- Int. J. Immunopathol. Pharmacol. 14:119, 2001
- ANTI-INFLAMMATORY ACTIONS OF FLAVONOIDS AND STRUCTURAL
- REQUIREMENTS FOR NEW DESIGN
- T.C. THEOHARIDES 1,2,
M. ALEXANDRAKIS 1,3, D. KEMPURAJ1 and M. LYTINAS 1
- 1 Department of Pharmacology and
Experimental Therapeutics, and 2 Internal
Medicine, Tufts
- University School of Medicine, New England Medical Center, 136 Harrison Avenue, Boston,
- Massachusetts, USA
- 3 Department of Hematology, Division of
Health Sciences, University of Crete, Heraklion, Greece
- Flavonoids are low molecular weight compounds rich in seeds, citrus fruits, olive oil,
tea and red
- wine, with potent antioxidant, cytoprotective and antiinflammatory activities.
Flavonoids are
- composed of a three-ring structure (A,B and C) with various substitutions; they can be
subdivided
- according to the presence of an oxy group at position 4, a double bond between carbon
atoms 2 and
- 3 or a hydroxyl group in position 3 of the C (middle) ring. Particular hydroxylation
patterns of the B
- ring of the flavones permit them to inhibit histamine, tryptase, interleukin-6 and
interleukin-8
- release from human umbilical-cord derived cultured mast cells, as well as from
macrophages. The
- catechol (o-dihydroxy) group in the B ring as in quercetin confers potent inhibitory
ability, while a
- pyrogallol (trihydroxy) group, as in myricetin, produces even higher activity. However,
addition of
- one hydroxyl group on position 2' of the B ring, as in the flavonol morin, renders this
compound
- inactive. The C2-C3 double bond of the C ring appears to increase scavenger activity
because it
- confers stability to the phenoxy-radicals produced, while the 4-oxo (keto double bond at
position 4
- of the C ring) increases free radical scavenger activity by delocalizing electrons from
the B ring.
- The 3-OH group on the C ring appears tobe critical for anti-inflammatory activity.
Inhibition of
- mast cell secretion was shown to be mediated by a 78-kD phosphoprotein which has been
cloned
- and serves as a bridge between the cell surface and the cytoskeleton. Phosphorylation at
particular
- sites in the C-terminus unfolds the three dimensional structure of this protein making
actin binding
- sites accessible; crosslinking with actin in the cytoskeleton prevents secretion of
inflammatory
- mediators. These properties present unique opportunities for the synthesis of new
compounds for
- the treatment of inflammatory and possibly proliferative disorders.
- Key words: allergy, flavonoids, inflammation, mast
cells, secretion
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