Ascidian alkaloids

Two new polycyclic pyridoacridine alkaloids, arnoamine B, 289, and its demethylated analogue, arnoamine A, have been isolated from the ascidian Cystodytes sp. These new compounds are the first known examples of pyrroles fused to pyridoacridines, have antifungal properties, and are cytotoxic in several human tumor cell lines <1998JOC1657>. Both these compounds have been synthesized, starting from the hydrazone 290 with a Fischer indole synthesis (Scheme 73) <2000JOC5476>. 

The most well known and most widely used compounds mentioned in the chapter are the doubly protected monosaccharide derivatives (cf. Schemes 16-18 and 27-29), which serve as building blocks for the regio- and stereospecific synthesis of a host of more complex carbohydrates. A number of newly discovered alkaloids contain fused 5 6 6-triheterocyclic systems these compounds may come from not only traditional (plant) sources, for example, compounds 96, 292-294, 446, and 447, but also insects (compounds 531-533), marine animals of various kinds, for example, sponges (compounds 58 R = H or OH) and ascidians (compound 289), and amphibians (compound 535). Although the majority of these alkaloids are known to be toxic in sufficient quantity, any possible therapeutic applications have apparently not yet been disclosed. 

Steglich s group coupled A-methyl bromoindolylmaleimide 36 with 5-tributylstannyl-l-methyl-1//-imidazole to afford 37 and then converted 37 to didemnimide C (38), an alkaloid isolated from the Caribbean ascidian Didemnum conchyliatum [25]. 5-Tributylstannyl- 1-methyl-IH-imidazole, in turn, was prepared according to Undheim s direct metalation method from 1-methyl- l/Z-imidazole [26]. 

Trabectedin (36 Yondelis, ecteinascidin-743, ET-743 Zelfia and Johnson and Johnson, 2007), a tetrahydroisoquinoline alkaloid produced hy the ascidian Ecteinascidia turbinate,received approval for its sale in Europe, Russia and South Korea by Zelfia and Johnson and Johnson under the brand name YondelisT for the treatment of advanced soft tissue sarcoma (STS). Trabectedin (36) binds to the minor groove of DNA and inhibits cell proliferation by disrupting the cell cycle. 

In 2002, Munro et al. reported the isolation of coproverdine (271) from a New Zealand Ascidian. The name of this isolate was derived from the descriptor attached to the voucher specimen (green sheep-shit-like in appearance), hence coproverdine copro Greek dung, ovis Latin sheep, verde Latin green). This alkaloid was isolated from Nature in optically active form [a]p — 8.0 (c 0.36, EtOH). However, the absolute configuration was not assigned. Coproverdine showed cytotoxic activity against a variety of murine and human tumor cell lines (240). 

At higher levels of the tree of life, the hemichordates are peculiar for pyrazine steroidal alkaloids. In the chordates are the ascidians that give most alkaloids that are reminiscent of those isolated from... 

Carroll, A.R. Bowden, B.F. Coll, J.C. (1993) Novel cytotoxic iodotyrosine-based alkaloids from colonial ascidians, Aplidium sp. Aust. J. Chem., 46, 825-32. 

Davis, R.A. Carroll, A.R. Pierens, G.K. Quinn, R.J. (1999A)New lamellarin alkaloids from the Australian ascidian, Didemnum chartaceum. J. Nat. Prod., 62, 419-24. 

Makarieva, T.N. Ilyin, S.G. Stmiik, V.A. Lyssenko, K. A. Denisenko, V.A. (1999) Pibocin, the first ogoline alkaloid from the far-eastern ascidian Eudistoma sp. Tetrahedron Lett., 40,1591-4. 

Searle, P.A. Molinslg, T.F. (1994B) Five new alkaloids from the tropical ascidian, Lissoclinum sp. J. Org. Chem., 59, 6600-5. 

Vervoort, H.C. Fenical, W. Keifer, P.A. (1999) A cyclized didemnimide alkaloid from the Caribbean ascidian Didemnum conchyliatum. J. Nat. Prod., 62,389-91. 

Tasmanian collections of Clavelina cylindrica yielded the alkaloids cylindricines F (174) and G (175), the first thiocyanates isolated from an ascidian [169]. Cylindricines H-J (176-178) were later isolated from the same species [170]. 

A Micronesian ascidian, Nephteis fasicularis, was the source of fasicularin (179), a tricyclic, thiocyanate-containing alkaloid that was active in a DNA damaging assay [171]. The structure was confirmed by total synthesis [172],... 

However, pyrroloquinolines and pyridoacridines are the alkaloids of major interest as metabolites in sponges and ascidians [227], Many of these compounds have generated interest both as challenging problems for structure elucidation and synthesis as well as for their cytotoxicities [228-230],... 

As representative of the derivatives of pyridoacridine, eilatin, a marine alkaloid inhibits in vitro cell proliferation in chronic myeloid leukemia patients [244], Other members of the pyridoacridines, such as alkaloids isolated from a Cystodytes sp. ascidian, inhibit topoisomerase II [245], Additionally, analogues derivatives of these type of alkaloids showed interesting anti-HIV activity [246],... 

Fused tetracyclic and pentacyclic alkaloids constitute a relatively new class of natural products isolated mostly from ascidians and sponges. Cytotoxic, antimicrobial and antiviral activities have been reported for many of these compounds. The manzamine alkaloids, Fig. (33) are characterized by a complex pentacyclic diamine linked to C-l of P-carboline moiety. Manzamine have been isolated mainly from six different genera of marine sponges Haliclona, Pellina, Xestospongia, Ircinia, Pachypellin and Amphimedon. 

The Tasmanian ascidian Clavelina cylindrica has yielded two interconvertible tricyclic alkaloids, cylindricine A (178) and B (179), which are toxic to brine shrimp [140]. 

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). 

Uddin MJ, Kokubo S, Ueda K, Suenaga K, Uemura D (2001) Haterumaimides F-I, Four New Cytotoxic Diterpene Alkaloids from an Ascidian Lissoclinum Species. J Nat Prod 64 1169... 

Uddin J, Ueda K, Siwu ERO, Kita M, Uemura D (2006) Cytotoxic Labdane Alkaloids from an Ascidian Lissoclinum sp. Isolation, Structure Elucidation, and Structure-Activity Relationship. Bioorg Med Chem 14 6954... 

Rudi A, Evan T, Aknin M, Kashman Y (2000) Polycitone B and Prepolycitrin A Two Novel Alkaloids from the Marine Ascidian Polycitor africanus. J Nat Prod 63 832... 

Appleton DR, Page MJ, Lambert G, Berridge MV, Copp BR (2002) Kottamides A-D Novel Bioactive Imidazolone-Containing Alkaloids from the New Zealand Ascidian Pycnoclavella kottae. J Org Chem 67 5402... 

Vervoort HC, Richards-Gross SE, Fenical W, Lee AY, Clardy J (1997) Didemnimides A-D Novel, Predator-Deterrent Alkaloids from the Caribbean Mangrove Ascidian Didemnum conchyliatum. J Org Chem 62 1486... 

Verbitski SM, Mayne CL, Davis RA, Concepcion GP, Ireland CM (2002) Isolation, Structure Determination, and Biological Activity of a Novel Alkaloid, Perophoramidine, from the Philippine Ascidian Perophora namei. J Org Chem 67 7124... 

Makarieva TN, Ilyin SG, Stonik VA, Lyssenko KA, Denisenko VA (1999) Pibocin, the First Ergoline Marine Alkaloid from the Far-Eastern Ascidian Eudistoma sp. Tetrahedron Lett 40 1591... 

Makarieva TN, Dmitrenok AS, Dmitrenok PS, Grebnev BB, Stonik VA (2001) Pibocin B, the First A -O-Methylindole Marine Alkaloid, a Metabolite from the Far-Eastern Ascidian Eudistoma Species. J Nat Prod 64 1559... 

Rashid MA, Gustafson KR, Boyd MR (2001) New Cytotoxic W-Methylated P-Carboline Alkaloids from the Marine Ascidian Eudistoma gilboverde. J Nat Prod 64 1454... 

Carroll AR, Bowden BJ, Coll JC (1993) Studies of Australian Ascidians. II Novel Cytotoxic Iodotyrosine-Based Alkaloids from Colonial Ascidians, Aplidium sp. Aust J Chem 46 825... 

Van Wagoner RM, Jompa J, Tahir A, Ireland CM (1999) Trypargine Alkaloids from a Previously Undescribed Eudistoma sp. Ascidian. J Nat Prod 62 794... 

The marine mollusc Nerita albicilla was found to contain an oxindole alkaloid that was identified as isoteropodine (91), a previously known plant metabolite (94), by extensive NMR spectroscopic techniques (95). Four indole derivatives, named polyandrocarpamides A-D (92-95), were isolated from the colonial ascidian Polyandrocarpa sp. collected in the Philippines (96). 

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