Epoxide secondary metabolites

Epoxides are often encountered in nature, both as intermediates in key biosynthetic pathways and as secondary metabolites. The selective epoxidation of squa-lene, resulting in 2,3-squalene oxide, for example, is the prelude to the remarkable olefin oligomerization cascade that creates the steroid nucleus [7]. Tetrahydrodiols, the ultimate products of metabolism of polycyclic aromatic hydrocarbons, bind to the nucleic acids of mammalian cells and are implicated in carcinogenesis [8], In organic synthesis, epoxides are invaluable building blocks for introduction of diverse functionality into the hydrocarbon backbone in a 1,2-fashion. It is therefore not surprising that chemistry of epoxides has received much attention [9]. 

Based on the structural diversity of the many congeners originating from Laurencia, the elucidation of a bios5mthetic mechanism for the likely development of these metabolites is of much interest. The isolation and characterization of monoepoxide 30 (Scheme 1) from Laurencia okamurai [15] has allowed investigators to postulate that this compound (30) may be a common precursor for the biosynthesis of all other secondary metabolites derived from squalene [3]. Its absolute stereochemistry was verified via asymmetric synthesis utilizing a Sharpless asymmetric epoxidation [16] of trans, trara-famesol,... 

Plant secondary metabolites which mimic JH activity appear to be active on a narrow range of host species. What account(s) for this effect The majority of bioassays used last larval instars of P. apterus, O. fasciatus and pupae of T. molitor to test for activity of the juvenoids. Are these the most sensitive insects Six JHs have been identified to date different homologs have been isolated from specific insect orders. Juvenile hormone III appears to be ubiquitous [12, 13] and, in most species, is the only JH present. Juvenile hormone I and II are important in the regulation of metamorphosis and ovarian maturation in Lepidoptera [5] and the bis-epoxide appears to be the principle JH in higher Diptera [20]. Therefore, the nature of the JH in the test insect and the role that it plays in development must be considered in the selection of the bioassay a compound which mimics the action of JH in P. apterus (Hemiptera) is unlikely to be active in a Lepidopteran insect. 

Well established is the activation of polycyclic hydrocarbons to arene oxides 3,4-benzo(a)pyrene forms several arene oxides from which a secondary metabolite, the 9,lO-dihydrodiol-7,8-epoxide has been proved highly carcinogenicIt preferentially binds to deoxyguanosine and deoxyadenosine in DNA and by a series of further still unknown events leads to the formation of cancerous cells. The microsomal epoxide hydrase converts arene oxides and epoxides to inactive dihydrodiols and therefore coijipetes with the covalent binding process ... 

Epoxidation by the introduction of an oxygen atom into flunarizine produced l-[bis(4-fluoro-phenyl)methyl] - 4 - [(3-phenyloxiran - 2 - yl)methyl] piperazine (metabolite 2) and epoxide hydration to a diol, 3-[4-[bis(4-fluorophenyl)methyl]-l-piper-azinyl]-l-phenyl-l,2-propanediol (metabolite 10). Lavrijsen et al. (1992) found metabolites formed by epoxidation at the double bond (metabolite 2) and epoxide hydration (metabolite 10) in incubates with subcellular hepatocyte fractions of male and female rats. Metabolites formed by epoxidation and epoxide hydration were not detected in vivo (Meuldermans et al. 1983), probably because the resulting metabolites were metabolised in vivo, much more quickly than in vitro, into secondary metabolites. A diol metabolite, however, was described for the metabolism of l-butyl-4-dimamyl-piperazine in guinea pigs (Morishita et al. 1978). With supernatant fractions a rapid disappearance of the epoxide intermediate from incubate was observed. This seems to indicate that, for the epoxide hydrolysis, besides microsomal epoxide hydrolase, cytosolic epoxide hydrolase might also be involved. 

Germacrone (118), (+) -germacrone-4,5-epoxide (119), and curdione (120) isolated from Curcuma aromatica, which has been used as crude drug, were incubated with A. niger. From compound 119 (700 mg), two naturally occurring metabolites, zedoarondiol (121) and isozedoarondiol (122), were obtained (Takahashi, 1994). Compound 119 was cultured in callus of Curcuma zedoaria and C. aromatica to give the same secondary metabolites 121, 122, and 124 (Sakui et al., 1988) (Figures 20.40 and 20.41). 

Chlorowithanolides. Some withanolides, e.g., physaUn H (Fig. 7.29) as well as jaborosalactones 10 and 29 (Fig. 7.30), turned out to contain chlorine snbstituents at C-5a or -6(1. Secondary metabolites with this snbstitnent are generally very rare in the plant kingdom. Nevertheless, occnrrence of 5,6-chlorohydrins together with the corresponding 5,6-epoxides is common among the withanolides (Nicotra et al. 2006 and references therein). 

Modification reactions create the enormous diversity of plant natural products, providing new molecules with different biological activities from the basic scaffolds outlined above. The plant kingdom contains a large number of enzymes that catalyze hydroxylation, epoxidation, aryl migration, glyco-sylation, methylation, sulfation, acylation, pre-nylation, oxidation and reduction of secondary metabolite skeletons, examples of which are reviewed below, and illustrated, for phenylpropa-noid and flavonoid biosynthesis, in Fig- 5. Figure 6... 

Biological systems have evolved to exploit the reactivity of epoxides in the synthesis of a number of secondary metabolites (Fig. 4.1) [1], including ionophore antibiotics such as monensin (1) [2], terpene ethers, represented by thyrsiferol (2) [3], ladder toxins, represented by brevetoxin (3) [4], and annonaceous acetogenins, represented by murisolin (4) [5]. Chemical synthesis of cyclic ethers also frequently utilizes epoxides, often in the context of cascade cyclizations in which the hydroxyl group that is liberated... 

Other important epoxides are postulated in the biosyntheses of pheromones derived from epoxide intermediates like the insect pheromone a-(—)-(75, 2/ ,45, 5/ )-multistriatin [6]. Here again the enantioselectivity of the epoxidation is essential for the biological activity of the compounds. The fungus Chaetomium cochlioides rearranges enantiospecif-ically the epoxide 13 of a fatty acid precursor 12 to a branched aldehyde 14 (Fig. 4), an epoxide rearrangement step also reported from other pathways. This intermediate aldehyde is reduced to the alcohol 15 and gives, after another epoxidation step, the tetrahydrofiiran derivative 17 found as a secondary metabolite in a number of Chaetomium spp. [7]. 

Epoxides are not only key intermediates in several biosyntiieses they are also present in a number of secondary metabolites (Fig. 5). Again, the high reactivity of the epoxy moiety contributes to the bioactivity of these metabolites. This reactivity ensures short half-lives of metabolites, e.g., in juvenile hormones, pheromones, or the toxicity of some antibiotics. The methyl ester of 10,11-epoxyfamesenate 18 is a juvenile hormone synthesized by many insects. The pheromone disparlure 19 (see also Chapter 3 in this book) formed by the gypsy moth Lymantria dispar is active in only one enantiomeric form [8],... 

Figure 5 Some bioactive epoxides containing secondary metabolites.

Most reactive metabolites produced by CYP metabolic activation are electrophilic in nature, which means that they can react easily with the nucleophiles present in the protein side chains. Several functional groups are recurrent structural features in M Bis. These groups have been reviewed by Fontana et al. [26] and can be summarized as follows terminal (co or co — 1) acetylenes, olefins, furans and thiophenes, epoxides, dichloro- and trichloroethylenes, secondary amines, benzodioxoles (methylenediox-yphenyl, MDP), conjugated structures, hydrazines, isothiocyanates, thioamides, dithiocarbamates and, in general, Michael acceptors (Scheme 11.1). 

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