Synthesis of Clovamide Analogues That Inhibit NO Production in Activated BV-2 Microglial Cells

• Published in: Biological & pharmaceutical bulletin Vol. 40; no. 9; pp. 1475 - 1482
• Main Authors: Park, Ju-Young, Kim, Byung-Wook, Lee, Hae Un, Choi, Dong-Kug, Yoon, Sung-Hwa
• Format: Journal Article
• Language: English
• Published: Japan The Pharmaceutical Society of Japan 01.09.2017; Japan Science and Technology Agency
• Subjects: Animals; Anti-Inflammatory Agents - chemical synthesis; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacology; BV2 cell; Caffeic acid; Caffeic Acids; Catechol; Cell Line; clovamide methyl ester; Cytotoxicity; Dihydroxyphenylalanine; Functional groups; Levodopa; Lipopolysaccharides; Mice; microglia; Microglia - metabolism; Microglial cells; Nitric oxide; Nitric Oxide - biosynthesis; Nitric Oxide Synthase Type II - metabolism; Nitric-oxide synthase; Plant Extracts; Structure-Activity Relationship; trifluoromethyl analogue; Tyrosine - analogs & derivatives; Tyrosine - chemical synthesis; Tyrosine - chemistry; Tyrosine - pharmacology; nitric oxide; trifluoromethyl analogue; BV2 cell; microglia; clovamide methyl ester
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.b17-00303

A series of methyl ester of clovamide analogues, where the hydroxyl group of catechol moiety in caffeic acid and L-3,4-dihydroxyphenylalanine (L-dopa) was replaced with various functional groups, were synthesized and their inhibitory effects on nitric oxide (NO) production and inducible NO synthase (iNOS) expression in lipopolysaccharide (LPS)-induced BV2 cells were tested. Among the synthesized compounds, 3,5-ditrifluoromethyl analogue 9l (IC50=2.8 µM) exhibited a potency about 26.3 times greater than that of the parent compound 9a (IC50=73.6 µM) and suppressed NO production dose-dependently without cytotoxicity. Compound 9l also inhibited iNOS expression in LPS-induced BV2 cells at 2.5, 5 and 10 µM concentrations. These results suggested that the dihydroxyl group of catechol moiety in caffeic acid unit is not essential for the suppression of NO production and that 9l has potential as a potent inhibitor of NO production.