Novel nitric oxide-releasing derivatives of brusatol as anti-inflammatory agents: design, synthesis, biological evaluation, and nitric oxide release studies.

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