Marine tripeptide

The enantioselective total synthesis of (-)-hemiasterlin, a marine tripeptide with cytotoxic and antimitotic activity, was achieved by E. Vedejs and co-workers. The asymmetric Strecker reaction was used to construct the key tetramethyltryptophan subunit. The aldehyde substrate was first converted to the corresponding chiral imine with (R)-2-phenylglycinol under scandium triflate catalysis. The addition of tributyltin cyanide resulted in the formation of a-amino nitriles as an 8 1 mixture of diastereomers. Subsequently the cyano group was converted to a primary amide, and the chiral auxiliary was removed under catalytic hydrogenation conditions. 

Crews, P. Farias, J.J. Emrich, R. Keifer, P.A. (1994) Milnamide A, an unusual cytotoxic tripeptide from the marine spoage Auletta cf. constricta. J. Org. Chem., 59, 2932-4. 

Figure 7.39. The diversity of antifreeze proteins and antifreeze glycoproteins in marine fishes. Shown are the structures of four types of AFPs (I-IV) and the AFGP found in Antarctic notothenioids and Arctic cod. AFPs I-IV are shown as ribbon structures. The tripeptide repeat (-ala-ala-thr-) and carbohydrate moiety (galactosyl-lV-acetylgalactosamine) of AFGPs illustrate the key element of AFGP structures in noto-thenioid and Arctic cod.

The solid phase synthesis of many organic molecules utilizes carbodiimide mediated reactions. An example is the synthesis of l,4-benzodiazepine-2,5-dione using EDCCl in NMP in a key synthesis step. Often carbodiimides are used in the synthesis of complex proteins. A recent example is the synthesis of the tripeptide backbone of the novel immunosuppressent sanglifehrin A. In the synthesis of the marine alkaloid, variolin B, the formation of an annelated pyrimidine ring is achieved using a carbodiimide mediated cyclization process. 

Tunicates are the only marine invertebrates in which alkaloid biosynthesis has been extensively investigated (189). In addition to the eudistomins, described below, the tripeptide tunichromes have been investigated, by Nakanishi and coworkers at Columbia University, in the solitary tunicate Ascidia nigra (191) and shermilamine, a benzo-3,6-phenanthroline alkaloid, has been studied in Cystodytes dellechiajei, by Steffan and coworkers at the University of Munich (192). The origin of the (3-carboline ring system of the eudistomins has been studied, by Baker s group at Florida Tech, in Eudistoma olivaceum (193, 194). 

The more complex sulphur requirements of the marine animals are met largely by cysteine, cystine, methionine, biotin, and thiamine (Young and Maw, 1958) (Fig. 4). Cysteine is a component of the tripeptide glutathione and a precursor of taurine. Methionine is as an essential amino acid involved in biosynthesis of proteins, creatine and adrenaline. Adenosylmethionine is considered to be the active part in transmethylation, e.g. of choline. Methionine is part of the pathways to homocysteine, cystathionine and methylthioadenosine (Young and Maw, 1958). Various organisms convert cysteine and/or cystine into mercapturic acids, cysteine sulphinic acid, and thiazolidine derivatives (Zobell, 1963). 

Eisenin, pGlu-Gln-Ala-OH, a tripeptide extracted from the brown Japanese marine alga Eisenia hicyclis Setchdl. It shows the immunological activity to augment natural cytotoxicity of peripheral blood lymphocytes in humans [R. Katakai, M. Oya,J. Org. Chem. 1974, 39, 1974 T. Kojima et al., J. Immunother. 1993, 13, 36]. 

Hemiasterlin, a tripeptide isolated from several marine sponges (HemiastereUa minor, Auletta sp., Cymbastela sp., Siphonochalina sp.) exhibiting potent cytotoxicity against a variety of cancer cell lines in vitro via a tubulin antimitotic mechanism. Its relatively simple structure allows structural modifications to obtain analogues with high potency such as taltobulin (HTI-286 also known as SPAllO), which show more potent in-vitro cytotoxicity and antimitotic ac-... 

Toske, S.G. et al., AspergiUamides A and B modified cytotoxic tripeptides produced by a marine fungus of the genus Aspergillus, Tetrahedron, 54, 13459, 1998. 

Casapullo, A., Minale, L., and Zollo, F. (1994a) The unique 6-(p-hydroxyphenyl)-2H-3,4-dihydro-l,l-dioxo-l,4-thiazine and the new tripeptide L-Glu-Gly-4-Hydroxystyrylamine from the marine sponge Anchinoe tenacior. Tetrahedron Lett., 35, 2421-2422. 

Giordano, A Monica, C.D., Landi, F., Spinella, A and Sodano, G. (2000) Stereochemistry and total synthesis of janolusimide, a tripeptide marine toxin. Tetrahedron Lett., 41, 3979-3982. 

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