HPETE’s

Synthesis of 5-, 11-, and 15-HETE s. Conversion of HETE s into the Corresponding HPETE s... 

The first step in the biosynthesis of eicosanoids from arachidonic acid is generally a lipoxygenation reaction. The resulting hydroperoxides (HPETE s) can undergo reduction to the corresponding alcohols (HETE s). Preparative routes to the 5-, 11-, and 15-HETE s and HPETE s have been developed as oudine below. 

Figure 23-7. Conversion of arachidonicacid to leukotrienesand lipoxins of series 4 via the lipoxygenase pathway. Some similar conversions occur in series 3 and 5 leukotrienes. (HPETE, hydroperoxyeicosatetraenoate HETE, hydroxyeicosatetraenoate , peroxidase (2), leukotriene A4 epoxide hydrolase , glutathione S-transferase ...

An acetone powder of P. homomalla was subsequently used to generate allene oxide 64 from exogenous 8P-HPETE [91]. This highly unstable compound (t1/2 = ca. 15 s at 0 °C, pH 7.4) was obtained by performing the biosynthesis at low temperature (0 °C) for 2 min in a vortexed emulsion of pH 6 buffer and pentane. Under these conditions, the allene oxide partitioned into the pentane where it was relatively protected from hydrolysis. HPLC analysis of the... 

HPETE, 12(.S)-hydroperoxyeicosatetraenoic acid 15-HPETE, 15(S)-hydropcroxycicosatctracnoic acid 4-HPNE, 4-hydroperoxy-2-nonenal... 

Lipoxygenation is the major pathway of dioxygenation of arachidonic acid in blood platelets and leads to the 12-S -hydropcroxy acid 12-HPETE and the corresponding 12-hydroxy acid 12-HETE. Several pathways for the synthesis of 12-HETE have been developed. However, despite the availability of this substance, its biological role remains undetermined. 

Next, 15-LOX oxidizes both 15-HPETE and 5-HPETE to LTA4 (Figure 26.4). Rat peritoneal monocytes and human leukocytes are also able to oxidize AA into the dihydroxy derivative, 5(S), 15(,V)-dihydroxy-6,l 3-/ran.v-8,11 -c/.v-cicosatctracnoic acid (5,15-DiHETE). It has been shown [18] that 5,15-DiHETE was formed by a double oxidation of AA catalyzed by both 5-LOX and 15-LOX lipoxygenases (Figure 26.5). It is interesting that the... 

Corey, E.J., Albright, ).0., Burton, A.E. and Hashimoto, S. (1980) Chemical and enzymic syntheses of 5-HPETE, a key biological precursor of slow-reacting substance of anaphylaxis (SRS), and 5-HETE. Journal of the American Chemical Society, 102,1435-1436. 

Finally, there has been speculation and recent experimental support for the involvement of a Nazarov-type cyclization in the biosynthesis of c/ s-jasmonic acid ° and marine-derived prostanoids. Radiolabel tracer studies have demonstrated Ae intermediacy of 8-HPETE (104) in the biosynthesis of prostanoid intermediate preclavulone A (lO ). This remarkable conversion was proposed to proceed by formation of allene oxide (105) followed by isomerization to (107) via the 2-oxidocyclopentadienyl cation (106 Scheme 41). To demonstrate the chemical feasibility of this proposal, Corey reported the transformation of epoxysilane (108) to, inter alia, the cyclopentenone (111 Scheme 42). The reaction is presumed to involve formation of the allene oxide (109) followed by isomerization to the 2-oxi-dopentadienylic cation (110). Conrotatory closure of (110) is expected to produce the cis isomer of (111) as observed. 

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