1.4- Endoperoxides

Studies of the biosynthesis of PGE2 from arachidonic acid have shown that all three oxygens come from O2 The enzyme involved prostaglandin endoperoxide syn tliase has cyclooxygenase (COX) activity and catalyzes the reaction of arachidonic acids with O2 to give an endoperoxide (PGG2)... 

In the next step the —OOH group of PGG2 is reduced to an alcohol function Again prostaglandin endoperoxide synthase is the enzyme responsible The product of this step IS called PGH2... 

Dialkyl peroxides have the stmctural formula R—OO—R/ where R and R are the same or different primary, secondary, or tertiary alkyl, cycloalkyl, and aralkyl hydrocarbon or hetero-substituted hydrocarbon radicals. Organomineral peroxides have the formulas R Q(OOR) and R QOOQR, where at least one of the peroxygens is bonded directly to the organo-substituted metal or metalloid, Q. Dialkyl peroxides include cyclic and bicycflc peroxides where the R and R groups are linked, eg, endoperoxides and derivatives of 1,2-dioxane. Also included are polymeric peroxides, which usually are called poly(alkylene peroxides) or alkylene—oxygen copolymers, and poly(organomineral peroxides) (44), where Q = As or Sb. 

Symmetrical diaLkyl peroxides are commonly named as such, eg, dimethyl peroxide. For unsymmetrical diaLkyl peroxides, the two radicals usually are hsted ia alphabetical order, eg, ethyl methyl peroxide. For organomineral peroxides or complex stmctures, ie, where R and R are difficult to name as radicals, the peroxide is named as an aLkyldioxy derivative, although alkylperoxy is stUl used by many authors. CycHc peroxides are normally named as heterocychc compounds, eg, 1,2-dioxane, or by substitutive oxa nomenclature, eg, 1,2-dioxacyclohexane however, when the two oxygens form a bridge between two carbon atoms of a ring, the terms epidioxy or epiperoxy are frequendy used. The resulting polycycHc stmcture has been called an endoperoxide, epiperoxide, or transaimular peroxide. 

Unsaturated aUphatic endoperoxides form bis(epoxides) and/or epoxy aldehydes upon thermolysis (80,81). Thus 3,5-epidioxycyclopentene [6573-26-8] reacts as follows. 

The endoperoxides of polynuclear aromatic compounds are crystalline soHds that extmde singlet oxygen when heated, thus forming the patent aromatic hydrocarbon (44,66,80,81). Thus 9,10-diphenyl-9,10-epidioxyanthrancene [15257-17-7] yields singlet oxygen and 9,10-diphenylanthracene. 

Prostaglandin Endoperoxides. The naturally occurring endoperoxides, PGG, PGG2, PGH, and PGH2, as well as a number of their... 

Characteristic reactions of singlet oxygen lead to 1,2-dioxetane (addition to olefins), hydroperoxides (reaction with aHyhc hydrogen atom), and endoperoxides (Diels-Alder "4 -H 2" cycloaddition). Many specific examples of these spectrally sensitized reactions are found iu reviews (45—48), earlier texts (15), and elsewhere iu the Engchpedia. 

In the pharmaceutical literature some pyrazoles fused to the prostaglandin structure are cited. Thus, 9,ll-azo-PGE2 (701), a stable endoperoxide analogue that is eight times as potent as PGG2, is a compound that specifically blocks TXA2 synthetase (79MI40401). 

Synthesis of Several Analogs of the Prostaglandin Endoperoxide PGH2... 

Synthesis of Prostaglandins via an Endoperoxide Intermediate Stereochemical Divergence of... 

Prostaglandin biosynthesis from C20 polyunsaturated fatty acids occurs by way of the endoperoxides PGG2 and PGH2. 

A chemical synthesis of prostaglandins by a free radical pathway through an endoperoxide intermediate showed a strong stereochemical preference for the formation of the endoperoxides having cis alpha and omega appendages. 

Clavulones I and II are members of an unusual family of marine prostanoids from the coral Clavularia viridis which are biosynthesiied by a cationic (i.e. non-radical, non-endoperoxide) pathway. The total synthesis of clavulones I and II was accomplished from cyclopentadiene as SM goal. 

PGH2 is the precursor to a number of prostaglandins and related compounds, depending on the enzyme that acts on it. One of these cleaves the O—O bond of the endoperoxide and gives PGE2. 

All prostaglandins are cyclopentanoic acids derived from arachidonic acid. The biosynthesis of prostaglandins is initiated by an enzyme associated with the endoplasmic reticulum, called prostaglandin endoperoxide synthase, also known as cyclooxygenase. The enzyme catalyzes simultaneous oxidation and cyclization of arachidonic acid. The enzyme is viewed as having two distinct activities, cyclooxygenase and peroxidase, as shown in Figure 25.28. 

FIGURE 25.29 (a) The structures of several commou analgesic agents. Acetaminophen is marketed under the tradename Tylenol. Ibuprofen is sold as Motrin, Nuprin, and Advil, (b) Acetylsalicylate (aspirin) inhibits the cyclooxygenase activity of endoperoxide synthase via acetylation (covalent modification) of Ser ... 

This group is prepared by the reaction of the anion of 9-hydroxyanthracene and the tosylate of an alcohol. Since the formation of this group requires an S 2 displacement on the alcohol to be protected, it is best suited for primary alcohols. The group is cleaved by a novel singlet oxygen reaction followed by reduction of the endoperoxide with hydrogen and Raney nickel. 

Antimalarial drug artemisinine, sesquiterpenic 8-lactone with 1,2,5-trioxane (endoperoxide) fragment 98CSR273. 

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