Cancer is a leading cause of death worldwide. Multidrug resistance (MDR) is a main reason\nof chemotherapy failure in many patients and is often related to overexpression of ATP-binding\ncassette (ABC) transporters, including P-glycoprotein (P-gp/ABCB1). Agents that are capable of\nmodulation of the activity of these transporters might be effective in overcoming MDR. In this study, a\nnew set of 1,4,5,6,7,8-hexahydro 5-oxo quinoline-3-carboxamide derivatives bearing 4-methylthiazole\nmoiety and their tetrahydroquinoline counterparts were synthesized. MDR reversal activity of\nthese 16 newly synthesized derivatives was tested in P-gp overexpressing MES-SA-DX5 human\nuterine sarcoma cells by flow cytometric determination of Rhodamine123 efflux. The effect of the\nmost potent compounds in induction of apoptosis and alterations of cell cycle was examined in\nthese cells by a flow cytometric method. Inherent cytotoxicity of the synthesized compounds was\nevaluated against MCF-7, A-549 and K562 cancer cell lines, as well as MES-SA-DX5 and their parental\nnon-resistant MES-SA and also HEK-293 non-cancerous cells by MTT assay. Compounds A1 and A2\nwith 5-oxo-hexahydroquinoline structure bearing 2,4-dichlorophenyl and 4-bromophenyl moieties,\nrespectively, and their tetrahydroquinoline counterparts B1 and B2 significantly blocked P-gp efflux,\ninduced apoptosis and showed the highest cytotoxicities against MES-SA-DX5 cells. However,\nonly A2 and B2 compounds were relatively selective against cancer and MDR cells as compared to\nnon-resistant and non-cancerous cells. These findings demonstrate that 5-oxo-hexahydroquinoline\nand 5-oxo-tetrahydroquinoline derivatives represent promising agents with therapeutic potential in\ndrug resistant cancers.
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