title: 4-(N-Phenyl-N'-substituted benzenesulfonyl)-6-(4-hydroxyphenyl)quinolines as inhibitors of mammalian target of rapamycin.
abstract: A series of 4-(N-phenyl-N'-substituted benzenesulfonyl)-6-(4-hydroxyphenyl)quinolines was designed, synthesized and evaluated for their biological potential as anticancer agents by screening the molecules against panel of five human cancer cell lines viz. HL-60, MiaPaCa-2, HCT116, PC-3 and HEP-G2. The series has shown good mTOR inhibitory activity at 0.5 μM concentration. The representative compound 7h was found to be most active with the IC50 of 613 nM against mTOR. In supportive evidence, the western blotting experiment revealed that compound 7h is more potent in inhibiting p-mTOR (S2448) activity in 2-4h at 5 and 10 μM concentrations and was selective and specific towards mTORC1 versus mTORC2. Towards understanding the mechanistic aspects we studied cell cycle analysis, mitochondrial membrane potential loss in MiaPaca-2 cells for compound 7h. The docking study for this series was performed to understand the binding mode of the compounds and its consequent effect in biological activity, the initial interaction studies were found to be useful in design of molecules, where compound 7h has shown additional H-bond interaction with Lys2171 apart from Val2240 and also a small hydrophobic cleft was observed with Leu2185, Met2345 and Ile2356.
authors.affiliation: Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180 001, India; Academy of Scientific and Innovative Research, Anusandhan Bhawan, 2 Rafi Marg, New Delhi 110 001, India.
authors.forename: Vunnam
authors.initials: V
authors.lastname: Venkateswarlu
authors.affiliation: Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180 001, India; Academy of Scientific and Innovative Research, Anusandhan Bhawan, 2 Rafi Marg, New Delhi 110 001, India.
authors.forename: Anup Singh
authors.initials: AS
authors.lastname: Pathania
authors.affiliation: Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180 001, India.
authors.forename: K A
authors.initials: KA
authors.lastname: Aravinda Kumar
authors.affiliation: Discovery Informatics, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180 001, India; Academy of Scientific and Innovative Research, Anusandhan Bhawan, 2 Rafi Marg, New Delhi 110 001, India.
authors.forename: Priya
authors.initials: P
authors.lastname: Mahajan
authors.affiliation: Discovery Informatics, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180 001, India; Academy of Scientific and Innovative Research, Anusandhan Bhawan, 2 Rafi Marg, New Delhi 110 001, India.
authors.forename: Amit
authors.initials: A
authors.lastname: Nargotra
authors.affiliation: Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180 001, India; Academy of Scientific and Innovative Research, Anusandhan Bhawan, 2 Rafi Marg, New Delhi 110 001, India.
authors.forename: Ram A
authors.initials: RA
authors.lastname: Vishwakarma
authors.affiliation: Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180 001, India; Academy of Scientific and Innovative Research, Anusandhan Bhawan, 2 Rafi Marg, New Delhi 110 001, India. Electronic address: fmalik@iiim.ac.in.
authors.forename: Fayaz A
authors.initials: FA
authors.lastname: Malik
authors.affiliation: Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180 001, India; Academy of Scientific and Innovative Research, Anusandhan Bhawan, 2 Rafi Marg, New Delhi 110 001, India. Electronic address: sdsawant@iiim.res.in.
authors.forename: Sanghapal D
authors.initials: SD
authors.lastname: Sawant
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D006801:Humans; D020128:Inhibitory Concentration 50; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011804:Quinolines / Q000737:chemistry*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011804:Quinolines; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: 4-(N-Phenyl-N′-substituted benzenesulfonyl)-6-(4-hydroxyphenyl)quinolines; Cancer cell-lines; Cytotoxicity; mTOR inhibitor