Sesterterpenoids

Sesterterpenoids constitute a rather small group of 45 compounds belonging to eight skeletal types. Geranylfarnesyl pyrophosphate is considered as their biosynthetic precursor, and this is supported by experimental evidence. Geranylfarnesol (492) itself has been isolated from the wax of the insect Ceroplastes albolineatus. A comprehensive review of sesterterpenes was published in 1977 (111). 

Of all terpenes, triterpenoids are the most distributed in nature, and are ubiquitous among the dicotyledons. Thble 8.1.5 lists higher plant families especially prolific in producing triterpenoids. On the basis of isolation studies, ursolic acid, )8-amyrin and friedelin have been most commonly encountered. Lists of occurrences of triterpenoids at compound level are available (86, 155, 207, 208, 229, 245, 309). 

Cyclic triterpenoids occur only in normal configuration. The usefuness of triterpenoids in plant systematics has been assessed (155, 317). Their use as chemotaxonomic markers in Leguminosae (181) and Euphorbiaceae (306) has received special attention. 

Cyclization of squalene, in the vast majority of cases, proceeds by its oxidation first to squalene 2,3-epoxide, in which the chirality at C-3 is usally S. The epoxida-tion is effected by a mixed function oxygenase requiring oxygen and NADPH. Accumulations of squalene epoxide in the presence of certain specific enzyme inhibitors has been demonstrated. Cyclization is triggered by proton attack on the epoxide. In many protozoa and ferns, direct proton-initiated cyclization of squalene to triterpenoids occurs. In some of these cases, incorporation of labelled squalene but not of labelled squalene 2,3-epoxide has been demonstrated (90). 

A comprehensive rationale for structural and stereochemical outcome of squalene cyclization in terms of conformation dictated by the cyclase has been build up by the Zurich school. It provides a convenient basis for discussing various triterpene structures (263, 323). These conformations are described in terms of section-wise folding of the squalene chain into a chair (C), or boat (B) conformation or a part remaining unfolded (U). The following discussion of triterpenoids relevant to wood chemistry is based on these considerations. 

The incorporation of all trans-geranylfamesyl pyrophosphate (6 n = 4) but not the corresponding alcohol or cis-geranylfamesyl pyrophosphate into ophio-bolin F (69) is an interesting example of the specificity of the enzymes. This sesterterpenoid is obviously the parent system which is oxidised in turn into ophiobolins C (69 5,21-dioxo), B (69 14a-hydroxy-5,21-dioxo), and A (69 14a,17R-oxido-5,21-dioxo). The earlier results from the incorporation of 

In biosynthetic terms, steroids are metabolic products of triterpenoids. Because of the key importance of cholesterol, the biosynthesis of this steroid and related 

The ability to biosynthesise steroids and arthropod steroid metabolism is reviewed in Section 13. Recent advances in steroid biochemistry have been reported. 

Cyclisation of Squaiene.—In higher animals and fungi the first formed cyclic triterpenoid is lanosterol (73). The acyclic precursor squaiene (7) is epoxidised to give (3S)-2,3-oxidosqualene (71) which is then cyclised to lanosterol. Bloch and co-workers have isolated the two enzymes involved from liver tissue and shown that the oxidosqualene cyclase has a molecular weight of about 90,000. 

Further studies of the steric requirements of this enzyme by van Tamelen and Corey and their co-workers show that the enzyme is relatively insensitive to the nature of the oxygen-free end and does not need to rearrange the biological equivalent of the carbonium ion (72) to produce a free terpenoid. However, the environment of the epoxide group is important. Although these two enzymes can be purified and are both active individually, the possibility of an enzyme complex linking the various steps between famesyl pyrophosphate (6 = 2) and lanosterol was examined. In the presence of [4S- H]NADPH the lanosterol contained 

The structure of ophiobolin A (5.137) was established by chemical degradation and by X-ray crystallography of a bromo derivative. The spectroscopic characteristics of ophiobolin A led to the identification of the oxygen functions and the double bonds. The relationship between the aldehyde and the cyclo-pentanone was revealed by the formation of a y-lactone on reduction and partial re-oxidation. A cyclic pyridazine was formed with hydrazine. Tetra-hydro-ophiobolin A formed an unusual cyclic peroxide involving these two groups. Vigorous oxidation of tetrahydro-ophiobolin A afforded a heptanoic acid lactone, which revealed the structure of the side-chain. 

Ophiobolin B (5.138) was isolated from the culture filtrates of Helminthosporium zizaniae or Ophiobolus heterostrophus. It was related to ophiobolin A through a common hydrogenolysis product. Several other ophiobolins have also been isolated. 

The ophiobolin carbon skeleton is formed by the cyclization of geranylfar-nesyl diphosphate, as shown in 5.139, although an isomerization of the 2-trans double bond to the cis isomer is required to generate the correct stereochemistry. The incorporation of [2- C]mevalonic acid and geranylfarnesyl diphosphate 

Retigeranic acid, a sesterterpenoid from the lichen Lobaria retigera, was separated by HPLC into two stereoisomers, retigeranic acid A (551) and retigeranic acid B (552) the structures of both components were determined by X-ray analysis (675). 

The structures of these rather complex sesterterpenoids were a challenge to organic chemists and between 1982 and 1990 no less than 5 syntheses of the retigeranic acids have been pubhshed. Corey et al. 

Three sesterterpenes (624, 625, 626) have been isolated from the genus Cheilanthes (357, 358, 359). Cheilarinosin (624) has the same ophiobolane skeletone as the ophiobolins, which are phytotoxins produced by plant pathogens, Helminthosporium (360) and Cochliobo-lus (361). 

Diplopterol, C30H50O, is the first fern triterpenoid reported. It was isolated from the dry fronds of Gleichenia Japonica by Ageta et al. 421) and was identified as hydroxyhopane (659) 422) in 1963. Early 

17-Hydroxy-24-0-[2-(a-L-arabinosyl )-6-(6-D-glucosyl)-6-D-glucosyl ]hopan-28,22-olide 

The second group contains oleananes (644), ursanes (649), friede-lanes (647), danunaranes (636), shionanes (639) and others. They are derived from squalene (627) in the chair-chair-chair-boat conformation 

Such triterpenes are quite commonly observed in seed plants, but, in contrast to seed plant triterpenes which have an oxygen function at C-3, fern triterpenes with a few exceptions lack the C-3 oxygen. It is not known whether the oxygen function at C-3 is originally derived from the oxygen of 2,3-oxidosqualene or is introduced after cyclization. 

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A 1,2-metalate rearrangement of a higher order cuprate, known as a Kodenski rearrangement [64], was used as a key step in the synthesis of the marine antiinflammatory sesterterpenoid manoalide 95 (Scheme 9.20) [65]. Treatment of the alkenyl lithium 89 (prepared from the alkenylstannane 88 with s-BuLi in a diethyl ether-pentane mixture) with the homocuprate 91 (produced from iodoalkane 90) gave the iodoalkene 94 in 72% overall yield from 88. The reaction proceeds as fol-... 

Sponge-derived sesterterpenoids are potent anti-inflammatory metabolites which inhibit phospholipase A2 (Sipkema et ah, 2005a). In arachi-donic acid pathway of inflammatory response (Fig. 8.3), phospholipase A2 catalyzes the release of membrane-bound phospholipids to produce inflammatory mediators once stimulated by tissue injury. Manoalide (Fig. 8.4) is a best known sponge-derived anti-inflammatory sesterterpe-noid. Dysidotronic acid (Fig. 8.5), non-complex manoalide analogue, has been identified as an anti-inflammatory metabolite of the sponge Dysidea sp. The mechanism by which dysidotronic acid inhibit inflammation is much more selective and potent than manoalide. This sesquiterpenoid... 

Additionally, during the search for biologically active sponge metabolites belonging to the sesterterpenoid class, a sulfated sesterterpene hydroquinone, halisulphate, Fig. (20), was isolated from the dark brown sponge Halichotidriidae sp. 

Manoalide, a marine anti-inflammatory sesterterpenoid, has been synthesized555 using a 1,2-metallate rearrangement of a higher order cuprate and a Pd(0)-catalysed carbonylation of an iodoalkene to generate the central dihydropyranone ring. 

Cimino, G., Fontana, A., Giminez, F., Marin, A., Mollo, E., Trivellone, E., and Zubia, E., Biotransformation of a dietary sesterterpenoid in the Mediterranean nudibranch Hypselodoris orsini, Experi-entia, 49, 582, 1993. 

De Silva, E. D., and Scheuer, P. J., Manoalide, an antibiotic sesterterpenoid from the marine sponge Lujfariella variabilis (Polejaeff), Tetrahedron Lett., 21, 1611, 1980. 

Idiadione (56) was synthesized from citronellal, establishing the stere-ogenic center as S [31], Cytotoxic sesterterpenoid cacospongionolide D (57) was isolated from Fasciospongia cavernosa from the Bay of Naples [32]. Thorectolide monoacetate (58), obtained from a New Caledonian marine sponge identified as a Hyrtios species [33], in contrast possessed antiinflammatory properties. The bicyclic lactone astakolactin (59) was obtained... 

During their studies on the stereochemistry of intramolecular 1,3-diyl trapping reaction as depicted in Scheme 13, Little and collaborators utilized the reductive decarboxylation in preparing the required compound 31.24 The usefulness of Barton decarboxylation was also realized by Braekman and colleagues during their studies on ichthyotoxic sesterterpenoids in providing the needed methyl ketone 32 from the carboxylic acid 33.25 Helmchen has developed an easy route to a stable... 

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.

Table 5. Retinoids (Re), Sesterterpenoids (St), and Miscellaneous Terpenoids from Natural Sources and the Bioassay Systems in which the Compounds Exhibited Inhibitory Activities Code Compound Source Occurrence Assay System References...

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

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