Terpenoids meroterpenoids

Biosynthesis of polyketide-terpenoid (meroterpenoid) metabolites, andibenin A... 

IPP and DMAPP are reactive hemiterpene intermediates in the pathways leading to more complex terpenoid structures. They are also used as alkylating agents in the formation of meroterpenoids as indicated above, but examples of these structures are discussed under the section appropriate to the major substructure, e.g. alkaloids, shiki-mate, acetate. Relatively few true hemiterpenes are produced in nature, with isoprene, a volatile compound which is released by many species of plants, especially trees, being the notable example. Isoprene is formed by loss of a proton from the allylic cation (Figure 5.7). 

Tables 2-5 list monoterpenoids (Mo), sesquiterpenoids (Sq), diterpenoids (Di), and retinoids (Re), sesterterpenoids (St), meroterpenoids and miscellaneous terpenoids (Me), respectively, discussed in this review. The bioassay systems in which the compounds exhibited inhibitory effects, together with the major sources of the compounds, are included in the Tables. Most of these terpenoids are isolated from natural sources, and their structures are shown in Figs. (2)-(5). Some terpenoids which exhibit significant and/or a broad range of chemopreventive and anti-inflammatory activities are discussed below.

Fig. (5). Structures of retinoids, sesterterpenoids, meroterpenoids, and miscellaneous terpenoids described in this review...

Several terpenoids have been evaluated for their inhibitory effects on EBV-EA activation induced by TPA. Table 6 shows the inhibitory effects of monoterpenoids [70,71], sesquiterpenoids [20,119-123], diterpenoids [21,123-131], and meroterpenoids [117] against TPA (32 pmol, 20 ng)-induced EBV-EA activation in Raji cells. The inhibitory effects were compared with that of [3-carotene, a vitamin A precursor that has been studied intensively in cancer chemoprevention using animal models [2,4]. All of the terpenoids tested caused higher viability (60-80%) of Raji cells even at mol ratio of compound to TPA = 1000 1 indicating their very low cytotoxicity at that high concentration (refer to Table 6). 

Both cell cultures and animal studies have shown that many of the naturally occurring mono-, sesqui-, di-, sester-, and meroterpenoids as well as retinoids possess potentially chemopreventive activities. Terpenoids are minor but ubiquitous components of our diet, and have the advantage of being non-toxic or relatively non-toxic to humans. More mechanistic-oriented basic research is needed to elucidate the mechanisms of action. Studies of derivatives of these naturally occurring terpenoids are also necessary to elucidate the structure-activity relationship and to guide the development of novel chemopreventive agents. 

The term meroterpenoids is generally used to denote a wide range of natural products of mixed (polyketide-terpenoid) biogenesis [121]. In our laboratory, the titanocene-catalyzed 6-endo/6-endo cyclization of 31, ob-... 

The labelling studies described above provide definitive evidence for the mixed polyketide-terpenoid biogenesis of the andibenins, andilesins, andi-tomins, austin and terretonin. The formation of the bicyclo [2.2.2] octane system in the first two classes of metabolite provides a rare example of a biosynthetic Diels-Alder reaction. The biosynthetic relationship of austin and andibenin was supported by the isolation of austin from another mutant strain of A. variecolor [81]. Further metabolites related to austin have been isolated from Emericella dentata [82] and Penicillium diversum [81]. Other complex metabolites which are almost certainly further products of the meroterpenoid pathway are fumiga-tonin (102) and paraherquonin (103) which have been isolated from Aspergillus... 

Although it may be considered as a meroterpenoid (see Chapter 5) mycophenolic acid (4.32) is discussed here because its structure reveals the interaction between polyketides and terpenoids. A metabolite of a Penicillium species, which was probably mycophenolic acid, was first described by Gosic in 1896. It was more firmly characterized by Alsberg and Black in 1913 as a metabolite of... 

Fig. 1. Biosynthesis of terpenoids and meroterpenoids, emphasizing the central position of the enzyme IPP isomerase.

The phytochemical diversity of C. saliva is well illustrated by more than 500 com-potmds isolated from this plant, encompassing all major classes of phytochemicals (polyketides, terpenoids, alkaloids, flavonoids, stilbenoids, oxylipins). Undoubtedly, the most important and peculiar secondary metabolites of C. saliva are cannabinoids, a class of mono- to tetracyclic C21 (or C22) meroterpenoids encompassing more than 100 members. These compounds are synthesized in secretory cells of glandular trichomes, most concentrated in unfertilized female cannabis flowers prior to senescence. A number of detailed accounts on the cannabinoid chemistry have been reported in the literature [6-8], also recently by Appendino et al. [9]. In this paragraph, we will provide an updated, although not comprehensive, account of the chemistry of this fascinating class of secondary metabolites. 

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