Synthesis of baicalein derivatives as potential anti-aggregatory and anti-inflammatory agents

Author:

Huang Wen-Hsin1,Lee An-Rong1,Chien Pei-Yu1,Chou Tz-Chong2

Affiliation:

1. School of Pharmacy, National Defense Medical Center, Taipei, Taiwan

2. Department of Physiology, National Defense Medical Center, Taipei, Taiwan

Abstract

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 μm 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 μm) was found to exhibit the most potent activity compared with N-nitro-L-arginine methyl ester (L-NAME, IC50 > 300 μm). 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-CI (4b), 4-CI (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.

Publisher

Oxford University Press (OUP)

Subject

Pharmaceutical Science,Pharmacology

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