P-46 パプアニューギニア産海綿Neamphius huxleyiから得られた新規抗HIVデプシペプチドneamphamide Aの構造決定(ポスター発表の部)

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Marine sponges have been proved to be a prolific source of anti-HIV metabolites. Among such compounds, a group of depsipeptides has especially attracted considerable interests among synthetic chemists due to their unique structural components as well as potent anti-HIV activity with the EC_<50> values in the order of nM. As part of our program to discover novel anti-HIV leads from natural biological sources, we discovered a new anti-HIV depsipeptide designated neamphamide A (1) from the lipophilic extract of a Papua New Guinea collection of the marine sponge Neamphius huxleyi. Spectroscopic analysis using NMR and MS revealed that 1 is a depsiundecapeptide consisted of 4 usual (Asn, Thr, Arg, Leu) and 5 unusual amino acids (4-amino-7-guanidino-2,3-dihydroxyheptanoic acid=Agdha, 3,4-dimethylglutamine=3,4-diMeGln, NMeGln, β-methoxytyrosine=βOMeTyr, homoproline=Hpr) with its N-terminus protected by a hydroxy fatty acid (3-hydroxy-2,4,6-trimethylheptanoic acid=Htmha). The stereochemistry of the 9 amino acid residues were determined as L-Asn1, (3S,4R)-3,4-diMe-L-Gln, D-αThr1, D-αThr2, D-Arg, L-Leu, L-NMeGln, D-Asn2, and L-Hpr by chemical degradation, derivatization of the products with Marfey's reagent (L-FDAA) or GITC (2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl isothiocyanate), and diastereomeric separation of the resulting derivatives by LC-MS. The 4S-stereochemistry of Agdha was established by isolating a diol-cleavage product of 1, which was oxidized and then acid-hydrolized to give L-Arg. The R-configurations of the C2 and C3 chiral centers in Agdha were established based on 1D NOESY data for two cyclized Agdha derivatives obtained from 1 and on comparing H-H coupling constants of lactamized Agdha with the literature values. The βOMeTyr residue decomposed during acid hydrolysis. To facilitate configurational assignment of this residue, 1 was oxidized by treating with RuCl_3-NaIO_4 prior to acid hydrolysis and the product was properly derivatized for chiral GC-MS analysis. The elution of (2S,3S)-isomer was observed by monitoring a characteristic fragment pattern for the OMeAsp derivative, thus (R)-βOMe-L-Tyr in 1 was assigned. Finally, (2R,3R,4R)-stereochemistry of the Htmha moiety was deduced by isolating free fatty acid from the hydrolysate of 1 and comparing its NMR data with the literature values, followed by LC-MS analysis of its (+)-phenylglycine methyl ester derivative alongside the synthetic standards. Neamphamide A (1) and callipeltin A, the first anti-HIV depsipeptide isolated from the New Caledonian marine sponge Callipelta sp., share a common octapeptide backbone (from Agdha to βOMeTyr) and a fatty acid residue. In addition, 1 possesses the C-terminal Hpr residue, which is also a feature of another class of anti-HIV depsipeptides, the papuamides. It should be noted that all these peptides contain 3,4-diMeGln and βOMeTyr, which so far have only been found in this family of peptides. Neamphamide A (1) protected the human T cell line CEM-SS from cytopathic effect of HIV-1_<RF> at EC_<50> 28nM, while its direct cytotoxicity toward the cells was TC_<50> 260nM.
天然有機化合物討論会の論文
2005-09-15

P-46 パプアニューギニア産海綿Neamphius huxleyiから得られた新規抗HIVデプシペプチドneamphamide Aの構造決定(ポスター発表の部)

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