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Overexpression of the efflux pump P-glycoprotein (P-gp) is one of the important mechanisms of multidrug resistance (MDR) in many tumor cells. In this study, 26 novel 5-oxo-hexahydroquinoline derivatives containing different nitrophenyl moieties at C 4 and various carboxamide substituents at C 3 were designed, synthesized and evaluated for their ability to inhibit P-gp by measuring the amount of rhodamine 123 (Rh123) accumulation in uterine sarcoma cells that overexpress P-gp (MES-SA/Dx5) using flow cytometry. The effect of compounds with highest MDR reversal activities was further evaluated by measuring the alterations of MES-SA/Dx5 cells' sensitivity to doxorubicin (DXR) using MTT assay. The results of both biological assays indicated that compounds bearing 2-nitrophenyl at C 4 position and compounds with 4-chlorophenyl carboxamide at C 3 demonstrated the highest activities in resistant cells, while they were devoid of any effect in parental nonresistant MES-SA cells. One of the active derivatives, 5c , significantly increased intracellular Rh123 at 100 µM, and it also significantly reduced the IC 50 of DXR by 70.1% and 88.7% at 10 and 25 µM, respectively, in MES-SA/Dx5 cells. The toxicity of synthesized compounds against HEK293 as a noncancer cell line was also investigated. All tested derivatives except for 2c compound showed no cytotoxicity. A molecular dynamics simulation study was also performed to investigate the possible binding site of 5c in complex with human P-gp, which showed that this compound formed 11 average H-bonds with Ser909, Thr911, Arg547, Arg543 and Ser474 residues of P-gp. A good agreement was found between the results of the computational and experimental studies. The findings of this study show that some 5-oxo-hexahydroquinoline derivatives could serve as promising candidates for the discovery of new agents for P-gp-mediated MDR reversal., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Mammalian target of rapamycin (mTOR) is a phosphoinositide 3-kinase-related protein kinase which controls cell growth and is frequently deregulated in many cancers. Therefore, mTOR inhibitors are used as antineoplastic agents for cancer treatment. In this study, 1,2,4-triazine derivatives containing different arylidene-hydrazinyl moieties were designed and synthesized. Cytotoxicity of the compounds was evaluated on HL-60 and MCF-7 cell lines by MTT assay. S1, S2 and S3 exhibited good cytotoxic activity on both cell lines with an IC50 range of 6.42 - 20.20 µM. In general, substitution of a five-membered heterocyclic ring containing NO2, such as 5-nitrofuran-2-yl, resulted in the best potency. Molecular docking analysis was performed to study the possible interactions and binding modes of all the triazine derivatives with mTOR receptor. The most promising compound, S1, was well accommodated within the active site and had the least estimated free energy of binding (even less than the inherent ligand of the protein, PDB ID: 4JT6). It is concluded from both MTT assay and docking studies that the arylidene moiety linked to the hydrazinyl part of the structure had a prominent role in cytotoxicity and mTOR inhibitory activity. [ABSTRACT FROM AUTHOR]

• Ten novel series of 5-Oxohexahydroquinolines derivatives were designed and synthesized as inhibitors of P-gp targeting multidrug resistance in cancer. • All compounds increased the accumulation of the P-gp substrate rhodamine 123 in P-gp- overexpressing MES-SA/DX5 cancer cells. • Compounds G2, G3, G7, and G8 with the highest inhibitory potential could reverse P-gp-mediated drug resistance in MES-SA/DX5 cells. • Derivatives G3 and G7 exhibited considerable antiproliferative effects against several cancer cell lines. • In silico studies revealed the interaction of most potent compounds with the drug-substrate binding site of P-gp. 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. [Display omitted] [ABSTRACT FROM AUTHOR]