Anthony Richard Carroll

Flinderoles A−C: Antimalarial Bis-indole Alkaloids from Flindersia Species

With the aim of finding new natural product antimalarials, the novel indole alkaloids flinderole A-C were found to have selective antimalarial activities with IC(50) values between 0.15-1.42 microM. Flinderole A was isolated from the Australian plant Flindersia acuminata and flinderoles B and C from the Papua New Guinean plant F. amboinensis. Flinderoles A-C contain an unprecedented rearranged skeleton compared to their related isomers of the borreverine class of compounds.

Chemical aspects of mass spawning in corals. I. Sperm-attractant molecules in the eggs of the scleractinian coral Montipora digitata

This paper provides the first evidence for sperm chemotaxis in the Scleractinia. Montipora digitata Dana, 1845 (Scleractinia: Coelenterata) is a hermaphroditic coral which reproduces bi-annually, releasing egg-sperm bundles during the mass spawning at Magnetic Island (19°10′S; 146°52′E) in late spring-early summer, and autumn each year. The buoyant egg-sperm bundles float to the surface where they break apart, releasing eggs and sperm into the ocean. Fertilisation occurs after ∼30 min. Unfertilized eggs were collected, washed free of sperm, and freeze-dried. The eggs were extracted with dichloromethane, fractionated by chromatography on silica gel, and the fractions assayed for their ability to attract M. digitata sperm. The active fraction was further fractionated by high-performance liquid chromatography, resulting in the isolation of three highly unsaturated fatty alcohols: (1) dodeca-2,4-diynol; (2) tetradec-13-ene-2,4-diynol; (3) (14Z)-heptadeca-14,16-diene-2,4-diynol. Of these three compounds, only Compound 1 attracted sperm of M. digitata. Synthetic Compound 1, produced from simple precursors by known reactions, possessed sperm-attracting activity comparable to the naturally derived attractant. Preliminary experiments suggest that the natural mixture of Compounds 1, 2 and 3 in the ratio 1:4:9 is more effective in attracting sperm from M. digitata than sperm from other Montipora species. Sperm attractants may act to reduce the incidence of hybridisation between different species of Montipora.

Clavatadine A, A Natural Product with Selective Recognition and Irreversible Inhibition of Factor XIa †

Bioassay-guided fractionation of a CH2Cl2/MeOH extract of the sponge Suberea clavata using the serine protease factor XIa to detect antithrombotic activity led to the isolation of the new marine natural products, clavatadines A and B. Clavatadines A and B inhibited factor XIa with IC50s of 1.3 and 27 microM, respectively. A crystal structure of protein-inhibitor (clavatadine A) complex was obtained and revealed interesting selective binding and irreversible inhibition of factor XIa. The cocrystal structure provides guidance for the design and synthesis of future factor XIa inhibitors as antithrombotic agents.

Polyalkylated cyclopentindoles: Cytotoxic fish antifeedants from a sponge, Axinella sp.

Abstract A Western Australian sponge, Axinella sp., yielded three polyalkylated indoles unsubstituted at C3, thus apparently not derived from tryptophan. The three compounds, herbindoles A, B, and C, are cytotoxic against KB cells and are fish antifeedants.

Variability of terpene content in the soft coralSinularia flexibilis (Coelenterata: Octocorallia), and its ecological implications

Colonies of the soft coralSinularia flexibilis (Quoy & Gaimard) (Coelenterata, Octocorallia) were collected at Lizard Island (14°40′S and 145°28′E) Research Station. Extraction of the corals and quantitative chemical analysis for the three major diterpene components, flexibilide, dihydroflexibilide, and sinulariolide, afforded average ratios of 4∶3∶1 respectively. Colonies, sized on the basis of the sterile stalk circumference, were analyzed for possible correlations between size and chemical composition. The major metabolite, flexibilide, was inversely correlated with colony size, while sinulariolide concentration showed a direct correlation. The concentration of dihydroflexibilide was independent of colony size. Samples were further analyzed with respect to site of collection. Colonies were collected at three distinct reefal sites. One was characterized by large monospecific stands ofParites cylindrica, a second was a sandy bottom site with a mixed community of soft corals and occasional scleractinians, while the third site was a very diverse reef community with many species of scleractinian corals.Sinularia flexibilis was well represented at each site, and the concentration of flexibilide and sinulariolide varied significantly among sites. The concentration of flexibilide was significantly higher at the third, highly competitive site, while the concentration of sinulariolide was highest at thePorites-dominated site. Dihydroflexibilide levels were independent of site. It seems likely that concentrations of flexibilide, a highly cytotoxic molecule involved in interference competition, and sinulariolide, a known algicide probably responsible for colony maintenance, may be influenced by their environments.

Aplidiopsamine A, an Antiplasmodial Alkaloid from the Temperate Australian Ascidian, Aplidiopsis confluata

A polyaromatic alkaloid, aplidiopsamine A was isolated from the temperate Australian ascidian, Aplidiopsis confluata, and its structure was determined from interpretation of mass, 1D and 2D NMR spectra. Aplidiopsamine A is the first alkaloid to possess the tricyclic aromatic substructure 3H-pyrrolo[2,3-c]quinoline conjugated to an adenine. Aplidiopsamine A exhibited significant inhibition of growth of chloroquine resistant and sensitive strains of the malaria parasite, Plasmodium falciparum, and minimal toxicity toward human cells.

Aplysamine 6, an Alkaloidal Inhibitor of Isoprenylcysteine Carboxyl Methyltransferase from the Sponge Pseudoceratina sp.

The anticancer target isoprenylcysteine carboxyl methyltransferase (Icmt) was the focus of a natural product high-throughput screening campaign. The Australian marine sponge Pseudoceratina sp. yielded aplysamine 6, a new bromotyrosine derivative with an alpha,beta-unsaturated amide linkage, as the bioactive constituent. Its structure was determined by 1D and 2D NMR spectroscopy.

Leptoclinidamines A-C, indole alkaloids from the Australian ascidian Leptoclinides durus.

Three new indole alkaloids, leptoclinidamines A-C (1-3), were isolated from the Australian ascidian Leptoclinides durus. Their structures were determined by analysis of 2D NMR spectra. Leptoclinidamines A and B both contain an indoleglyoxylic acid attached to an L-arginine. The structure of leptoclinidamine A was confirmed by total synthesis. Leptoclinidamine C contains the naturally rare 1,3-dimethyl-5-(methylthio)histidine attached to a 6-bromoindole-3-carboxylic acid. Leptoclinidamine C (3) and both enantiomers of leptoclinidamine A (1) were tested for antimalarial, antitrypanosomal, and cytotoxic activity, but none of the compounds were bioactive.

Exiguaquinol: a novel pentacyclic hydroquinone from Neopetrosia exigua that inhibits Helicobacter pylori MurI.

Bioassay-guided fractionation of the methanol extract of the Australian sponge Neopetrosia exigua led to the isolation of exiguaquinol (2), a new pentacyclic hydroquinone that inhibited Helicobacter pylori glutamate racemase (MurI) with an IC(50) of 4.4 microM. Its structure and relative configuration were assigned on the basis of spectroscopic data. Exiguaquinol (2), bearing a novel pentacyclic ring skeleton, is the first natural product to show inhibition of H. pylori MurI. Its protein-ligand modeling is also discussed.

Botryllamides A-D, new brominated tyrosine derivatives from styelid ascidians of the genus Botryllus

Abstract Four new bromotyrosine derivatives, botryllamides A-D (1–4) were isolated from the styelid ascidian Botryllus sp. from Siquijor Is., Philippines, and from Botryllus schlosseri from the Great Barrier Reef, Australia. Their structures were deduced from 1D and 2D NMR spectral data.