title: Synthesis of baicalein derivatives as potential anti-aggregatory and anti-inflammatory agents.
abstract: The direct acylation of trimethoxyphenol (1) with substituted cinnamoyl chlorides followed by Fries rearrangement and cyclization afforded a practical route for the synthesis of novel baicalein derivatives 4 functionalized on the B-ring in good overall yields. In the methylthiazoletetrazolium bromide (MTT) assay, none of the synthetic polyhydroxyflavonoids were cytotoxic at concentrations up to 200 microM on lipopolysaccharide (LPS)-activated murine RAW 264.7 macrophages over 24 h, while in the same cells they significantly inhibited NO production. Among the derivatives, 4d (IC50=46.1 +/- 0.3 microM) was found to exhibit the most potent activity compared with N-nitro-(L)-arginine methyl ester (L-NAME, IC50 >300 microM). Compounds 4b, 4e, 4f, 4h and 4i remarkably inhibited platelet aggregation induced by arachidonic acid and collagen in rabbit washed platelets compared with aspirin. Analysis of their structure-activity relationships indicated that, in the structural modification on the B-ring of baicalein (4a), introduction of appropriate electro-withdrawing substituents such as 2-Cl (4b), 4-Cl (4d), and 4-phenyl (4i) notably increased the potency on the inhibition of LPS-activated NO production and arachidonic acid- and collagen-induced aggregation. Baicalein itself was equally effective in the inhibition of LPS-activated NO production and collagen-induced aggregation but less active against arachidonic acid-induced aggregation. Our in-vitro results suggested that by appropriate structural modification of baicalein it may be possible to develop novel therapeutic agents against platelet-aggregation and inflammation.
authors.affiliation: School of Pharmacy, National Defense Medical Center, Taipei, Taiwan. wenhsin@ndmctsgh.edu.tw
authors.forename: Wen-Hsin
authors.initials: WH
authors.lastname: Huang
authors.forename: An-Rong
authors.initials: AR
authors.lastname: Lee
authors.forename: Pei-Yu
authors.initials: PY
authors.lastname: Chien
authors.forename: Tz-Chong
authors.initials: TC
authors.lastname: Chou
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000009:adverse effects; D001241:Aspirin / Q000494:pharmacology; D002460:Cell Line; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D044950:Flavanones / Q000138:chemical synthesis* / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D011817:Rabbits; D013624:Taiwan; D013678:Technology, Pharmaceutical / Q000379:methods
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D044950:Flavanones; D008070:Lipopolysaccharides; D010975:Platelet Aggregation Inhibitors; D016718:Arachidonic Acid; D009569:Nitric Oxide; C006680:baicalein; D001241:Aspirin; D019331:NG-Nitroarginine Methyl Ester