Novel synthetic coumarins that targets NF-κB in Hepatocellular carcinoma

Neelgundmath, M. and Dinesh, K. R. and Mohan, C. D. and Li, Feng and Dai, Xiaoyun and Siveen, K. S. and Paricharak, Shardul and Mason, Daniel J. and Fuchs, Julian E. and Sethi, Gautam and Bender, Andreas and Rangappa, K. S. and Kotresh, O. and Basappa, (2015) Novel synthetic coumarins that targets NF-κB in Hepatocellular carcinoma. Bioorganic & Medicinal Chemistry Letters, 25 (4). pp. 893-897. ISSN 0960-894X

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Hepatocellular carcinoma (HCC) is the fifth most common malignant tumor worldwide, and is the third most common cause of cancer related death. Constitutive activation of NF-κB is the underlying mechanism behind tumorigenesis and this protein regulates the expression of genes involved in proliferation, survival, drug resistance, angiogenesis and metastasis. The design of inhibitors which suppress NF-κB activation is therefore of great therapeutic importance in the treatment of HCC. In this study, we investigated the effect of newly synthesized coumarin derivatives against HCC cells, and identified (7-Carbethoxyamino-2-oxo-2H-chromen-4-yl)methylpyrrolidine-1 carbodithioate (CPP) as lead compound. Further, we evaluated the effect of CPP on the DNA binding ability of NF-κB, CXCL12-induced cell migration and invasion, and the regulated gene products in HCC cells. We found that CPP induced cytotoxicity in three HCC cells in a time and dose dependent manner, and suppressed the DNA binding ability of NF-κB. CPP significantly decreased the CXCL12-induced cell migration and invasion. More evidently, CPP inhibits the expression of NF-κB targeted genes such as cyclin D1, Bcl-2, survivin, MMP12 and C-Myc. Furthermore, the molecular docking analysis suggested that CPP interacts with the p50 binding domain of the p65 subunit, scoring best among the 26 docked coumarin derivatives of this study. Thus, we are reporting CPP as a potent inhibitor of the pro-inflammatory pathway in Hepatocellular carcinoma.

Item Type: Article
Additional Information: Unmapped bibliographic data: PY - 2015/2/15/ [EPrints field already has value set] JO - Bioorganic & Medicinal Chemistry Letters [Field not mapped to EPrints]
Uncontrolled Keywords: Hepatocellular carcinoma, Coumarin, NF-κB, Bioinformatics, Inflammation
Subjects: Physical Sciences > Chemistry
Divisions: PG Campuses > Manasagangotri, Mysore > Chemistry
Depositing User: Praveen Kumari B.L
Date Deposited: 25 May 2015 05:30
Last Modified: 08 Oct 2015 10:33

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