Wen-Hsin Huang

Antioxidative and Anti-Inflammatory Activities of Polyhydroxyflavonoids of Scutellaria baicalensis GEORGI

The active ingredients of ‘golden root’ of Scutellaria baicalensis GEORGI (Huang-Qin), a valuable traditional Chinese medicine, are polyhydroxyflavonoids, namely baicalein, oroxylin A and wogonin. With the objective of overcoming their poor solubility and to investigate their structure and activity relationships, baicaleinyl 7-O-sulfate was prepared, and extensive comparative antioxidative and anti-inflammatory tests were conducted. All the polyhydroxyflavonoids exhibited significant antioxidative and free-radical scavenging activities. In respect of their nitric oxide (NO) inhibition, wogonin was superior to all the other flavonoids, while oroxylin A was most potent in the inhibition of lipid peroxidation. Wogonin proved to be the most potent (82.9% inhibition, p<0.05) in its anti-inflammatory activity against carrageenan-induced rat hind paw edema. There was a correlation between the in-vivo anti-inflammatory activity and the in-vitro antioxidative activities.

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

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.

Zinc Sulphadiazines: Novel Topical Antimicrobial Agents for Burns

Two new zinc sulphadiazine (Zn(SD)2)‐amine complexes, zinc sulphadiazine‐methylamine (Zn(SD)2(CH3NH2)2) and zinc sulphadiazine‐ethylenediamine (Zn(SD)2(C2H8N2)3·H2O), were prepared and compared with silver sulphadiazine (AgSD). The compounds were readily obtained by reaction of zinc nitrate hexahydrate with sulphadiazine or its salt in methylamine and ethylenediamine, respectively.

Synthesis of 5,6,7-trimethoxyflavone as a key intermediate for the preparation of baicalein

Approaches towards the preparation of 5,6,7-trimethoxyflavone (8), a key intermediate for the synthesis of baicalein, are discussed. Of the synthetic routes, the most efficient was accomplished by direct Fries acylation of trimethoxyphenol (1) with cinnamoyl chloride followed by oxidative cyclization of the resulting chalcone 6 with I 2 /DMSO in good overall yields (70%). Demethylation of 8 using 47% HBr/AcOH readily produced baicalein. The chalcone 6 could also be prepared by Claisen-Schmidt condensation of acetophenone 2 with benzaldehyde catalyzed in alkali.

Novel Daidzein Analogs and Their in Vitro Anti-Influenza Activities

A series of novel isoflavonoids were synthesized based on structural modifications of daidzein, an active ingredient of traditional Chinese medicine (TCM) and evaluated for their anti‐influenza activity, in vitro, against H1N1 Tamiflu‐resistant (H1N1 TR) virus in the MDCK cell line. Among them, 4‐oxo‐4H‐1‐benzopyran‐8‐carbaldehydes 11a–11g were most promising, and they demonstrated better activities and selectivities comparable to those the reference ribarivin, a nucleoside antiviral agent. 3‐(4‐Bromophenyl)‐7‐hydroxy‐4‐oxo‐4H‐1‐benzopyran‐8‐carboxaldehyde (11c) displayed the best inhibitory activity (EC50, 29.0 μM) and selectivity index (SI>10.3). Analysis of the structureactivity relationships (SAR) indicated that both the non‐naturally‐occurring Br‐substituted B‐ring and appropriate CHO and OH groups on the A‐ring might be critical for the activity and selectivity against H1N1 TR influenza viruses.