cis,cis- and trans,trans-Ceratospongamide, New Bioactive Cyclic Heptapeptides from the Indonesian Red Alga Ceratodictyon spongiosum and Symbiotic Sponge Sigmadocia symbiotica

Abstract

Chemical investigation of the marine red alga (Rhodophyta) Ceratodictyon spongiosum containing the symbiotic sponge Sigmadocia symbiotica collected from Biaro Island, Indonesia, yielded two isomers of a new and bioactive thiazole-containing cyclic heptapeptide, cis,cis-ceratospongamide (1) and trans, trans-ceratospongamide (2). Isolation of these peptides was assisted by bioassay-guided fractionation using a brine shrimp toxicity assay (Artemia salina). The structures of the ceratospongamides, which each consist of two L-phenylalanine residues, one (L-isoleucine)-L-methyloxazoline residue, one L-proline residue, and one (L-proline)thiazole residue, were established through extensive NMR spectroscopy, including (1)H-(13)C HMQC-TOCSY, and (1)H-(15)N HMBC experiments, as well as chemical degradation and chiral analysis. cis,cis- and trans,trans-ceratospongamide are stable conformational isomers of the two proline amide bonds. Molecular modeling of these two ceratospongamide isomers showed the trans, trans isomer to be quite planar, whereas the cis,cis isomer has a more puckered overall conformation. trans,trans-Ceratospongamide exhibits potent inhibition of sPLA(2) expression in a cell-based model for antiinflammation (ED(50) 32 nM), whereas the cis,cis isomer is inactive. trans,trans-Ceratospongamide was also shown to inhibit the expression of a human-sPLA(2) promoter-based reporter by 90%.

Bioactive peptides from marine sources: pharmacological properties and isolation procedures

“…They were isolated from the marine red alga (Rhodophyta) Ceratodictyon spongiosum containing the symbiotic sponge Sigmadocia symbiotica. trans,trans-Ceratospongamide exhibits potent inhibition of secretory phospholipase (sPLA) expression in a cell-based model for antiinflammation (ED 50 = 32 nM), whereas the cis,cis isomer is inactive [144].…”

Chemistry and Biology of Anti-Inflammatory Marine Natural Products. Phospholipase A2 Inhibitors

“…This intriguing algal-sponge pair gives rise to a rare kind of marine cyclic heptapeptidic metabolites: cis,cis- (20) and trans,trans-ceratospongamides (21) (Fig. 7) were isolated from the organic extract of this species thanks to a bioassay-guided fractionation [40]. The structural characterization of these two stable conformers was brought to an end mainly by NMR spectral measurement and their absolute configuration was determinated by ozonolysis followed by chiral GC-MS analysis.…”

Total synthesis of cis, cis-ceratospongamide

“…1 Recently, the isolation of two special conformationally stable cyclic heptapeptides, cis, cisand trans, trans-ceratospongamides (1, 2) have attracted our attentions. 2 These two conformationally stable isomers were isolated from the marine red alga (Rhodophyta) ceratodictyon spongiosum by Gerwick and co-workers in the 2000. Both conformationally stable isomers of ceratospongamide contain two phenylalanine residues, one proline-thiazole amide unit, and one proline-isoleucine dipeptide further linked to an oxazoline segment.…”

“…Amazingly, these two conformational isomers showed completely different bioactivities; the trans, transisomer exhibits potent inhibition of sPLA 2 expression in a cell-based model for anti-inflammation (ED 50 32 nM), whereas the cis, cis-isomer is inactive. 2 Intrigued by the unusual molecular architecture of ceratospongamides, and the different bioactivity that the conformation caused, we have carried out the total synthetic studies. In an early communication, 3 we have reported our preliminary results towards the total synthesis of ceratospongamide.…”