Cembranoid diterpene

Metabolism studies are essential for approval of any clinically useful drug. Microorganisms have been successfully used as in vitro models for prediction of mammalian drug metabolism due to the significant similarity of certain microbial enzyme systems, specifically fungi, with mammalian liver enzyme systems.66 The following metabolism study represents the first for a cembranoid diterpene and may aid future development of other cembranoids as clinically useful drugs. 

Sarcophyton species contain diterpenes up to 10% of their dry weight, and this large quantity of secondary metabolites plays an important role in the survival of Octo-corals with defensive, competitive, reproductive, and possibly pheromonal functions. Soft corals lacking physical defense thus seem to be protected from predation by the presence of diterpene toxins in their tissue. Nearly 25 species of this genus occurring in different seawaters have been examined chemically so far, and more than 80 cembranoid diterpenes have been isolated from the Sarcophyton genus since the 1970s. 

Chemical examination of Sarcophyton glaucum collected at Ishigaki island, Okinawa Prefecture, resulted in the isolation of seven cembranoid diterpenes, namely sarcophytol A (3), sarcophytol A acetate (4), sarcophytol B (5), sarcophy-tonin A (6), and minor constituents sarcophytol C (7), D (8), and E (9). These compounds were found to be susceptible to autooxidation while being purified. The structural determination of these compounds was made mainly based on proton and carbon nuclear magnetic resonance (NMR) spectral evidence and degradative studies by ozonolysis. X-ray crystallographic analysis for the two crystalline compounds, sarcophytol B (5) and D (8), has been reported. The total lipid extracts of S. glaucum comprise about 40% sarcophytol A (3), 5% each of sarcophytol A acetate (4) and sarcophytonin A (6), about 1% sarcophytol B (5), and minor amounts of sarcophytol C (7), D (8), and E (9). 

A new epoxy-bridged cembranoid diterpene 49 possessing antifouling activity was reported from an unidentified Thai soft coral species of the Sarcophyton genus, whose structure was assigned by NMR and NMR experiments. Two new cembranoids, 50 and 51, which showed cytotoxic activity on ehrlichacities tumor... 

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. 

Bioassay-guided fractionation of an aqueous extract from a Philippine Islands collection of the soft coral Lohophytum spp. yielded cembranoid diterpenes, Fig. (3), which exhibited moderate HIV-inhibitory activity in a cell-based in vitro anti-HIV assay [44], while new isomalabaricane triterpenes. Fig. (4), have been isolated from the sponge Stelletta spp. [45]. Other anti-HIV diterpenes also included the dolabellane diterpenes isolated from the Brazilian brown algae Dictyota pfaffi [46] and Dictyota menstrualis [47]. To investigate the effect of these diterpenes in the reverse transcription of the viral genomic RNA, the recombinant HIV-1 RT was assayed in vitro in the presence of each compound. All compounds inhibited the RNA-dependent DNA-polymerase activity of HIV-1 RT and consequently virus replication. 

The total synthesis of the cembranoid diterpene (+)-crassin acetate methyl ether was accomplished by W.G. Dauben et al. In the final stages of the total synthesis, the sensitive a-methylene group was introduced onto the six-membered lactone by using the Eschenmoser methenylation procedure. The lactone was deprotonated with LDA and then treated with Eschenmoser s salt. In the second step, the dimethylamino group was exhaustively methylated and the quaternary ammonium salt underwent a smooth Hofmann elimination upon deprotonation with DBU. 

Thus, for example, the cyclic propargylic allylic ether (242 equation 49) rearranges completely within 30 min upon treatment with Bu"Li in THF-hexane at -20 C, whereas the acyclic analog (244 equation SO) requires 12 h under comparable conditions. Alcohol (243) serves as a useful intermediate for the synthesis of cembranoid diterpenes. ... 

Paquette, L.A., Wang, T.-Z., Philippo, C.M.G., and Wang, S., Total synthesis of the cembranoid diterpene lactone (-i-)-cleomeolide. Some remarkable conformational features of nine-membered belts linked in a 2,6-fashion to a methylenecyclohexanc core, J. Am. Chem. Soc., 116, 3367, 1994. Moskva, V.V., and Razumov, A.I., Phosphinic and phosphinous acids. Part 34. Phosphorylated 1,3-dioxolanes, Trans. Kazan. Khim.-Tekhnol. Inst., 34, 273, 1965 Chem. Abstr, 68, 39729y, 1968. Razumov, A.L, and Gurevich, P.A., Synthesis of phosphorylated 1,3-dioxoles, Zh. Obshch. Khim., 38, 944, 1968 J. Gen. Chem. USSR (Engl. Transl.), 38, 909, 1968. 

Paquette, L.A., Wang, T.-Z., Philippo, C.M. G., and Wang, S., Ibtal synthesis of the cembranoid diterpene lactone (-r)-cleomeolide. Some remarkable conformational features of nine-membered belts linked in a 2,6-fashion to a methylenecyclohcxane core, J. Am. Chem. Soc., 116, 3367, 1994. 

Cembranoids are present both in plants and animals. The majority of the cembranoids of plant origin was isolated from tobacco. Cembranoid diterpenes, which serve as a trail pheromone and defense secretions, have been obtained from termites Nasutitermes exitiosus [160], Trinervitermes bettonianus [161], and various species of Cubitermes [162] and the ant Monmorium pharaonis [163],... 

Bowden, B.F., J.C. Coll, and S.J. Mitchell Studies of Australian Soft Corals. XVIII. Further Cembranoid Diterpenes from Soft Corals of the Genus Sarcophyton. Aust. J. Chem. 33, 879 (1980). 

Kinamoni, Z., A. Groweiss, S. Carmely, Y. Kashman, and Y Loya Several New Cembranoid Diterpenes from Three Soft Corals of the Red Sea. Tetrahedron 39, 1643 (1983). 

UcHio, Y., H. Nabeya, M. Nakayama, S. Hayashi, and T. Hash Cembrenene and Mayol, Two New Cembranoid Diterpenes from the Soft Coral Sinularia mayi. Tetrahedron Lett. 22, 1689 (1981). 

Compound 9 is one example of a series of mebabolites of cembranoid diterpenes from the soft coral Sarcophyton trocheliophorum. The compounds are mildly cytotoxic and represent modifications of the antitumor promoter sarcoph-ytol A. Bis-esters with MPA were prepared, and the stereocenters at C7 and C14 were assigned on the basis of AS values in the H NMR spectmm. ... 

Greenland GJ, Bowden BE Cembranoid diterpenes related to sarcophytol A from the soft coral Sarcophyton trocheliophorum (Alcyonacea). Aust. J. Chem. 1994 47 2013IU2021. 

Fontan, L.A. and Rodriguez, A.D. (1991) Isolation of eupahnerin, a nor cembranoid diterpene from the Caribbean gorgonian Eunicea mammosa. J. Nat. Prod., 54, 298-301. 

Li, G., Zhang, Y, Deng, Z., van Oftvegen, L., Proksch, P., and Lin, W. (2005h) Cytotoxic cembranoid diterpenes from a soft coral Sinularia gibberosa. J. Nat. Prod., 68, 649-652. 

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