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. Areas considered for anti-inflammatory drug intervention include: a) arachidonic acid metabolism. b) Signal transduction mechanisms in activated inflammatory cell functions c) inflammatory cell functions such as generation of reactive oxygen metabolites. d) Bio-synthesis and actions of cytokines and related peptides involved in inflammation process.  Plant products shown to interfere with any  one of these systems may be considered as potential products for lead structures as anti-inflammatory drugs. (M. Duwiejua et al, plants as source of  anti-inflammatory substances in” Drugs from Natural Products – Pharmaceuticals and Agrochemicals” Ed. Alan Harvey, Pub. By ELLIS Harwood, New york, 1993, PP 152). See our flavones list                                      Screening of  several types of compounds for their activity as 5-lipoxygenase enzyme Inhibitors, cyclooxygenase enzyme inhibitors is gaining importance to assess  their potential to treat inflammatory and allergic diseases.Leukotrienes are important mediators of smooth muscle constriction, increased vascular permeability and leucocyte chemotaxis.  Leukotrienes are formed as initial step in the metabolism of arachidonic acid and enzyme 5-lipoxygenase catalyzes the initial step. Thus inhibition of 5-lipoxygenase provide a new therapeutic approach to treat inflammatory skin diseases such as psoriasis and dermatitis etc. Leukotrienes are elevated in the skin of patients with psoriasis and eczema, but prostaglandins are not significantly elevated.Infact for inflammatory dermatitis, non-steroidal and inflammatory drugs (NSAIDS) do not significantly improve.                                     Four plausible mechanisms  for 5-lipoxygenase inhibition are; (1) Antioxidant and  or free radical scavenging (2) Iron chelation (3) The Inhibition of 5-lipoxygenase inhibition translocation (4) and substrate mimicking. Contact :: orgachemweb@gmail.com                                     The status of research in 5-lipoxygenase inhibition is reviewed  (J.H. Musser et al  J. Med. Chem., 1992, 35 (14), 2501 and D.G. Batt et al, Progr. Med. Chem.,1992, 29,1.)                                      Prostaglandin endoperoxide synthatase, often called cyclooxygenase (COX) catalyze the conversion of arachidonic acid into prostaglandins and  thrombaxane.  The existence  of COX-1 and COX-2 are well established.  Both  COX-1 and COX-2, although display common structural features and  similar enzymatic activities, but differ in the regulation of  their expression.                                     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  non-selective inhibitors.  The current hypothesis, although questionable, is that the anti-inflammatory activity of NSAIDS was due to inhibition of COX-2 and unwanted side effects were due to inhibition of COX-1.  Thus  there is upsurge in the discovery of selective COX-2 inhibitor (Juan-Miguel  jimene’z et al, Progress with selective COX-2 inhibitors, IDrugs 2000, pub by Current Drugs 3 (8), P.907). 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. 2. Hydroxy substituent at 4’. 3. Free rotation of B-ring.  For example quercetin has LO- inhibitory activity but morin (5,7,2’,4’,3- pentahydroxyflavone, wherein 2’-hydroxy is chelated to1-oxygen, free rotation of aryl group at 2-position is hindered), is a poor LO- inhibitor.                        Thus to sum up  flavonoids exhibit COX or 5-LO activity.  Their activity is increased by  a) a planar heterocyclic ring b)3’,4’-dihydroxyl substitution as in luteolin – 5,7,3’,4’-tetrahydroxyflavone. c) 3 -hydroxy substitution. d) Additional hydrophlic substitutents.                               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. Flavonoids such as taxifolin, eriodictyol, hesperitin and luteolin (5,7,3’,4’-tetrahydroxy flavone) inhibit the production of reactive oxygen species by activated neutrophils, by inhibiting either the release of enzyme myelo peroxidase or its activity.                                    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. See our flavones list                                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.  In the next few years, selective COX-2 inhibitors belonging to different structural classes may emerge.  In this context, flavones,coumarins and chalcones with proven cyclooxygenase inhibitors, 5-Lipoxygenase inhibitors or   antioxidant activity may offer possibilities for new drug discovery.

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For further information contact :  ORGACHEM LABORATORIES


Contact :: orgachemweb@gmail.com

For further information contact :  ORGACHEM LABORATORIES