Molecules (2020)
Update date:2022-08-17
Topics:
Bartolucci, Gianluca
Braconi, Laura
Bua, Silvia
Coronnello, Marcella
Dei, Silvia
Lapucci, Andrea
Manetti, Dina
Romanelli, Maria Novella
Supuran, Claudiu T.
Teodori, Elisabetta
A new series of N,N-bis(alkanol)amine aryl diesters was synthesized and studied as dual P-glycoprotein (P-gp) and carbonic anhydrase XII inhibitors (CA XII). These hybrids should be able to synergistically overcome P-gp mediated multidrug resistance (MDR) in cancer cells. It was reported that the effux activity of P-gp could be modulated by CA XII, as the pH reduction caused by CA XII inhibition produces a significant decrease in P-gp ATPase activity. The new compounds reported here feature both P-gp and CA XII binding moieties. These hybrids contain a N,N-bis(alkanol)amine diester scaffold found in P-glycoprotein ligands and a coumarin or benzene sulfonamide moiety to target CA XII. Many compounds displayed a dual activity against P-gp and CA XII being active in the Rhd 123 uptake test on K562/DOX cells and in the hCA XII inhibition test. On LoVo/DOX cells, that overexpress both P-gp and CA XII, some coumarin derivatives showed a high MDR reversal effect in Rhd 123 uptake and doxorubicin cytotoxicity enhancement tests. In particular, compounds 7 and 8 showed higher activity than verapamil and were more potent on LoVo/DOX than on K562/DOX cells overexpressing only P-gp. They can be considered as valuable candidates for selective P-gp/CA XII inhibition in MDR cancer cells.
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Doi:10.1016/j.molcata.2007.08.028
(2007)Doi:10.1021/jacs.0c04107
(2020)Doi:10.1016/j.tet.2011.07.077
(2011)Doi:10.1063/1.444244
(1982)Doi:10.1002/cctc.201501379
(2016)Doi:10.1016/j.tetlet.2014.07.091
(2014)