Diterpenoids sources

Terpenoids are classified according to the number of five-carbon multiples they contain. Monoterpenoids contain 10 carbons and are derived from two isopentenyl diphosphates, sesquiterpenoids contain 15 carbons and are derived from three isopentenyl diphosphates, diterpenoids contain 20 carbons and are derived from four isopentenyl diphosphates, and so on, up to triterpenoids (C30) and tetraterpenoids (C40). Monoterpenoids and sesquiterpenoids are found primarily in plants, bacteria, and fungi, but the higher terpenoids occur in both plants and animals. The triterpenoid lanosterol, for example, is the precursor from which steroid hormones are made, and the tetraterpenoid /3-carotene is a dietary source of vitamin A (Figure 27.6). 

The genera of Aconitum (commonly known as Monkshood) and Delphinium, and to a lesser extent Rumex, Consolida, and Spiraea, have long been recognized as a rich source of alkaloid natural products [1], The diterpenoid alkaloids are generally classified into two major groups the Ci9-diterpenoid alkaloids (sometimes referred to as the Cig-norditerpenoid alkaloids) and the C2o-diterpenoid alkaloids. Within the C2o-diterpenoid alkaloids, at least 11 separate classes have been isolated, including the hetisine alkaloids (Chart 1.1). 

There is a long history of the use of Aconitum, Delphinium and Consolida species as the source of poisons and medicinals [1]. These three genera in Ranunculaceae family yield diterpenoid and norditerpenoid alkaloids. The name Delphinium derived from dolphine-delphine due to the shape of their flower buds [2]. Aconitum has an evil reputation from the antiquity [3]. The plant was used as poison in old Greece, also in north-west Pacific the natives used it to poison the whales and also as arrow poison. In England in the ancient times the plant was used against wolves, boars, tigers as well as against rodents, and it was also a homicide material [4]. 

Paclitaxel (21), formerly known as taxol , is a nitrogen-containing diterpenoid compound isolated from the bark of Taxus brevifolia Nutt. (Pacific yew). As an anticancer agent, paclitaxel acts as a tubulin stabilizer and leads to cell cycle arrest.Since paclitaxel was originally isolated from the bark of the slow-growing species, 77 brevifolia, sourcing was a major obstacle in the development of this drug and its introduction into the market.However, as described later in this chapter, this has now been overcome. 

Mono-, sesqui-, and some diterpenoids are found in marine and terrestrial flora. They are, therefore, not always unambiguous tracers for higher plant sources. However, diterpenoids with the abietane and pimarane (Fig. 1), and less common phyllocladane and kaurane, skeletons are predominant constituents in resins and supportive tissue of coniferous vegetation (Coniferae), which evolved in the late Paleozoic (200—300 million years ago). Diterpenoid biomarkers have been characterized in... 

Terpenoids are one of the many classes of allelochemicals known to play an important role in such Interactions (13). Of particular interest are the diterpenoids. These are widely distributed in plants, and are also present in fungi and marine organisms, and as such provide a ready source for the isolation of new compounds (13-15). 

The diterpenoid taxol (Figure 1.12) was first isolated from the pacific yew tree (Taxus brevifolia) in the late 1960s. Its complete structure was elucidated by 1971. Difficulties associated with the subsequent development of taxol as a useful drug mirror those encountered during the development of many plant-derived metabolites as drug products. Its low solubility made taxol difficult to formulate into a stable product, and its low natural abundance required large-scale extraction from its native source. 

Sideritis (Labiatae) have been a rich source of novel bi- and tetra-cyclic diterpenoids. Andalusol (10), which has been isolated from S. arborescens, was assigned the ent-labdane configuration. Its structure was deduced by a combination of spectroscopic measurements and an X-ray analysis of the degradation product (11). 

Naturally Occurring Substances.—Beyeria (Euphorbiaceae) species have been the source of a number of tetracyclic diterpenoids. Some of these were new or poorly defined species and their classification has now been clarified. " The presence of enf-kaurenal has again been recorded in Fusarium monoliforme, whilst ent-kaur-16-en-19-oic acid (72) has been isolated from Mikania hirsutissima (Composi-tae). Microbiological hydro xylation of ent-kaur-16-en-19-oic acid by... 

Diterpenes are found in nature, mainly in plants, but also in other natural sources, e.g. micro-organisms and insects. The following table presents just a few of these sources, and their major diterpenoidal components. 

The conifers are an important source of diterpenoids. Several labdanes have been detected in the neutral fraction of the oleoresin of Araucaria excelsa, including manool as well as nor-labdanes [42]. Some neutral diterpenoids, such as enMabd-8, 13(E)-dien-15-ol and its acetate, were obtained after extraction of the resin of Araucaria bidwillii [43], while the normal series of the above labdanes have been isolated from Cistus creticus subsp. creticus [44]. From Pinus sylvestris, 3P-hydroxybiformene has been obtained, while from the needles of the American red wood pine (Pinus resinosa), 8,13-epoxy-labd-14-en-19-oic acid, was isolated. In Pinus nigra, labdane acids have been found to be the major acid components of its needles [45,46]. The occurrence of diterpenoids including labdanes in conifers has been published as a review of the chemistry of the order Pinales [47],... 

Included in this chapter is a catalog of all known C20-diterpenoid alkaloids showing the correct structures, physical properties, plant sources, and key references. Previously published books (19 21) and recent reviews (15-16) have reported incorrect structures for several well-known C20-diterpenoid alkaloids. This catalog should be very useful for it presents in a single place important structural information on the C20-diterpenoid alkaloids that has been scattered through hundreds of papers and dozens of review articles. 

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 4. Diterpenoids (Di) from Natural Sources and the Bioassay Systems in which the Compounds...

Tanshen (Salvia miltiorrhiza Bung), a medicinal plant, has been used in traditional Chinese medicine for its tranquilizing, sedative, circulation-promoting and bacteriocidal effects. [73], It has proven to be a rich source of abietane o-quinone diterpenoids. Miltirone (197) is a tricyclic diterpenoid quinone which has been isolated from the roots of salvia miltiorrhiza Bung. The isolation of miltirone constitutes a new addition to naturally occurring quinines related to tanshinones [74,75] isolated from the same source. 

Plants of the Teucrium genus (Lamiaceae), known as germander, are also a rich source of diterpenoids. More than 200 diterpenoids having the -clerodane skeleton have been isolated from the aerial parts of about 80... 

Coleus diterpenoids. Coleus species have been a rich source of highly oxidized spiroabietanes, a number of which have been described recently. Coleons M (36 R = Ac), N (37), P (38), Q [12a-hydroxy-epimer of (38)], and coleon R, which possesses 3a-, 12a-, and 6/8-acetoxy-groups and a 7a-hydroxy-group, have been isolated39 from Plectranthus caninus whereas coleon O (36 R = H) was isolated from Coleus somaliensis. 

Various studies have also been reported on sesquiterpenoid lactones in Xanthium strumarium and Vemonia species,452,453 diterpenoids of Isodon species,454 and triterpenoids in Lycopodium species.455 Analyses of the carotenoids of Medicago species and of berries from a range of sources reinforce previously held views that the distribution of carotenoids in these sources has no taxonomic significance.456,457 Although most higher plants that have been investigated do not retain the capacity to biosynthesize the normal pattern of terpenoids when in tissue culture, it has been reported that Ruta graveolens did retain this ability.458... 

The chemistry of atractyloside has been reviewed. A further relative (87) of cafestol has been isolated from green coffee beans. Sideritis (Labiatae) species have continued to attract attention as a source of diterpenoids. The comparative phytochemistry of Canary Island species has been reviewed. A number of 15-hydroxykaurenes (88)—(90) have been isolated from S. crispata, S. ilicifolia, and S. tragoriganum together with the atisine (91) and beyerene (92) derivatives, ent-18-Acetoxy-3/8,7a,15/S-trihydroxykaur-16-ene has also been obtained from S. scardica. 

Again, soft corals and gorgonians are a rich source of diterpenoids of 19 structural classes, some of which are specific to them (35, 36). Besides tobacco plants, cembranoid diterpenes are limited to soft corals. Lophotoxin (126) isolated from sea whips of the genus Lophogorgia is a sodium channel inhibitor (3). Xenicin (127) from the soft coral Xenia elongata and briarein A (128) from the gorgonian Briareum asbestinum represent non-cembranolide diterpenes. Diterpenoids of these classes show antimicrobial, cytotoxic, and insecticidal activities. 

The Amherstiae copals have been a rich source of labdane and rearranged labdane diterpenoids. The full description of oliveric acid (7) isolated from one of these, Daniellia oliveri, has appeared. ... 

The roots of Salvia miltiorrhiza contain diterpenoid quinone pigments known as tanshinones. A phenolic diterpenoid, sal viol (18), has been isolated from the same source. Its n.m.r. spectrum showed an overall resemblance to ferru-ginol, with the addition of a CH-OH resonance whose multiplicity located the... 

---