Sponge metabolites

An intriguing application of Zincke processes occurred in Marazano s synthesis of dimeric, tetrameric, and even octameric pyridinium macrocycles, including cyclostellettamine B, a sponge-derived natural product. The same strategy produced a synthesis of haliclamine A (121, Scheme 8.4.41), a cytotoxic sponge metabolite. Intermediate 119, itself produced via a Zincke route, underwent an intramolecular Zincke reaction, providing macrocycle 120, which was reduced to the natural product. 

Very many naturally occurring 3-alkyl- or 3-acylfurans are now routinely synthesized by preparing a substrate for treatment with 3-furyllithium, itself made from 3-bromofuran according to Fukuyama, Tokoroyama, and Kubota, who used it to obtain pyroangensolide and fraxinellone.212 Equally, 2-lithiofuran is used for such natural products as the acetylenic furans from Alphonsea ventricosa213 and other compounds.214 For the synthesis of the sesquiterpenoid sponge-metabolite pleraplysillin-2 78, the lithiofuran 79 and therefore the bromofuran 80 was needed to secure the orientation a suitable preparation was devised for 80.215... 

The pyrrole ring is widely distributed in nature. It occurs in both terrestrial and marine plants and animals [1-3]. Examples of simple pyrroles include the Pseudomonas metabolite pyrrolnitrin, a recently discovered seabird hexahalogenated bipyrrole [4], and an ant trail pheromone. An illustration of the abundant complex natural pyrroles is konbu acidin A, a sponge metabolite that inhibits cyclin-dependent kinase 4. The enormous reactivity of pyrrole in electrophilic substitution reactions explains the occurrence of more than 100 naturally occurring halogenated pyrroles [2, 3]. 

The related stannylpyrrole 90, which was reported by Dubac [72], has been used to synthesize the sponge metabolite mycalazol 11 (91) and related compounds, which have activity against the P388 murine leukemia cell line [74]. 

Anodic oxidation of halogenated tyrosines was studied in connection with some sponge metabolites (cavemicolin model compounds). The methyl exter of 3,5-dibromotyrosine afforded four different products in a 41 10 26 23 ratio with 23% overall yield as a result of equilibration. (Scheme 44) [93JCS(P2)3117], A related compound was obtained as a mixture of stereoisomers 56 from a Diels-Alder reaction between N-acetyldehydroalanine methyl ester and l-methoxy-l,3-cyclohexadiene (87TL2371). 

The tricyclic marine sponge metabolites asmarine A 109 and B 110 showed toxicity to human tumor cell lines <1998TL1445, 2000JNP299>, and a number of simpler analogues have been prepared <2003T6493> see Section 10.11.7.3.1. 

Discovery of medicinally important metabolites from marine sponges renewed the interest of sponge aquaculture which has been studied early in the twentieth century for commercial supply of sponge metabolites. Sponge mariculture is considered to be the most cost-effective method (Duckworth and Battershill, 2003). Several drawbacks associated with the... 

Puupehenone (63) is a member of a distinctive family of sponge metabolites — a sesquiterpene joined to a C6-shikimate moiety — first exemplified by the quinol-quinone pair of avarol and avarone. Among the varied activities that have been reported for this diverse class of compounds is the property of ilimaquinone to inhibit replication of the HIV virus.78 Preliminary screening of puupehenone against Mycobacterium tuberculosis showed 99% inhibition of the organism. A series of chemical modifications have been conducted on puupehenone to study the effect on its biological activity. 

Additionally, during the search for biologically active sponge metabolites belonging to the sesterterpenoid class, a sulfated sesterterpene hydroquinone, halisulphate, Fig. (20), was isolated from the dark brown sponge Halichotidriidae sp. 

Triterpenoids are a minor group of sponge metabolites of these malabaricane/isomalabaricane triterpenoids, Fig. (21) are known from Jaspis and Stelletla sponge species. All of this group shows cytotoxicity and anti-HIV activity [136-139]. 

The structures of these compounds were assigned primarily by spectroscopic methods. The recrystalization of the natural Et A12-oxide (67) and the 21 -G-methyl-A12-formyl derivative of compound 63 gave single crystals and allowed X-ray analysis of these systems [74]. The absolute stereochemistry of 70 was determined by chiral GC of the L-Cys unit and by ROESY spectrum of its acetyl derivative [75]. The structures of Et s are related to the microbially derived safracins and saframycins -antitumor agents first isolated from cultured Streptomyces species [76] -as well as to the sponge metabolites renieramycin and xestomycin [77]. 

The homochiral f -branched carboxylic acids (13 or enf-13 Table 1) have been used for the synthesis of a variety of natural products21 such as California red scale pheromone,14 a-skytanthine,22 the southern com rootworm pheromone,15 and norpectinatone.16 Pure (5)-3-trichloromethylbutyric acid (a structural subunit of some sponge metabolites) was prepared via conjugate addition of ClaCMgCl to the chiral cro-tonate (16) followed by hydrolysis (Scheme S).23... 

The stereochemistry of the modified tryptophan amino acids in the previously known konbamide and keramamide A sponge metabolites (/ ) has been determined to be l for both 2-bromo-5 -hydroxytryptophan and 6-chi oro-5 - hydro x v-/V-methyltryptophan, respectively (1066). However, based on synthetic studies, doubt has been raised as to the structure of konbamide (1067). A series of investigations of Okinawan Theonella sp. sponges has uncovered the new halo-genated keramamides, E (1031), H (1032) (1068), L (1033) (1069), M (1034), and N (1035) (1070). 

The antifouling sponge metabolite pseudoceratidine (1245) was characterized from the Japanese Pseudoceratina purpurea (1253). This spermidine derivative has excellent larval settlement and metamorphosis inhibitory activity against the barnacle Balanus amphitrite (ED50 = 8.0 pig cm-3), and is the first example of an antifouling spermidine derivative. The four tauroacidins A (1246/1247) and B (1248/1249), with tyrosine kinase inhibitory activity, were isolated from the... 

Purealin, another brominated tyrosine metabolite of the sponge Psammaplysilla purea, blocks the sliding movement of sea urchin Anthocidaris crassispina sperm flagella (2537). Numerous sponge metabolites are feeding deterrents to predatory... 

Duckworth AR, Battershill CN (2003) Developing Farming Structures for Production of Biologically Active Sponge Metabolites. Aquaculture 217 139... 

Grkovic T, Kaur B, Webb VL, Copp BR (2006) Semi-Synthetic Preparation of the Rare, Cytotoxic, Deep-Sea Sourced Sponge Metabolites Discorhabdins P and U. Bioorg Med Chem Lett 16 1944... 

Rogers EW, de Oliveira MF, Berlinck RGS, Konig GM, Molinski TF (2005) Stereochemical Heterogeneity in Verongid Sponge Metabolites. Absolute Stereochemistry of (+)-Fistularin-3 and (+)-ll-ep(-Fistularin-3 by Microscale LCMS-Marfey s Analysis. J Nat Prod 68 891... 

Boehlow TR, Harbum JJ, Spilling CD (2001) Approaches to the Synthesis of Some Tyrosine-Derived Marine Sponge Metabolites Synthesis of Verongamine and Purealidin N. J Org Chem 66 3111... 

Metabolites of the phylum Porifera account for almost 50% of the natural products reported from marine invertebrates. Of the 2609 poriferan metabolites, 98% are derived from amino acid, acetogenin, or isoprenoid pathways. Isoprenoids account for 50% of all sponge metabolites, while amino acid and polyketide pathways account for 26% and 22%, respectively. A significant number of sponge metabolites appear to be derived from mixed biosynthetic pathways. Most structures reported containing carbohydrate moieties were glycosides. 

A second group of bioactive sponge metabolites with an unusual structural motif are the terpene isocyanides, which often co-occur with structurally related isothiocyanates and forma-mides.157-159 Less commonly encountered nitrogenous based substituents present in sponge terpene metabolites include isocyanates, thiocyanates, and dichloroimines (carbonimidic dichlorides). The biochemistry and ecology of these unique marine metabolites have been targeted for study by numerous researchers.159 160... 

The thiophene can be considered a four-carbon synthon via reductive desulfurization with Raney nickel. A strategy using the thiophene as a lynch-pin for the construction of complex building blocks was utilized in a total synthesis of the cytotoxic sponge metabolite haliclamine A <02JOC6474>. Thienyl cyclopropyl ketone (108) was elaborated into 109. Reduction of 109 with Raney Ni gave 110 which was taken on to haliclamine A. 

Corey and Roberts reported a total synthesis of the dysidiolide 46, a marine sponge metabolite with biological activities against A-549 human lung carcinoma and P388 murine leukemia cancer cell lines20 (Scheme 4.3p). The unwanted alcohol (47) was converted to the ketone 48 via Dess-Martin periodinane oxidation. The asymmetric reduction of 48 with the CBS catalyst 28b efficiently gave the alcohol 49, which was transformed into the dysidiolide 46 via photochemical oxidation. 

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