title: Novel nitric oxide-releasing derivatives of brusatol as anti-inflammatory agents: design, synthesis, biological evaluation, and nitric oxide release studies.
abstract: 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.
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College , No. 1 Xian Nong Tan Street, Beijing 100050, China.
authors.forename: Weibin
authors.initials: W
authors.lastname: Tang
authors.forename: Jianlin
authors.initials: J
authors.lastname: Xie
authors.forename: Song
authors.initials: S
authors.lastname: Xu
authors.forename: Haining
authors.initials: H
authors.lastname: Lv
authors.forename: Mingbao
authors.initials: M
authors.lastname: Lin
authors.forename: Shaopeng
authors.initials: S
authors.lastname: Yuan
authors.forename: Jinye
authors.initials: J
authors.lastname: Bai
authors.forename: Qi
authors.initials: Q
authors.lastname: Hou
authors.forename: Shishan
authors.initials: S
authors.lastname: Yu
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000009:adverse effects / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D005260:Female; D008070:Lipopolysaccharides / Q000009:adverse effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000096:biosynthesis*; D010069:Oxadiazoles / Q000737:chemistry; D029424:Pulmonary Disease, Chronic Obstructive / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D036702:Quassins / Q000009:adverse effects / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D012907:Smoking / Q000009:adverse effects; D013329:Structure-Activity Relationship
chemical_list: C528141:1,2,5-oxadiazole 2-oxide; D000893:Anti-Inflammatory Agents; D008070:Lipopolysaccharides; D010069:Oxadiazoles; D036702:Quassins; C020237:brusatol; D009569:Nitric Oxide