title: Design, synthesis and biological evaluations of chirally pure 1,2,3,4-tertrahydroisoquinoline analogs as anti-cancer agents.
abstract: A series of fifteen chiral 1,2,3,4-tetrahydroisoquinoline (THIQ) derivatives have been synthesized and their antiproliferative properties have been studied. The in vitro screening was performed against five cancer cell lines; MCF-7 (breast cancer), A549 (lung cancer), DU-145 (prostate cancer), Hela (cervical cancer) and HepG2 (liver cancer). Most of the compounds showed promising activity with IC50 Values ranging from 0.72 to 92.6 μM. Among them, compounds 9a and 9b have shown significant activity against human prostate cancer cell line, i.e., DU-145 with IC50 value 0.72 and 1.23 μM respectively. To investigate the mechanism of action, detailed biological studies of compounds 9a and 9b were carried out on the human prostate cancer cell line, DU-145. Flow cytometric analysis revealed that these compounds induced cell cycle arrest at G2/M phase. Tubulin polymerization assay and immunofluorescence analysis results suggested that these compounds effectively inhibit microtubule assembly formation in DU-145. The apoptosis inducing properties were evaluated by DNA fragmentation analysis, Caspase-3 activity assay, Annexin V-FITC assay and Western blot analysis of proapoptotic protein, Bax and antiapoptotic protein Bcl-2.
authors.affiliation: Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology (CSIR-IICT), Tarnaka, Hyderabad 500 007, India; Academy of Scientific and Innovative Research, New Delhi 110025, India.
authors.forename: Triparagiri
authors.initials: T
authors.lastname: Ramanivas
authors.affiliation: National Institute of Pharmaceutical Education and Research, Balanagar, Hyderabad 500037, India.
authors.forename: Bottu
authors.initials: B
authors.lastname: Sushma
authors.affiliation: Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology (CSIR-IICT), Tarnaka, Hyderabad 500 007, India.
authors.forename: V Lakshma
authors.initials: VL
authors.lastname: Nayak
authors.affiliation: Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology (CSIR-IICT), Tarnaka, Hyderabad 500 007, India.
authors.forename: Kunta
authors.initials: K
authors.lastname: Chandra Shekar
authors.affiliation: Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology (CSIR-IICT), Tarnaka, Hyderabad 500 007, India; Academy of Scientific and Innovative Research, New Delhi 110025, India. Electronic address: aksrivastava@iict.res.in.
authors.forename: Ajay Kumar
authors.initials: AK
authors.lastname: Srivastava
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D061986:MCF-7 Cells; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D007546:Isoquinolines
keywords: 1,2,3,4-Tetrahydroisoquinolines (THIQ); Annexin V-FITC assay and apoptosis; Caspase-3; Cell cycle analysis; Tubulin polymerization