Lipoxygenases and Inhibitors New

8/13/2019 Lipoxygenases and Inhibitors New

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Lipoxygenases are a family of iron-containingenzymes that catalyse the dioxygenation (theaddition of oxygen) of polyunsaturated fatty

acids in lipids containing a cis,cis-1,4-pentadiene structure. It catalyses the followingreaction:

fatty acid + O2 = fatty acid hydroperoxide


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Since the mechanism of lipoxygenase involves theoxidized active Fe3+ state and the generation of radicalspecies this enzyme can be blocked by a variety ofmechanisms besides reversible binding .


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The advantage of inhibiting 5-LO is essentially to theeffects of all LTs and hence provide agents with

therapeutic potential in a range of allergic andinflammatory diseases including asthma ,allergicrhinitis ,rheumatoid arthritis ,inflammatory boweldisease and possibly psoriasis .


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There are potential disadvantages arise from thepossibility that complete LT inhibition could giverise undesirable side effects although no indicationsof any essential physiological role of LTs haveappeared since the discovery of this mediators .

The search for selectivity 5-LO over cyclooxygenase

(CO) has been an important consideration , firstly toavoid the side effects in counter by currentlymarketed CO inhibitors (NSAIDs) and secondly toprove the clinical relevance of inhibition ofleukotrines alone .


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Anti oxidants :

5-LO is particularly susceptible to inhibition by compounds with lowredox potentials . phenidone was among the first compounds to

be identifiedAs compounds in the class based around the hetero atom substitutedpyrazole ring are nafazatrone which act as one of electronreducing agent ( redox inhibitors) which act directly or indirectlyreduce either Fe3+ in the active enzyme or one of radicalintermediates to give the inactive ferrous form.

phenidone


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Chelate to iron would inhibit 5-LO , synthesizedarachidonohydroxamic acid and a number of Nalkyl derivatives . these indeed proved to be potent5LO inhibitors , and rapidly many hydroxyamateinhibitors were prepared which possessed high invitro potency .

Iron chelators :


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Inhibitors of 5-LO Activating Protein (FLAP)

FLAP inhibitors are a novel class of compounds which inhibitcellular leukotriene biosynthesis without acting directly on 5-LO . Instead, they bind to the 18 kda membrane 5-LO (FLAP) thus

preventing the activation of 5-LO.


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Substrate Stereospecific inhibitors :

At Zeneca, this work was begun in the late 1980s where ( activesite directed) inhibitors were designed to fit 5-LO selectivelywithout the need for redox or strong iron ligand properties


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Mounting evidence suggests that lipoxygenasemetabolites have a profound influence on thedevelopment and progression of human cancers.Compared with normal tissues, significantly elevatedlevels of LO metabolites have been found in lung,prostate, breast, colon, and skin cancer cells, as well asin cells from patients with both acute and chronicleukemia.

LO inhibitors have prevented carcinogen-induced lungadenomas and rat mammary gland cancers.


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1- Burger's Medicinal Chemistry and Discovery 5th Edition Volume 3: Therapeutic Agents Editedby Manfred E. Wolff

2- Martindale the complete drug reference 3rd Edition Edited by Sean C. Sweetman

3- Basic & Clinical Pharmacology 6th Edition(Middle East Edition)

4- Wikipedia


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Lipoxygenases and Inhibitors New

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