Maria Valeria D'Auria

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.

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.

Discovery that theonellasterol a marine sponge sterol is a highly selective FXR antagonist that protects against liver injury in cholestasis.

Background The farnesoid-x-receptor (FXR) is a bile acid sensor expressed in the liver and gastrointestinal tract. Despite FXR ligands are under investigation for treatment of cholestasis, a biochemical condition occurring in a number of liver diseases for which available therapies are poorly effective, mice harboring a disrupted FXR are protected against liver injury caused by bile acid overload in rodent models of cholestasis. Theonellasterol is a 4-methylene-24-ethylsteroid isolated from the marine sponge Theonella swinhoei. Here, we have characterized the activity of this theonellasterol on FXR-regulated genes and biological functions. Principal Findings Interrogation of HepG2 cells, a human hepatocyte cell line, by microarray analysis and transactivation assay shows that theonellasterol is a selective FXR antagonist, devoid of any agonistic or antagonistic activity on a number of human nuclear receptors including the vitamin D receptor, PPARs, PXR, LXRs, progesterone, estrogen, glucorticoid and thyroid receptors, among others. Exposure of HepG2 cells to theonellasterol antagonizes the effect of natural and synthetic FXR agonists on FXR-regulated genes, including SHP, OSTα, BSEP and MRP4. A proof-of-concept study carried out to investigate whether FXR antagonism rescues mice from liver injury caused by the ligation of the common bile duct, a model of obstructive cholestasis, demonstrated that theonellasterol attenuates injury caused by bile duct ligation as measured by assessing serum alanine aminostrasferase levels and extent of liver necrosis at histopathology. Analysis of genes involved in bile acid uptake and excretion by hepatocytes revealed that theonellasterol increases the liver expression of MRP4, a basolateral transporter that is negatively regulated by FXR. Administering bile duct ligated mice with an FXR agonist failed to rescue from liver injury and downregulated the expression of MRP4. Conclusions FXR antagonism in vivo results in a positive modulation of MRP4 expression in the liver and is a feasible strategy to target obstructive cholestasis.

Isolation of callipeltins A–C and of two new open-chain derivatives of callipeltin A from the marine sponge Latrunculia sp. A revision of the stereostructure of callipeltins

Two new callipeltin-related acyclic peptides (2 and 3) have been isolated, together with callipeltins A–C from the marine sponge Latrunculia sp. collected at the Vanuatu Islands. The gross structures of new compounds were elucidated by spectroscopic data. The application of the Marfeys analysis on the new derivatives and on callipeltin A (1), allowed us to revise the configuration of two amino acid units in callipeltin A.

Conicasterol E, a small heterodimer partner sparing farnesoid X receptor modulator endowed with a pregnane X receptor agonistic activity, from the marine sponge Theonella swinhoei.

We report the isolation and pharmacological characterization of conicasterol E isolated from the marine sponge Theonella swinhoei. Pharmacological characterization of this steroid in comparison to CDCA, a natural FXR ligand, and 6-ECDCA, a synthetic FXR agonist generated by an improved synthetic strategy, and rifaximin, a potent PXR agonist, demonstrated that conicasterol E is an FXR modulator endowed with PXR agonistic activity. Conicasterol E induces the expression of genes involved in bile acids detoxification without effect on the expression of small heterodimer partner (SHP), thus sparing the expression of genes involved in bile acids biosynthesis. The relative positioning in the ligand binding domain of FXR, explored through docking calculations, demonstrated a different spatial arrangement for conicasterol E and pointed to the presence of simultaneous and efficient interactions with the receptor. In summary, conicasterol E represents a FXR modulator and PXR agonist that might hold utility in treatment of liver disorders.

Stereochemical assignment of the C23-C35 portion of sphinxolide/reidispongiolide class of natural products by asymmetric synthesis

Abstract The absolute configuration of the seven stereogenic centers contained in the C23–C35 portion of reidispongiolide A is determined by asymmetric synthesis of the corresponding fragment obtained by ozonolysis of the natural macrolide.

Natural Ligands for Nuclear Receptors: Biology and Potential Therapeutic Applications

Nuclear receptors are key regulators of various processes including reproduction, development, and metabolism of xeno- and endobiotics. Research in the last two decades has focused to the development of novel drugs specifically targeting nuclear receptors for the treatment of a variety of diseases, such as cancer, diabetes, dyslipidemia, fatty liver disease, drug hepatotoxicity and cholestasis. The search for novel NRs agonists and antagonists with enhanced selectivity prompted the exploration of the extraordinary chemical diversity associated to natural products. In recent years a number of natural products were disclosed as ligands of NRs and proved to have remarkable affinity and in some cases peculiar mode of action. In this review the natural ligands of the subfamily NR1, NR2, and NR3 will be described with an emphasis to their mechanisms of action and pharmacological profiles.

The molecular mechanism of bee venom phospholipase A2 inactivation by bolinaquinone.

The molecular basis of the inactivation of bee venom PLA2 by the marine natural product bolinaquinone (BLQ) was studied by several spectral techniques (CD, fluorescence, and NMR spectroscopy, mass spectrometry), biomimetic reactions, and molecular modeling. Our data suggest competitive inhibition based on a BLQ–PLA2 noncovalent molecular recognition. However, BLQ is also able to react selectively with Lys133 through conjugate addition followed by a β elimination. The biological implications of both the covalent and noncovalent molecular events are discussed.

Synthetic studies on callipeltin A: stereoselective synthesis of (2R,3R,4S)-3-hydroxy-2,4,6-trimethylheptanoic acid

An efficient and highly stereocontrolled synthesis of protected (2R,3R,4S)-3-hydroxy-2,4,6-trimethylheptanoic acid, the β-hydroxy acid unit that acylates the N-terminus of callipeltin A, has been devised starting from methyl (2S)-2-methyl-3-hydroxypropionate. Comparison of NMR data with the corresponding fragment obtained from the acid hydrolysate of callipeltin A indicates that the stereostructure of the above fragment should be revised.

Stereoselective synthesis of (2R,3R,4R)-3-hydroxy-2,4,6-trimethylheptanoic acid and determination of the absolute stereochemistry of the natural product from callipeltin A

Abstract A revised stereostructure of 3-hydroxy-2,4,6-trimethylheptanoic acid, the β-hydroxy acid that acylates the N-terminus of callipeltin A, is proposed on the basis of analysis of J -coupling in the 1 H NMR spectrum of the acetonide derivative obtained from the acid hydrolysate of callipeltin A. The proposed structure was definitively confirmed by enantioselective synthesis.