title: Novel 5-oxo-hexahydroquinoline derivatives: design, synthesis, in vitro P-glycoprotein-mediated multidrug resistance reversal profile and molecular dynamics simulation study.
abstract: 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 C4and various carboxamide substituents at C3were 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 C4position and compounds with 4-chlorophenyl carboxamide at C3demonstrated 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 IC50of 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 for2ccompound showed no cytotoxicity. A molecular dynamics simulation study was also performed to investigate the possible binding site of5cin 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.
authors.affiliation: Medicinal and Natural Products Chemistry Research Center; Department of Medicinal Chemistry, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
authors.forename: Omolbanin
authors.initials: O
authors.lastname: Shahraki
authors.affiliation: Medicinal and Natural Products Chemistry Research Center.
authors.forename: Najmeh
authors.initials: N
authors.lastname: Edraki
authors.affiliation: Medicinal and Natural Products Chemistry Research Center; Department of Medicinal Chemistry, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Khoshneviszadeh
authors.affiliation: Medicinal and Natural Products Chemistry Research Center.
authors.forename: Farshid
authors.initials: F
authors.lastname: Zargari
authors.affiliation: Medicinal and Natural Products Chemistry Research Center; Department of Medicinal Chemistry, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
authors.forename: Sara
authors.initials: S
authors.lastname: Ranjbar
authors.affiliation: Department of Physiology and Pharmacology "Vittorio Ersparmer", Sapienza University of Rome, Rome, Italy.
authors.forename: Luciano
authors.initials: L
authors.lastname: Saso
authors.affiliation: Medicinal and Natural Products Chemistry Research Center.
authors.forename: Omidreza
authors.initials: O
authors.lastname: Firuzi
authors.affiliation: Medicinal and Natural Products Chemistry Research Center.
authors.forename: Ramin
authors.initials: R
authors.lastname: Miri
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: C000618475:5-oxo-hexahydroquinoline; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D011804:Quinolines
keywords: 1,4-dihydropyridine; P-glycoprotein; cancer; molecular dynamics simulation; multidrug resistance