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| FLAVONES
AND
RELATED HETEROCYCLES AS POTENTIAL ANTI -INFLAMMATORY AGENTS,
5-LIPOXYGENASE
INHIBITORS CYCLOOXYGENASE – 2 INHIBITORS.
The contribution of higher plant derived products as drugs
or lead
molecules for the discovery of new drugs is well recorded.
Steroid,
diosgenin obtained from Dioscorea floribunda, Codeine and
morphine
from Papaver somnifera, atropine from Atropa belladona,
quinine from Cinchona officinalis, vincristine from Catharanthus
roseus, taxol from Taxus baccata, digoxin from Digitalis
species and pilocarpine from Pilocarpus species are the
classical
examples of natural product drugs . Further modifications –
synthetic
analogs – of these drugs are also available in the market. Contact :: orgachemweb@gmail.com
There are serval reports that plant derived products are capable of
interfering
with biochemical processes involved in inflammation.
Screening of several types of compounds for their activity as
5-lipoxygenase
enzyme Inhibitors, cyclooxygenase enzyme inhibitors is gaining
importance
to assess Contact :: orgachemweb@gmail.com
The status of research in 5-lipoxygenase inhibition is reviewed
COX-1 is expressed in many tissues and its metabolites are involved in various physiological functions such as gastric cytoprotection, vascular homeostasis and renal sodium and water balance. COX-2 is an immediate early gene and its expression is induced in response to cell activation by harmones, tumor promoters, growth factors or proinflammatory agents. Prostanoids, which are synthesised by COX-2 are involved in inflammatory processes, pain and fever.
Mechanism for the action of non-steroidal anti-inflammatory drugs
(NSAIDS)
is essentially by the inhibition of COX. However, several side
effects,
such as gastrointestinal and renal side effects, are associated with
NSAIDS.
With the availability of rapid bio-assays for measuring in vitro
inhibition of COX-1 and COX-2, it is observed that most of the NSAIDS
are Contact :: orgachemweb@gmail.com 5-LIPOXYGENASE (LO) INHIBITORY ACTIVITY OF FLAVONOIDS Activity of 5-Lipoxygenase results in the production of leukotrienes, a family of bioactive lipids, with important pro-inflammatory consequences.Flavonoids with 5-lipoxygenase activity include quercetin (5,7,3’,4’,3 – pentahydroxyflavone), baicalein and the coumarin, esculetin, with IC 50 values between 0.1 and 5 Micro.M. (M. Duwiejua et al Loc.cit). Essential structural features of flavonoids to act as Lipoxygenation inhibitors include the following structural features: 1. Carbonyl substituent at position
–4; Catechin
lacks 4-carbonyl and therefore it does not inhibit LO-enzyme. But
it is a good antioxidant.
Thus to sum up flavonoids exhibit COX or 5-LO activity.
Their
activity is increased by
Higher polarity by itself does not confer activity. For example
highly
polar caffeic acid esters, chlorogenic acid, rosamarinic acid are
completely
inactive. Wedelolactone (a coumestan) has comparable
LO-inhibitory
activity (IC 50, 2.5 Micro M) and nordihydroguaretic acid is a potent
LO-inhibitors
(IC 50,1.5 Micro M). This suggest that some degree of lipophilicity is
required for lipoxygenase inhibition. The presence of
3’,4’-dihydroxy
system (catechol system) in ring B appear to confer 5-LOinhibitory
activity
suggesting that such compounds act via free radical scavenging
mechanism.
Complete alkylation of the hydroxyl groups as in the case of
pentamethyl
quercetin – abolishes cyclooxygenase inhibiting properties. Contact :: orgachemweb@gmail.com
Inhibition of inflammation by flavonoids is not limited only to
arachidonic
acid metabolism. Flavonoids have been shown to be strong
antioxidants
because of their affinity for divalent ions of heavy metals which
catalyses
the process involved in free radical generation. A series of 3,4-dihydroxy chalcones were synthesised to evaluate their effects against 5-Lipoxygenase and cyclooxygenase. Several chalcones of this series exhibited potent inhibitory effects on 5-Lipoxygenase with antioxidative effects and some also inhibited cyclooxygenase. 2',5'-Disubstituted-3,4-dihydroxy chalcones with hydroxy or alkoxy groups exhibited optimal inhibition. Thus the activity of 2',5'-dimethoxy – 3,4 dihydroxychalcone as cyclooxygenase inhibitor is of the same degree as fluefenamic acid. Further its activity as 5-LO is more than quercetin. Some of these potent 5-LO inhibitors inhibited arachidonic acid – induced mouse ear edema more than phenadione (Satoshi sogaura et al, 3,4-dihydroxy chalcones as potent Lipooxygenase and cyclooxygenase inhibitors, J. Med. Chem., 1993, 36, 3904).
Flavonoids such as chrysin (5,7-dihydroxy flavone), quercitin and (-)-epi-catechin
,all hydroxy flavones, with vicinal dihydroxy system and / or chelated
hydroxyl carbonyl system were found to be good antioxidants under
various
test conditions.COX-2 inhibitors. In 1999, eight years after the concept of OX -2 was introduced, the first selective drugs, celecoxib and rofecoxib were introduced. They have good clinical efficacy in pain, rheumatoid arthritis and osteoarthritis but still gastrointestinal side effects, although to a lesser extent, persist. They carry standard gastric warning labeling as with other classical NSAIDS. An ideal drug should lack completely COX-1 activity but should have selective COX-2 inhibitory activity (Juan-Miguel Jime’nez et alloc. Cit). At least 30 potential COX-2 inhibitors are in the pipeline. In all these molecules the common structural feature is five membered heterocyclics with Vicinal diaryl groups out of which at least one aryl group carry sulphonamide (SO2-NH2) or methane sulphonyl group (SO2-CH3). (Juan-Miguel Jime’nez et al. loc. Cit).
Three novel types of selective COX-2 inhibitors are now emerging. These
are Vicinal diarylheterocyclics, with an acidic sulphonamide
group
or modified classical NSAID’S.
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For further
information
contact : ORGACHEM LABORATORIES
For further
information
contact : ORGACHEM LABORATORIES