Isolation and structural elucidation of cytotoxic agents from marine invertebrates and plants sourced from the Great Barrier Reef, Australia

Agrawal, Madhavi (2007) Isolation and structural elucidation of cytotoxic agents from marine invertebrates and plants sourced from the Great Barrier Reef, Australia. PhD thesis, James Cook University.

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The interest in the marine environment has been stimulated by the array of biological activities of marine natural products and hence their potential biomedical applications. The advent of high throughput screening has allowed a large number of compounds to be tested for a range of biological activities, in order to assess their potential as pharmaceuticals. This study aimed to discover drug leads from marine invertebrates collected from the Great Barrier Reef (GBR) by screening extracts for pharmacological activity. The pharmacological target was aimed to find novel cytotoxic compounds with potential as anticancer agents. Cytotoxicity was assessed in vitro using the P388D1 mouse lymphoma cell line. Thus 308 samples of marine invertebrates and plants were collected from the central section of the Great Barrier Reef (GBR). Bioassay guided fractionation led to the isolation and structural elucidation of seven new and twenty known cytotoxic metabolites. Structural elucidation was done via 1D and 2D NMR spectroscopy.

Two new brominated polyether triterpenes, Armatols G (193) and H (194) were isolated from the red alga Chondria armata. Compounds (193) and (194) exhibited moderate cytotoxicity, with IC50 values of 5.80 and 6.30 μg/ml. The relative stereochemistry throughout each molecule was determined via NOe experiments and by using Chem 3D and its MM2 energy minimization program to predict the lowest energy conformation. It is proposed that hydrolysis of the acetate functionality and application of the Mosher’s method for the resultant secondary alcohol should afford the absolute stereochemistry for compound 194.

A new isomalabaricane triterpene, stelliferin D riboside (195) was isolated from the sponge Rhabdastrella globostellata along with the known isomalabaricanes, stelliferin A (43) and compound 51. Stelliferin A (43) and stelliferin D riboside (195) exhibited IC50 values of 0.16 and 1.10 μg/ml respectively.

Five furanoditerpenes were isolated from the sponge Spongia sp. Spongiadiol diacetate (97) was most cytotoxic with an IC50 value of 2.10 μg/ml. This was followed by the new compound isospongiatriol (196) and the known compound epispongiatriol (96) which exhibited IC50 values of 14.0 μg/ml and 16.30 μg/ml respectively. Spongiatriol triacetate (99) was inactive in the assay. Isospongiadiol (109) was not tested due to decomposition of the compound.

A new pentabrominated phenolic diphenyl ether (197) was isolated from the sponge Dysidea herbacea. Compound (197) exhibited a moderate IC50 value of 2.20 μg/ml. All 4 positional isomers of diphenyl ethers that contain a 2,4-dibrominated B-ring and a 1-hydroxytribrominated A-ring with the ether linkage at the 2-position have now been reported from marine sponges.

A deaminated analogue of the known pyridoacridine alkaloid stellettamine (188) was isolated from the ascidian Aplidium sp. (cf Aplidium cratiferum). It was named nordehydrocyclodercitin (200). Cytotoxicity assays could not be performed due to decomposition of the compound, but the cytotoxic activity of many pyridoacridine alkaloids is well documented

Two imidazole alkaloids, isonaamidine E (225) and its zinc complex, bis(isonaamidinato E)zinc (408) were isolated from a Leucetta sponge. The compound was assigned via spectroscopic methods. The electrospray results obtained for (408) were not readily interpreted in our hands, although molecular clusters that contained zinc and chlorine (from isotope patterns) were observed. The structure of 408 was verified by the addition of half an equivalent of ZnCl2 to an isonaamidine E sample, which afforded a 1H NMR spectrum that was identical to that observed for 408.

Item ID: 2047
Item Type: Thesis (PhD)
Keywords: marine invertebrates, marine plants, red algae, Great Barrier Reef, GBR, cytotoxins, anticancer agents, metabolites, pharmaceuticals, marine natural products, biomedicine, sponges, ascidian, Aplidium, Dysidea herbacea, Chondria armata, Leucetta, isomalabaricane triterpenes, polybrominated diphenyl ethers, pyridoacridine alkaloids, imidazole alkaloids
Date Deposited: 23 Dec 2008 00:29
FoR Codes: 03 CHEMICAL SCIENCES > 0304 Medicinal and Biomolecular Chemistry @ 0%
03 CHEMICAL SCIENCES > 0306 Physical Chemistry (incl Structural) > 030606 Structural Chemistry and Spectroscopy @ 0%
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