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Side chain functionalized aniline-derived ursolic acid derivatives as multidrug resistance reversers that block nuclear factor-kappa B (NF-κB) pathway and cell proliferation

Abstract

A series of inhibitors of NF-κB based on ursolic acid (UA) derivatives containing functionalized aniline or amides side chain were synthesized and evaluated for inhibition of NF-κB and the antitumor effects. These compounds exhibited significant inhibition activity to the NF-κB with IC50 values at micromolar concentrations in NCI-H460 lung adenocarcinoma cell line. A docking study of the most active compound 5Y8 revealed key interactions between 5Y8 and the active site of NF-κB in which the functionalized amides moiety at C-28 position and an ester group at C-3 position were important for improving activity. In particular, compound 5Y8 appeared to be the most potent compound against the NCI-H460 cell line, and displayed similar efficiency in drug-sensitive versus drug-resistant cancer cell lines, at least partly, by blocking the NF-κB signaling pathway and induce apoptosis. Mechanistically, compound 5Y8 might trigger apoptotic signalling pathway. Thus, the rational design of functionality aniline or amides side chain UA derivatives offers significant potential for the discovery of a new class of NF-κB inhibitors with the ability to induce apoptosis and reverse multidrug resistance in NCI-H460 lung adenocarcinoma cell line.

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Publication details

The article was received on 28 Feb 2017, accepted on 09 May 2017 and first published on 12 May 2017


Article type: Research Article
DOI: 10.1039/C7MD00105C
Citation: Med. Chem. Commun., 2017, Accepted Manuscript
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    Side chain functionalized aniline-derived ursolic acid derivatives as multidrug resistance reversers that block nuclear factor-kappa B (NF-κB) pathway and cell proliferation

    Z. Liao, R. Huang, S. Hua, X. Huang and H. Wang, Med. Chem. Commun., 2017, Accepted Manuscript , DOI: 10.1039/C7MD00105C

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