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Synthesis and structure‐activity relationships of 3′‐ and 4′‐substituted flavonols
Author(s) -
Woodman Owen,
Qin ChengXue,
Hughes Richard,
Williams Spencer
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1146-b
Subject(s) - flavonols , chemistry , substituent , stereochemistry , structure–activity relationship , organic chemistry , biochemistry , in vitro , flavonoid , antioxidant
The vascular activity of naturally occurring flavonols has been investigated, but the development of quantitative structure‐activity relationships is restricted by their limited structural variations. We synthesized a series of 4′‐substituted (OMe; Me; Cl; C(CH 3 ) 3 ) and 3′‐substituted (OMe; Me; Br)‐4′‐hydroxy flavonols and the activity of all compounds was screened by their ability to inhibit phenylephrine‐induced contraction. Of the flavonols tested, only those which bear a hydroxyl group at the 4′ position were active. Active flavonols were then examined for their ability to relax rat isolated aortic rings. The synthetic flavonols (4′‐hydroxyflavonol, pEC 50 =5.64±0.06, R max =104±1; 3′‐methoxy‐4′‐hydroxy flavonol, 5.48±0.07, 98±2; 3′‐methyl‐4′‐hydroxyflavonol, 5.58±0.05, 101±2; 3′‐bromo‐4′‐hydroxyflavonol, 5.54±0.12, 105±1, all n=5) were as active as the most active compound described to date, 3′, 4′‐dihydroxyflavonol (5.48±0.09; 102±3; n=6). This work reveals that a hydroxy group is the optimum substituent at the 4′ position. Provided that the hydroxy group is present at the 4′ position, alterations of substituents at the 3′ position have no effect on vasorelaxant activity. This study may lead to the development of new therapeutic flavonols with a hydroxy group fixed at the 4′ position and modifications to the 3′ position to improve physicochemical properties such as water solubility.