The Oxeatamides: nitrogenous spongian diterpenes from the New Zealand marine sponge Darwinella oxeata.

As part of our ongoing search for novel and bioactive compounds from New Zealand marine organisms, we investigated the extracts of the sponge Darwinella oxeata. NMR-guided fractionation led to the isolation of nine new nitrogenous spongian diterpenes, oxeatamide A (1), iso-oxeatamide A (2), oxeatamides B-G (3-8), and oxeatamide A 23-methyl ester (9), as well as two known compounds, membranolides C and D (10, 11).

Chemical synthesis of a masked analogue of the fish antifreeze potentiating protein (AFPP).

A recently identified Antarctic fish protein termed antifreeze potentiating protein (AFPP) is thought to act as an adjunct to the previously characterised antifreeze glycoproteins (AFGPs), the two acting together to inhibit ice crystal growth in vivo. Elucidating the functional properties of the new AFPP requires access to large amounts of pure product, but the paucity of natural material necessitates alternative approaches. We therefore embarked on the total chemical synthesis of the AFPP, through a convergent ligation strategy. After many challenges, mostly due to the solubility issues of the peptide fragments, and several revisions of the original synthetic strategy, we have successfully synthesized a masked analogue of AFPP. The key to the successful synthesis was the use of a solubilising tag attached through a hydrolysable linker.

The agminosides: naturally acetylated glycolipids from the New Zealand marine sponge Raspailia agminata.

Examination of the New Zealand sponge Raspailia agminata resulted in the isolation of five members of a novel family of glycolipids, agminosides A-E (1-5). These large and complex molecules contain up to six partially acetylated glucose residues. The chromatographic separation of these compounds was a challenge due to the similarity of the congeners and their lack of a chromophore. MS-guided isolation followed by extensive NMR analysis and chemical derivatization eventually led to the purification and identification of 1-5.

Stimulation of mammalian translation initiation factor eIF4A activity by a small molecule inhibitor of eukaryotic translation.

RNA helicases are the largest group of enzymes in eukaryotic RNA metabolism. The DEXD/H-box putative RNA helicases form the helicase superfamily II, whose members are defined by seven highly conserved amino acid motifs, making specific targeting of selected members a challenging pharmacological problem. The translation initiation factor eIF4A is the prototypical DEAD-box RNA helicase that works in conjunction with eIF4B and eIF4H and as a subunit of eIF4F to prepare the mRNA template for ribosome binding, possibly by unwinding the secondary structure proximal to the 5' m7GpppN cap structure. We report the identification and characterization of a small molecule inhibitor of eukaryotic translation initiation that acts in an unusual manner by stimulating eIF4A-associated activities. Our results suggest that proper control of eIF4A helicase activity is necessary for efficient ribosome binding and demonstrate the feasibility of selectively targeting DEAD-box RNA helicases with small molecules.