Open AccessNew Dual P-Glycoprotein (P-gp) and Human Carbonic Anhydrase XII (hCA XII) Inhibitors as Multidrug Resistance (MDR) Reversers in Cancer Cells
Author(s) -
Laura Braconi,
Elisabetta Teodori,
Chiara Riganti,
Marcella Coronnello,
Alessio Nocentini,
Gianluca Bartolucci,
Marco Pallecchi,
Marialessandra Contino,
Dina Manetti,
Maria Novella Romanelli,
Claudiu T. Supuran,
Silvia Dei
Publication year - 2022
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.2c01175
Subject(s) - chemistry , p glycoprotein , multiple drug resistance , efflux , carbonic anhydrase , cancer cell , chemosensitizer , k562 cells , cancer , pharmacology , biochemistry , enzyme , in vitro , medicine , biology , antibiotics
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.