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) deriva-tives 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 com-pounds 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 anal-ysis 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.(c) 2023 Elsevier B.V. All rights reserved.

Automated summary

In this study, novel 5-oxo-hexahydroquinoline derivatives were synthesized and tested for their ability to reverse multidrug resistance (MDR) in cancer cells overexpressing P-glycoprotein (P-gp). Most of the compounds showed enhanced intracellular accumulation of rhodamine 123, a P-gp substrate, and some exhibited better results than the established P-gp inhibitor verapamil. Certain compounds also effectively reversed resistance to doxorubicin and showed cytotoxic effects against leukemia and colon cancer cells. Molecular simulation analysis confirmed the interaction of selected compounds with the drug-substrate binding site of P-gp.