Angela Zampella

Homophymine A, an Anti-HIV Cyclodepsipeptide from the Sponge Homophymia sp

A new anti-HIV cyclodepsipeptide, homophymine A, was isolated from a New Caledonian collection of the marine sponge Homophymia sp. The structure of homophymine A was determined by interpretation of spectroscopic data, acid hydrolysis, and LC-MS analysis. Homophymine A contains 11 amino acid residues and an amide-linked 3-hydroxy-2,4,6-trimethyloctanoic acid moiety. Along with four D-, two L-, and one N-methyl amino acids, it also contains four unusual amino acid residues: (2S,3S,4R)-3,4-diMe-Gln, (2R,3R,4S)-4-amino-2,3-dihydroxy-1,7-heptandioic acid, L-ThrOMe, and (2R,3R,4R)-2-amino-3-hydroxy-4,5-dimethylhexanoic acid. In a cell-based XTT assay, homophymine A exhibited cytoprotective activity against HIV-1 infection with a IC50 of 75 nM.

Callipeltins B and C; Bioactive Peptides from a. Marine Lithistida Sponge Callipelta sp.

Abstract Following the characterization of callipeltin A (1), two new cytotoxic peptides, callipeltin B (2) and C (3), were isolated from the New Caledonian sponge Callipelta sp.. Callipeltin B (2) possess the same cyclic depsipeptidal structure as in callipeltin A (1) and differs from 1 by having the N-terminal 2,3-dimethylpyroglutamic acid unit instead of the tripeptide chain with the N-terminus blocked by an hydroxyacid. Callipeltin C (3) is simply the acyclic callipeltin A. The structures 2–3 have been determined by NMR experiments, FAB mass spectrometry, evaluation of the aminoacids obtained by acid hydrolysis and by comparison of the data with those of callipeltin A (1). Following the characterization of callipeltin A (1), two new peptides, callipeltin B (2) and C (3), were isolated form Callipelta sp.. Callipeltin B (2) possess the same cyclic depsipeptidal structure as in callipeltin A (1) and differs from 1 by having the N-terminal 2,3-dimethylpyroglutamic acid unit instead of the tripeptide chain with the N-terminus blocked by an hydroxyacid. Callipeltin C (3) is the acyclic callipeltin A. Callipeltins have been found to be cytotoxic against various human carcinoma cells.

Callipeltosides B and C, two novel cytotoxic glycoside macrolides from a marine lithistida sponge Callipelta sp.

Following the characterization of callipeltoside A (1), the first member of a novel class of marine glycoside macrolides, two more bioactive constituents, callipeltoside B (2) and C(3), were isolated from Callipelta sp. in very low amounts. The structures, assigned on the basis of spectral analysis, include the same 14-membered macrolide as in callipeltoside A (1) but differed in the saccharide moieties.

Farnesoid X Receptor Agonist for the Treatment of Liver and Metabolic Disorders: Focus on 6-ethyl-CDCA

6-ethyl-chedeoxycholic acid (6E-CDCA) is a farnesoid X receptor (FXR) ligand endowed with agonistic activity under development for treatment of cholestatic liver diseases including primary biliary cirrhosis (PBC) and liver-related metabolic disorders including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). FXR is a bile sensor that acts in coordination with other nuclear receptors to regulate essential steps of bile acid uptake, metabolism and excretion. 6E-CDCA has been investigated in preclinical models of cholestasis, liver fibrosis and diet-induced atherosclerosis. In a phase II clinical trial in patients with PBC, 6E-CDCA met the primary endpoint of a reduction in alkaline phosphatase levels but safety data indicated that the drug exacerbated pruritus, one of the main symptoms of PBC, suggesting that 6E-CDCA or FXR are mediators of pruritus in humans. Treatment of patients with diabetes and liver steatosis resulted in amelioration of insulin sensitivity despite a reduction a slight reduction in HDL and increased levels of LDL were observed. These side effects on bile acids and lipid metabolism were all predicted by pre-clinical studies, suggesting that potent FXR ligands hold promise but potential side effects might limit their development.

Solomonamides A and B, New Anti-inflammatory Peptides from Theonella swinhoei

Two unprecedented cyclic peptides, solomonamides A and B, were isolated from the marine sponge Theonella swinhoei. The structures were elucidated on the basis of comprehensive 1D and 2D NMR analysis and high-resolution mass spectrometry. A combined approach, involving Marfeys method, QM J based analysis, and DFT J/(13)C calculations, was used for establishing the absolute configuration of the entire molecule. Solomonamide A showed in vivo anti-inflammatory activity.

Discovery of sulfated sterols from marine invertebrates as a new class of marine natural antagonists of farnesoid-X-receptor.

We report the biochemical characterization of sulfated polyhydroxysterols isolated from marine invertebrates as potent antagonists of farnesoid-X-receptor (FXR), a ligand-regulated transcription factor involved in the regulation of lipid and glucose homeostasis in mammals. Molecular characterization of a library of sulfated polyhydroxysteroids resulted in the identification of a first FXR antagonist. In contrast to partial antagonists, this compound was endowed with an antagonistic activity on the expression of a subset of FXR-regulated genes in liver cells and abrogated the release of nuclear coreceptor from the promoter of these genes. The putative binding mode to FXR, obtained through docking calculations, suggested the crucial role played by the bent shape of the molecule as well as the presence of one hydroxyl group in its side chain. This compound is a major tool to explore the effect of FXR inhibition in pharmacological settings.

Reidispongiolide A and B, two new potent cytotoxic macrolides from the New Caledonian sponge Reidispongia coerulea

Abstract Two new 26-membered macrolides, reidispongiolide A ( 1 ) and B ( 2 ), have been isolated from the New Caledonian marine sponge Redispongia coerulea n.gen.n.sp. Levi and Levi and their structures elucidated. They are related to sphinxolides previously isolated from an unknown nudibranch and later from the sponge Neosiphonia superstes . 1 and 2 co-occurr with sphinxolide B ( 4 ) and D ( 3 ). These macrolides exhibited potent cytotoxicity against various human carcinoma cells.

Quantitative NMR-Derived Interproton Distances Combined with Quantum Mechanical Calculations of 13C Chemical Shifts in the Stereochemical Determination of Conicasterol F, a Nuclear Receptor Ligand from Theonella swinhoei

Here we report the first application of combined accurate ROE-distance analysis with DFT calculations of NMR chemical shifts to achieve the relative configuration assignment of a marine natural product, conicasterol F, a new polyhydroxylated steroid isolated from the marine sponge Theonella swinhoei. We demonstrate the substantial advantages of this combined approach as a tool for structural studies of natural products, providing a powerful alternative to, or information to underpin, total synthesis when more classical NMR data analysis fails to provide unequivocal results. In this paper, we also describe the isolation and structure elucidation of conicasterol F and its 24-ethyl derivative, theonellasterol I, and their pharmacological evaluation as human nuclear receptor modulators.

Theonellasterols and Conicasterols from Theonella swinhoei. Novel Marine Natural Ligands for Human Nuclear Receptors

Silica gel column chromatography, followed by HPLC purification on the apolar fraction of the methanol extract of marine sponge Theonella swinhoei, resulted in the isolation of a library of 10 polyhydroxylated steroids which we named theonellasterols B-H (1-7) and conicasterols B-D (8-10). The structures were determined on the basis of extensive spectroscopic data (MS, (1)H and (13)C NMR, COSY, HSQC, HMBC, and ROESY) analysis, and the putative binding mode to nuclear receptors (NRs) has been obtained through docking calculations. Pharmacological and structure-activity relationship analysis demonstrate that these natural polyhydroxylated steroids are potent ligands of human nuclear pregnane receptor (PXR) and modulator of farnesoid-X-receptor (FXR). In addition, the molecular characterization of theonellasterol G allowed the identification of the first FXR modulator and PXR ligand so far identified. Exposure of liver cells to this agent resulted in potent induction of PXR-regulated genes and modulation of FXR-regulated genes, highlighting its pharmacological potential in the treatment of liver disorders.

New jaspamide derivatives from the marine sponge Jaspis splendans collected in Vanuatu.

Two new jaspamide derivatives (1 and 2) along with jaspamide have been isolated from the marine sponge Jaspis splendans collected in Vanuatu. Their chemical structures were determined from 1D and 2D NMR studies and MS data. These two compounds inhibited the in vitro growth of the NSCLC-N6 human tumor cell lines with IC50 values in the microg/mL range.