Tunicates, alkaloids

Kobayashi J, Cheng JF, Ohta T Nozoe S, Ohizumi Y, Sasaki T, Eudistomidins B, C, and D Novel antileukemic alkaloids from the Okinawan marine tunicate Eudistoma glaucus, J Org Chem 55 3666—3670, 1990. 

The plethora of piperidine (242) and pyrrolidine alkaloids in Nature have made attractive targets for total synthesis, particularly since many contain a hydroxyl moiety adjacent to the amino group. This functionality is the case with the pseudodisto-mins-piperidines with antitumor activity isolated from the Okinawan tunicate Pseudodistoma kanaka. The limited availability of the natural material has prompted... 

Abas, S. Hossain, M.B. van der Helm, D. Schmitz, F.J. (1996) Alkaloids from the tunicate Polycarpa aurata from Chuuk atoll. J. Org. Chem., 61, 2709-12. 

Chbani, M. Pals, M. Delauneux, J.M. Debitus, C. (1993) Brominated indole alkaloids from the marine tunicate Pseudodistoma arborescens. J. Nat. Prod., 56,99-104. 

The pyridoacridine alkaloids, kuanoniamines A-D (133-136) were isolated from an unidentified Micronesian tunicate and its nudibranch predator, Chelynotus semperi. The structures were established by extensive NMR spectral analysis. Cytotoxicity against KB cells ranged from IC50 values >10 ig/mL for kuanoniamine B (134), 5 ig/mL for kuanoniamine D (136), to 1 ig/mL for kuanoniamine A (133) [145]. Kuanoniamine A (133) has also been synthesised [146,147]. 

The in vivo antitumour activity of extracts of the tunicate Ecteinascidia turbinata was noted in the late 1960s [152] but the active metabolites were only isolated and identified much later by two research groups. These complex alkaloids were termed the ecteinascidins and are... 

Some of these cytotoxic marine alkaloids are promising candidates for new drugs. For example, ecteinascidins, Fig. (29) are a family of tetrahydroisoquinolone alkaloids isolated from the Caribbean tunicate Ecteinascidici turbinata, which have been selected for clinical development. These compounds are presently in pre-clinical and clinical trials for human cancers [221-225], A series of totally synthetic molecules that are structurally related to the ecteinascidins is currently being prepared and evaluated as antitumor agents [226],... 

Meridianins, brominated indole alkaloids from the tunicate Aplidium meridianum, show cytotoxicity against LMM3 (murine mamarian adenocarcinoma cell line) with IC5o values of 11.4 jM for meridianin B (25), 9.3 iM for meridianin C (26), 33.9 iM for meridianin D (27), and 11.1 aM for meridianin E (28) [41]. 

Most of the marine metabolites bearing a sulfide group correspond to well-defined families of alkaloid compounds and they have mainly been obtained from tunicates and sponges. To a lesser extent they have also been found in bryozoans, molluscs, and algae. 

The sulfur-containing P-carboline marine alkaloids isolated from tunicates belong to three main chemical families the eudistomins, the eudistomidins, and the didemnolines. 

The P-carboline alkaloid eudistomidins were isolated from the Okinawan tunicate Eudistoma glaucus. A methyl sulfide group is present in eudistomidins C (27) [30] and E (28) [32] while a methyl sulfoxide occurs in eudistomidin F (29) [32]. Their structures were elucidated on the basis of spectroscopic data. The 5 configuration at C-10 of eudistomidin C (27) was established by synthesis of 10-(/ )-Omethyleudistomidin C [30]. The... 

Since the discovery of amphimedine by Schmitz and co-workers in 1983 [36], the polycyclic alkaloids based on the pyrido[, /]acridine skeleton have emerged as a well-defined class of marine metabolites, with significant biological activities, isolated from sponges and tunicates [37]. The less common group of sulfide pyridoacridines were only obtained from tunicates and they include the shermilamines, the varamines-lissoclins-diplamine group, and tintamine, another polycyclic alkaloid closely related to them. 

The shermilamines constitute a group of alkaloids characterized by a thiazinone ring attached to the pyridoacridine ring system. Shermilamine A (36) was the first known compound of this series and was isolated by Scheuer et al. from the tunicate Trididemnum sp. [38]. The complete... 

The ecteinascidins constitute a group of very complex alkaloid tris(tetrahydroisoquinolines) with potent in vivo antitumor activity and were isolated from the colonian Caribbean tunicate Ecteinascidia turbinata. The compounds are abbreviated as Et followed by a number that represents the value of the highest mass ion observed in the (+)-FABMS. Reports of the potent in vivo activity of extracts of that tunicate date back to 1969, when it was reported that such extracts gave T/C values of up to 272 vs P388, with four of six cures in one experiment, and they were also found to be powerful immunomodulators [72]. After a decade of effort, two research groups reported at the same time the structures of four [Et 743 (1), Et 729 (63), Et 745 (64), and Et 770 (66)] [72] and two [Et 743 (1), Et 729(63)] [73] ecteinascidins, respectively. The development of an isolation process that was efficient on a large scale allowed Rinehart s group to obtain additional ecteinascidins, Et 743 V2-oxide (67), Et 722... 

The marine isothiocyanates, with more than 80 compounds isolated so far, form the largest group of naturally occurring isothiocyanates. This well-established group of marine natural products is constituted mainly by terpene metabolites present as sesquiterpene and diterpene derivatives. The non-terpene isothiocyanate compounds include two cylindricine alkaloids and a series of long-chain aliphatic metabolites. Marine sponges constitute the main source of these compounds, although they are also found in nudibranches and tunicates. 

Although marine organisms produce a large number of isocyanates, isothiocyanates, and formamides, the corresponding thiocyanates have rarely been encountered. Indeed, the thiocyanate functionality has only been found in six sesquiterpenes (263-268), in four tricyclic quinoline alkaloids (271-274), and in psamaplin B (172) (included in the bromotyrosine derivatives discussed in the disulfide/polysulfide section). They have been found in marine sponges, as well as in nudibranches and tunicates. 

An Antarctica collection of the sponge Psammopemma sp. has yielded the new 4-hydroxyindole alkaloids, psammopemmins A (1378), B (1379), and C (1380), which embody the unique 2-bromopyrimidine unit (1337). The related meridia-nins B (1381), C (1382), D (1383), E (1384), and F (1385) were found in the tunicate Aplidium meridianum collected at 100 m near the South Georgia Islands (1338,1339). These protein kinase inhibitors have been synthesized (1340). The sponge Discodermia polydiscus has afforded 6-hydroxydiscodermindole (1386) (1341). 

Fig. 3.20 Didemnum sp., a tunicate that contains the fascaplysin alkaloids 1510-1521 (Photo F. J. Schmitz)...

Marine tunicates are also a source of brominated tyrosine derivatives. The colonial ascidian Aplidium sp., which was collected in Australia, yielded the novel iodinated tyrosine alkaloids 1973-1975 (1819). Collections of Botryllus sp. and Botryllus schlosseri from the Philippines and the Great Barrier Reef, respectively, have afforded botryllamides A-D (1976-1979) (1820). A Palauan ascidian Botrylloides tyreum produces several new botryllamides, including the brominated botryllamide G (1980) (1821). The simple brominated tyramines 1981 and 1982 were isolated from the New Zealand ascidian Cnemidocarpa bicornuta (1822) and an Indonesian Eudistoma sp. ascidian (1823). 

Hernandez Franco L, Bal de Kier Joffe E, Puricelli L, Tatian M, Seldes AM, Palermo JA (1998) Indole Alkaloids from the Tunicate Aplidium meridianum. J Nat Prod 61 1130... 

Sato H, Tsuda M, Watanabe K, Kobayashi J (1998) Rhopaladins A-D, New Indole Alkaloids from Marine Tunicate Rhopalaea sp. Tetrahedron 54 8687... 

Abourriche A, Abboud Y, Maoufoud S, Mohou H, Seffaj T, Charrouf M, Chaib N, Bennamara A, Bontemps N, Francisco C (2003) Cynthichlorine A Bioactive Alkaloid from the Tunicate Cynthia savignyi. II Farm 58 1351... 

Segraves NL, Lopez S, Johnson TA, Said SA, Fu X, Schmitz FJ, Pietraszkiewicz H, Valeriote FA, Crews P (2003) Structures and Cytotoxicities of Fascaplysin and Related Alkaloids from Two Marine Phyla - Fascaplysinopsis Sponges and Didemnum Tunicates. Tetrahedron Lett 44 3471... 

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