Eudistomin antiviral activity

Eudistomin K (155) (135) and its sulfoxide (171) (136) were isolated from the New Zealand ascidian Ritterella sigillinoides. The sulfoxide (171) also shows antiviral activity. The structure of 155 was determined by X-ray analysis (137) and that of 171 by semisynthesis from 155. Three other /3-carbolines, named eudistomins R, S, and T (172-174) were obtained from a Bermudian tunicate (E. olivaceum) by using an amino-bonded HPLC column (138). A 2-methyl-1,2,3,4-tetrahydro- -carboline with an /V-methylpyrrolidine at C-l, named woodinine (175), was isolated from a New Caledonian ascidian (Eudistoma fragum) (139), extracts of which exhibit antimicrobial activity. 

Other marine natural products with potent antitumour and antiviral activities, the eudistomins, continue to attract attention. As part of a new synthetic approach to the eudistomins, the stereoselective formation of the P-lactam fused oxathiazepine 110 has been reported <03SL738> C-N bond formation from 106 (via 105) was used to complete the seven-membered ring, and then this product 107 was converted into 110 via 108 and 109. Unfortunately, after ring opening the P-lactam in 110 and setting up the substituents for indole ring formation, this crucial indolisation was not successful. Other pathways are being explored but the P-lactam precursor concept is a clever one. 

The )8-carboline system alkylated at C-1 occurs frequently in the indole alkaloid series and in some cases in the 1,2,3,4-tetrahydro form, as shown above. The simplest homolog with a methyl substituent is caUed harman (Fig. 12). It has been found in several plant families and also in the higher fungus Coriolus maximus (174). Recently, particular interest in 1-substituted /3-carboline derivatives has also resulted from the antiviral activity against herpes simplex virus type 1 (HSV-1) discovered in eudis-tomins alkaloids (e.g., eudistomin S Fig. 12), isolated from the tunicate organism Eudistoma olivaceum (175). 

The eudistomins are a class of polycyclic alkaloids that contain a unique 1,3,7-oxathiazepine ring system as well as an iV,iV,0-trisubstituted hydrojq lamine substructure (Scheme 15.7). These natural products were isolated by Rinehart et al from the colonial tunicate Eudistoma olivaceum in 1984, and they exhibited strong antiviral activity against the Herpes sinplex... 

A were effective against herpes simplex virus-1 (HSV-land 11) [82, 83]. Eudistomin K sulfoxide and eudistomin K have high activities against polio vaccine type-1 virus. Platinum (If) and palladium (11) complexes of harmaline, harmalol, harmine, and harman and ( )-Debromoeudistomin K were also observed to exhibit antiviral activities against influenza virus (A and B) and herpes virus [84]. Recently, harman and its derivatives were found to possess anti-HIV activities against human peripheral blood mmuHiuclear (PBM) cells [85]. 

The 6-bromo and 7-bromo derivatives of norharman (13), known as eudistomin N and O, respectively, have been shown to have both antiviral and antimicrobial activity <87JA3378>. Compound (13) and some of its derivatives, including tetrahydro derivatives, were investigated for their ability to bind to benzodiazepine receptors in the brain. Trends showed that fully aromatic deriva-... 

Unlike carbazoles, haiogenated (3-carbolines are abundant in nature [1[. For example, the simple eudistomin O (7-bromo-(3-carboline) (40) is a ubiquitous marine ascidian metabolite [44[. Indeed, the tunicate genus Eudistoma has furnished most of the extant haiogenated (3-carbolines, some of which have significant antiviral (polio, herpes) and microbial activity. The Caribbean Eudistoma olivaceum produces at least 15 brominated carbolines [1[. A study of Eudistoma gilboverde uncovered the new eudistomins 41-43[45[, and the Australian ascidian Pseudodistoma aureum has... 

Van Maarseveen JH, De Hermkens PHH, Clercq E, Balzarini J, Scheeren HW, Kruse CG (1992) Antiviral and antitumor structure-activity relationship studies on tetracyclic eudistomines. J Med Chem 35 3223-3230... 

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). 

Several P-carboHne alkaloids related to eudistomins were isolated from Eudistoma glaucus and other species of Eudistoma, such as E. album, E.fragum, and E. gUboverde. Generally, these derivatives have antiviral and antitumor activities similar to those of eudistomins, but eudistomi-din A is also an antagonist of calmodulin (Kobayashi, Nakamura, and Ohizumi, 1986). Some members of this series are presented in Figure 28.21. 

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