Novel synthetic coumarins that targets NF-kappa B in Hepatocellular carcinoma

作者：Neelgundmath Mahabaleshwaraiah; Dinesh Koragere Rajashekar; Mohan Chakrabhavi Dhananjaya; Li Feng; Dai Xiaoyun; Siveen Kodappully Sivaraman; Paricharak Shardul; Mason Daniel J; Fuchs Julian E; Sethi Gautam; Bender Andreas; Rangappa Kanchugarakoppal S; Kotresh Obelannavar^*; Basappa

来源：Bioorganic & Medicinal Chemistry Letters, 2015, 25(4): 893-897.

DOI：10.1016/j.bmcl.2014.12.065

• Hepatocellular carcinoma
• Coumarin
• NF-kappa B
• Bioinformatics
• Inflammation

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-kappa B 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-kappa B 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-kappa B, 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-kappa B. CPP significantly decreased the CXCL12-induced cell migration and invasion. More evidently, CPP inhibits the expression of NF-kappa B 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 sub-unit, 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.

• 出版日期2015-2-15