone”, Department of Oncology, University of Turin, Piazza Nizza 44, 10126 Torino, Italy
Astrid Parenti
Section of Clinical Pharmacology and Oncology, Department of Health Sciences, University of Florence, Viale Pieraccini 6, 50139 Firenze, Italy
Marta Cecchi
Section of Pharmacology and Toxicology, Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Viale Pieraccini 6, 50139 Firenze, Italy
Alessio Nocentini
Section of Pharmaceutical and Nutraceutical Sciences, Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy
Gianluca Bartolucci
Section of Pharmaceutical and Nutraceutical Sciences, Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy
Marta Menicatti
Section of Pharmaceutical and Nutraceutical Sciences, Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy
Marialessandra Contino
Department of Pharmacy-Drug Sciences, University of Bari “A. Moro”, via Orabona 4, 70125 Bari, Italy
Nicola Antonio Colabufo
Department of Pharmacy-Drug Sciences, University of Bari “A. Moro”, via Orabona 4, 70125 Bari, Italy
Dina Manetti
Section of Pharmaceutical and Nutraceutical Sciences, Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy
Maria Novella Romanelli
Section of Pharmaceutical and Nutraceutical Sciences, Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy
Claudiu T. Supuran
Section of Pharmaceutical and Nutraceutical Sciences, Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy
Elisabetta Teodori
Section of Pharmaceutical and Nutraceutical Sciences, Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy
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.
