title: Adamantyl-tethered-biphenylic compounds induce apoptosis in cancer cells by targeting Bcl homologs.
abstract: Bcl homologs prominently contribute to apoptotic resistance in cancer cells and serve as molecular targets in treatment of various cancers. Herein, we report the synthesis of biphenyl-adamantane derivatives by a ligand free palladium on carbon based Suzuki reaction using diisopropylamine as a base for the coupling of adamantane based aryl chloride with a variety of aryl boronic acids. Among the biphenyl derivatives synthesized, compound 3'-(adamantan-1-yl)-4'-methoxy-[1,1'-biphenyl]-3-ol (AMB) displayed cytotoxic activity against hepatocellular carcinoma cell lines without significantly affecting the normal cell lines. Further, AMB caused increased accumulation of the HCC cells in subG1 phase, decreased the expression of Bcl-2, Bcl-xL, cyclin D1, caspase-3, survivin and increased the cleavage of PARP in a time-dependent manner. In silico molecular interaction studies between Bcl homologs and AMB showed that the biphenyl scaffold is predicted to form π-π interactions with Phe-101 and Tyr-105 and the adamantyl fragment is predicted to occupy another hydrophobic region in the kink region of the binding groove. In summary, we report on the synthesis and biological characterization of adamantyl-tethered biphenylic compounds that induce apoptosis in tumor cells most likely by targeting Bcl homologs.
authors.affiliation: Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Central College Campus, Palace Road, Bangalore 560001, India.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Anusha
authors.affiliation: Department of Studies in Chemistry, Manasagangotri, University of Mysore, Mysore 570006, India.
authors.forename: Chakrabhavi Dhananjaya
authors.initials: CD
authors.lastname: Mohan
authors.affiliation: Department of Studies in Chemistry, Manasagangotri, University of Mysore, Mysore 570006, India.
authors.forename: Hanumappa
authors.initials: H
authors.lastname: Ananda
authors.affiliation: Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Central College Campus, Palace Road, Bangalore 560001, India.
authors.forename: C P
authors.initials: CP
authors.lastname: Baburajeev
authors.affiliation: Frontier Research Center for Post-Genome Science and Technology, Hokkaido University, Sapporo 060-0808, Japan.
authors.forename: Shobith
authors.initials: S
authors.lastname: Rangappa
authors.affiliation: Gulf Medical University, Ajman, United Arab Emirates.
authors.forename: Jessin
authors.initials: J
authors.lastname: Mathai
authors.affiliation: Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW Cambridge, United Kingdom; Institute of General, Inorganic and Theoretical Chemistry, Department of Chemistry, University of Innsbruck, Innrain 82, 6020 Innsbruck, Austria.
authors.forename: Julian E
authors.initials: JE
authors.lastname: Fuchs
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600.
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600.
authors.forename: Muthu K
authors.initials: MK
authors.lastname: Shanmugam
authors.affiliation: Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW Cambridge, United Kingdom.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bender
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600.
authors.forename: Gautam
authors.initials: G
authors.lastname: Sethi
authors.affiliation: Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Central College Campus, Palace Road, Bangalore 560001, India. Electronic address: salundibasappa@gmail.com.
authors.lastname: Basappa
authors.affiliation: Department of Studies in Chemistry, Manasagangotri, University of Mysore, Mysore 570006, India. Electronic address: rangappaks@yahoo.com.
authors.forename: Kanchugarakoppal S
authors.initials: KS
authors.lastname: Rangappa
mesh_terms: D000218:Adamantane / Q000737:chemistry*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D001713:Biphenyl Compounds / Q000737:chemistry* / Q000494:pharmacology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D062105:Molecular Docking Simulation; D017434:Protein Structure, Tertiary
chemical_list: D000218:Adamantane; D051017:Apoptosis Regulatory Proteins; D001713:Biphenyl Compounds; C010574:biphenyl
keywords: Adamantyl-biphenyls; Apoptosis; Bcl homologs; Hepatoma; Molecular docking analysis