Adamantyl-tethered-biphenylic compounds induce apoptosis in cancer cells by targeting Bcl homologs

被引：37

作者：

Anusha, Sebastian ^{[1
]}

Mohan, Chakrabhavi Dhananjaya ^{[2
]}

Ananda, Hanumappa ^{[2
]}

Baburajeev, C. P. ^{[1
]}

Rangappa, Shobith ^{[3
]}

Mathai, Jessin ^{[4
]}

Fuchs, Julian E. ^{[5
,6
]}

Li, Feng ^{[7
]}

Shanmugam, Muthu K. ^{[7
]}

Bender, Andreas ^{[5
]}

Sethi, Gautam ^{[7
]}

Basappa ^{[1
]}

Rangappa, Kanchugarakoppal S. ^{[2
]}

机构：

[1] Bangalore Univ, Dept Chem, Biol Chem Lab, Cent Coll Campus,Palace Rd, Bangalore 560001, Karnataka, India

[2] Univ Mysore, Dept Studies Chem, Manasagangotri, Mysore 570006, Karnataka, India

[3] Hokkaido Univ, Frontier Res Ctr Postgenome Sci & Technol, Sapporo, Hokkaido 0600808, Japan

[4] Gulf Med Univ, Ajman, U Arab Emirates

[5] Univ Cambridge, Dept Chem, Ctr Mol Informat, Lensfield Rd, Cambridge CB2 1EW, England

[6] Univ Innsbruck, Inst Gen Inorgan & Theoret Chem, Dept Chem, Innrain 82, A-6020 Innsbruck, Austria

[7] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Pharmacol, Singapore 117600, Singapore

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2016年 / 26卷 / 03期

关键词：

Bcl homologs; Adamantyl-biphenyls; Apoptosis; Hepatoma; Molecular docking analysis; CARCINOMA IN-VITRO; HEPATOCELLULAR-CARCINOMA; SIGNAL TRANSDUCER; FAMILY-MEMBERS; KAPPA-B; MODULATION; INVASION; ALPHA; PROLIFERATION; INHIBITOR;

D O I：

10.1016/j.bmcl.2015.12.026

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 pi-pi 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. (C) 2015 Elsevier Ltd. All rights reserved.

引用

页码：1056 / 1060

页数：5

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