期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 65, 期 21, 页码 14655-14672出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.2c01175
关键词
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资金
- University of Florence (Fondo Ricerca Ateneo)
- Italian Association for Cancer Research
- [RICATEN20]
- [RICAT-EN21]
- [IF21408]
The study synthesized and studied new compounds that can inhibit both P-gp and hCA XII in cancer cells, overcoming multidrug resistance. Compounds 5 and 14 showed promising inhibitory effects in cancer cells overexpressing both P-gp and hCA XII.
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.
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