5-Oxohexahydroquinolines bearing 4-pyridyl methyl carboxylate as P-glycoprotein inhibitors and multidrug resistance reversal agents in cancer cells

Multidrug resistance (MDR) limits the therapeutic effect of conventional chemotherapeutic agents as well as novel targeted anticancer drugs. An important mechanism of MDR is the overexpression of ATP-binding cassette (ABC) transporters in cancer cells, among which P-glycoprotein (P-gp) has one of the highest contributions to drug resistance. In this study, 10 novel 5-oxo-hexahydroquinoline (5-oxo-HHQ) derivatives bearing 4-pyridyl methyl carboxylate moiety (G1-G10) were synthesized and examined for their MDR reversal activity in P-gp overexpressing MES-SA-DX5 cells. Moreover, all synthesized compounds were evaluated for their cell growth inhibitory effect in several cancer cell lines. Most of the tested compounds significantly enhanced the intracellular accumulation of rhodamine 123, a P-gp substrate, in MDR cells, some of them showing better results than verapamil, a well-established P-gp inhibitor. Moreover, most compounds, especially G2, G3, G7, and G8, bearing 2-chlorophenyl, 3-bromophenyl, 3-nitrophenyl and pyridin-4-yl moieties were effective in reversing resistance to doxorubicin when co-incubated with this chemotherapeutic agent in MES-SA-DX5 cells. Our results also showed that compounds G3 and G7 exhibited considerable cytotoxic effects against leukemia and colon cancer cells. In silico docking analysis also confirmed the interaction of compounds G2, G3, G7, and G8 with the drug-substrate binding site of P-gp. Molecular dynamic simulation study was performed to gain insight into the binding mode of compound G3 with P-gp. According to the results, hydrophobic interactions played a more prominent role than hydrogen-binding interactions. Taken together, our findings showed that designed 5-oxo-HHQ compounds are promising MDR reversal agents