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

• Published in: Journal of medicinal chemistry Vol. 57; no. 18; pp. 7600 - 7612
• Main Authors: Tang, Weibin, Xie, Jianlin, Xu, Song, Lv, Haining, Lin, Mingbao, Yuan, Shaopeng, Bai, Jinye, Hou, Qi, Yu, Shishan
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 25.09.2014; Amer Chemical Soc
• Subjects: Animals; Anti-Inflammatory Agents - adverse effects; Anti-Inflammatory Agents - chemical synthesis; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacology; Chemistry Techniques, Synthetic; Chemistry, Medicinal; Drug Design; Female; Life Sciences & Biomedicine; Lipopolysaccharides - adverse effects; Macrophages - drug effects; Macrophages - metabolism; Male; Mice; Nitric Oxide - biosynthesis; Oxadiazoles - chemistry; Pharmacology & Pharmacy; Pulmonary Disease, Chronic Obstructive - chemically induced; Pulmonary Disease, Chronic Obstructive - drug therapy; Pulmonary Disease, Chronic Obstructive - metabolism; Quassins - adverse effects; Quassins - chemical synthesis; Quassins - chemistry; Quassins - pharmacology; Science & Technology; Smoking - adverse effects; Structure-Activity Relationship; SYNTHASE; NO; OBSTRUCTIVE PULMONARY-DISEASE; IN-VITRO; QUASSINOIDS; ACID; INFLAMMATION; DONORS; HYDROGEN-SULFIDE; ANTIMALARIAL
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm5007534

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 μM) comparable to that of brusatol but were less cytotoxic. More importantly, even at very low doses (2 μmol/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 μmol/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.