Didemnins antitumor activity

Dtdemnins, Biologically active depsipeptides extracted from a Caribbean tunicate (sea squirt) family Didem-nidae. genus Trididemnum. The three components, didem-nins A, B and C are weakly basic compds with antiviral, antitumor activity. Didemnin A is the most abundant, whereas didemnin B is generally the most active. Extraction and purification K., L. Rinehart. Jr., Eur. pat. Appl. 48,149 and U.S. pat. 4,493,796 (1982, 1985 both to Univ. Illinois). Structure determn K, L. Rinehart. Jr. et ah, J. Am. Chem. Soc. 103, 1857 (1981). Revised structure and total synthesis K. L. Rinehart, Jr- et ah. ibid. 109, 6846 (1987). See also U. Sebmidt et ah. Tetrahedron Letters 29, 3057 (1988) eidem, ibid. 4407. Crystal structure of B M. B. Hossain el ah. Proc. Nat. Acad. Sci. USA 85, 4118 (1988). Efficient total synthesis of A and B Y. Hamada et ah. J. 

One of the methods used currently is to broaden the source of the screens hence, companies are now searching for new compounds from samples obtained fiom tropical rain forests to deserts and oceans. The didemnins, which displayed potent antiviral and antitumor activities, were the first pharmaceuticals obtained from a marine source to be tested in the clinic (59). These, and other marine-derived dru have relatively unusual structures that eventually may provide new activities against atypical targets (59). 

Jiang, T.L., Liu, R.H., and Salmon, S.E. (1983) Antitumor activity of didemnin B in the human tumor stem cell assay Cancer Chemother. Pharmacol., 11, l-i. 

Bugula neritina) and related organisms produce substances with antibacterial, antitumor (e.g. bryostatins, didemnin B, dolastatin, girodazol, halichondrin B), anti-inflammatory (e.g. pseudopterosin E, manoalide derivatives), antifungal, antiviral, or immuno-suppressive (e.g. microcolin A and B) activity [399,400]. These compounds and/or their synthetic derivatives may be important novel bioactive pharmaceutical substances. It is also very Hkely that some new natural marine substances or their derivatives can be used as antifouling compounds, insecticides, or fungicides. 

Although historically most useful antibiotics have come from spore forming microorganisms, marine organisms have yielded the candidate antitumor peptide didemnin B [77327-50-0] (2) and cytostatic peptides such as the patellamides (3). Many of the marine peptides have little or no antimicrobial activity. Antibacterial peptides called magainins are found in frog skin (4) and antibacterial proteins called defensins are found in mammalian white blood cells (5). The commercially important insecticidal proteins from Bacillus thuringensis (6) are not discussed herein nor are the numerous peptide siderophores (7,8), which, except for the albomycins (9), are usually not antimicrobial. 

The didemnins are cyclic molecules composed of amino acids that were isolated from the marine invertebrate Trididemnum solidum. One of the amino acids is proline. The didemnins exhibit antitumor, antiviral, and i m m u n osu ppressi ve activity. The group labeled "R" in the structure is a side chain that contains additional amino acids. 

Like didemnins, most eudistomins are powerful antiviral agents (HSV-1, herpesvirus) and antitumor agents (many human cancer lines colon, melanoma, ovarian, lung, kidney, breast). Structure-activity relationships have been studied for natural eudistomins and several synthetic derivatives. The most active molecules are eudistomins with an oxathiazepine ring, and the main results are srunmarized in Figure 28.20 (Van Maarseveen et al, 1992, 1997 Kurihara et al, 1996). 

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