Coumarins isoprenoid

Besides their essential roles in nature, isoprenoids are of commercial importance in industry. Some isoprenoids have been used as flavors, fragrances, spices, and food additives, while many are used as pharmaceuticals to treat an array of human diseases, such as cancer (Taxol), malaria (artemisinin), and HIV (coumarins). In contrast to the huge market demand, isoprenoids are present only in low abundance in their host organisms. Thus, isolation of the required isoprenoids consumes a large quantity of natural resources. Furthermore, owing to their structural complexity, total chemical synthesis is often not commercially feasible. For these reasons, metabolic engineering may provide an alternative to produce these valuable isoprenoids [88,89]. 

Coumarins are lactones of o-hydroxycinnamic acids in which side chains often are isoprenoid (78). Coumarin, esculin, and psoralen (a furanocoumarin) all strongly inhibit seed germination. Such inhibitors are produced by a variety of legumes and cereal grains. 

Finally, since many natural product compounds have been investigated with various chromatographic modes and detection techniques, a selection of examples has been summarized in this chapter. This information has been compiled in the form of tables for well-researched classes of secondary metabolites selected from the major subgroups of isoprenoids (mono-, sesqui-, di-, and triterpenes iridoids and secoiridoids carotenoids saponins and ecdysteroids), of phenolics (coumarins, flavonoids, and isoflavonoids), and of alkaloids. 

The restricted space available for these Reports unfortunately does not allow the discussion of a number of topics of interest to monoterpenoid chemists useful reviews of such topics include monoterpenoid alkaloids/ carbazole alkaloids/ isoprenoids and alkaloids of tobacco/" naturally occurring plant coumarins/ the biosynthesis of aromatic hemiterpenes/ and recent developments in the field of naturally occurring aroma components/ The poor quality of the Chemical Abstracts makes it difficult to assess the significance of a number of reviews of potential industrial interest/ A volume in the Methodicum Chimicum series includes a very brief discussion of some monoterpenoids/"... 

Although the general biosynthetic pathway to 3-prenylquinoline alkaloids and their relatives is apparent from the feeding experiments with labeled precursors discussed above (Scheme 28), many details remain to be resolved. Theories are based on chemotaxonomic and stereochemical evidence and have been reviewed for isoprenoid quinoline alkaloids and coumarins (38) some aspects will be discussed here. 

In earlier work on the phenolic constituents of Morns root bark, Uno isolated coumarins and related compounds 15,16) such as umbel-liferone and 5,7-dihydroxychromone, while Shibata reported isolation of a large quantity of p-tocopherol (more than 15 mg% for dried material) (77). Venkataraman a/, isolated a series of flavonoids with isoprenoid substituents from Moraceae which they described in review articles 18,19). Details were given by Deshpande et al. who described four flavones with isoprenoid substituents which the named mulberrin, mulberrochromene, cyclomulberrin, and cyclomulberrochromene, from the root bark of Morns alba L. Structures (1), (2), (3), and (4), were assigned to the four compounds, the position of C-alkylation at C-6 of the flavone moiety presumably having been deduced by chemical correlation with artocarpin (5) 20) (Fig. 1). 

The basic skeleton of isoprenoids may be modified by the introduction of a wide variety of chemical groups, by isomerization, shift of double bonds, methyl groups, etc. Hence a bewildering number of chemical structures arises. In addition compounds derived from other biogenic pathways may contain isoprene residues. For instance the K vitamins (D 8.1), ubiquinones (D 8.3), chlorophylls (D 10.1), plastoquinones, and tocopherylquinones (D 22.4) have isoprenoid side chains with up to ten isoprene units. Polyketides (D 3.3), alkaloids (D 8.4.2), and coumarins (D 22.2.2) may be substituted by dimethylallyl groups. The terpene residues are attached to nucleophilic sites, such as active methylene groups and phenolic oxygen atoms. 

This is the second example of the direct observation of an arene oxide during animal liver metabolism of arenes and has provided further evidence that the corresponding epoxides are the key molecules involved in aromatic hydrocarbon carcinogenesis (see also the section on halohydrin cyclization on p. 20). Since the first isolation of a natural product containing an intact epoxide group (1939) a large number of molecules of this type have been isolated. Typical examples recently reported include the coumarins (71) and (72), where the isoprenoid side-chains have been enzymatically epoxidized. The previously isolated Cecrqpia juvenile hormones (73 R = H or Me) have... 

There has been much interest in the biosynthesis of coumarins bearing isoprenoid-related substituents these are now considered to be mevalonate derived 338, 340, 341). In part this has stemmed from the important skin-sensitizing activity of some furanocoumarins which has been correlated with their photoreactivity towards pyrimidine bases of DNA 409). The proposal by Birch (72) that the two extra carbon atoms of the furan ring are derived by loss of three carbon atoms from an intermediate hydroxyisopropyldihydrofuranocoumarin has received considerable experimental support in recent years 152, 198, 199). Indeed, it has now been established that ( + )-marmesin (103), formed from umbelliferone (2) via 7-demethylsuberosin (86) is a key intermediate in the biosynthesis of linear furanocoumarins 105, 107,... 

An example of coumarins with isoprenoid substituents is osthenol, 7-hydroxy-8-(2-hydroxy-3-methyl-3-en-l-yl)coumarin (10-132), which together with osthol, 7-methoxy-8-(3-methyl-2-en-l-yl)coumarin and auraptenol, 7-methoxy-8-(2-hydroxy-3-methyl-3-en-l-yl)coumarin, occurs in citrus fruits. In common with many other coumarins, it is found in garden angelica Angelica archangelica, Apiaceae) and other plants. 

Consequences for the so-called segregation model ofisoprenoid biosynthesis The presence of such alternative pathways as outlined above could provide a further explanation for the observations obtained with the HMGR inhibitor mevinolin, viz. its great efficiency in blocking cytoplasmic sterol biosynthesis, but its low efficiency to affect ubiquinone biosynthesis, and its practically complete inefficiency to block the accumulation of isoprenoids and prenyl lipids of the chloroplast (summarized and discussed earlier 14, 17]. It could also explain the puzzling observation that, in contrast to phytosterols, prenyl-subsituted coumarins were not labeled from [2- ]acetate or [2- C]MVA in elicitor-treated cultures oiAmnd majus, suggesting that the DMAPP needed for the (plastid ) umbelliferone dimethylallyl transferases (EC 2.5.1.3) is formed from IPP synthesized de novo within the plastid, rather than from IPP imported into the plastid from the cytosol [86]. Elicitor-induced inhibition of phytosterol biosynthesis should occur by specific inhibition of one of the enz)ones on the c) osolic pathway from MVA to DMAPP. 

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