Novel Nitric Oxide-Releasing Derivatives of Brusatol as Anti-Inflammatory Agents: Design, Synthesis, Biological Evaluation, and Nitric Oxide Release Studies

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• 作者：Weibin Tang ; Jianlin Xie ; Song Xu ; Haining Lv ; Mingbao Lin ; Shaopeng Yuan ; Jinye Bai ; Qi Hou ; Shishan Yu
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：September 25, 2014
• 年：2014
• 卷：57
• 期：18
• 页码：7600-7612
• 全文大小：535K
• ISSN：1520-4804

文摘

Brusatol, a biologically active natural product, was modified in four distinct positions through the covalent attachment of a furoxan moiety, which acts as a nitric oxide (NO) donor. Forty derivatives were synthesized and evaluated for their inhibitory effects on excess NO biosynthesis in activated macrophages. Among them, compound 75 demonstrated inhibition (IC₅₀ = 0.067 渭M) comparable to that of brusatol but were less cytotoxic. More importantly, even at very low doses (2 渭mol/kg/day), compound 75 also showed substantial inhibitory efficacy against chronic obstructive pulmonary disease (COPD)-like inflammation in the mouse model induced by cigarette smoke (CS) and lipopolysaccharide (LPS). Particularly, this compound was over 100-fold less toxic (LD₅₀ > 3852 渭mol/kg) than brusatol and could be a promising lead for further studies. Notably, the improved properties of this derivative are associated with its NO-releasing capability.