New Dual P‑Glycoprotein (P-gp) and Human Carbonic Anhydrase XII (hCA XII) Inhibitors as Multidrug Resistance (MDR) Reversers in Cancer Cells

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.