Metabolites of the new Caledonian sponge Cladocroce incurvata

The deep-water New Caledonian sponge #Cladocroce incurvata$ contains two "polyketide" metabolites. Cladocrocin A (1) appears to be derived from fatty acid with ethyl side chains, thus incorporating butyrate units. Cladocroic acid (2) is a straight chain fatty acid which incorporates a terminal enyne functionality and a cycloproprane ring directly attached to the carboxylic acid function. The structures were elucidated by interpretation of spectral data, and the cis stereochemistry of the cyclopropane ring in cladocroic acid (2) was derived after the synthesis of cis - and trans - 2, 3 - methanohexanoic acid models and nmr spectral comparisons. (Résumé d'auteur

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, OSTa, 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

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 beta-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

Modulatory effect of bolinaquinone, a marine sesquiterpenoid, on acute and chronic inflammatory processes

The marine metabolite bolinaquinone is a novel inhibitor of secretory phospholipase A2 (sPLA2), with a potency on the human synovial enzyme (group II) higher than that of manoalide. This activity on the sPLA2 was confirmed in vivo in the 8-h zymosan rat air pouch on the secretory enzyme accumulation in the pouch exudate. Addnl., bolinaquinone decreased potently the synthesis and release of leukotriene B4 (LTB4) in calcimycin (A23187)-stimulated human neutrophils as a consequence of the inhibition of 5-lipoxygenase activity, as well as PGE2 and NO prodn. on zymosanstimulated mouse peritoneal macrophages. This compd. exerted anti-inflammatory effects by topical and oral routes on the mouse ear edema induced by 12-O-tetradecanoylphorbolacetate, with ID50 values of 76.7 mg/ear and 5.6 mg/kg, resp., with a significant decrease in PGE2, LTB4, and tumor necrosis factor-a (TNF-a) levels being more effective than indomethacin. This effect was confirmed in the mouse paw carrageenan edema after oral administration. Moreover, bolinaquinone was able to reduce the inflammatory response of adjuvant arthritis by inhibiting PGE2, NO, and TNF-a prodn. in paw homogenates without affecting PGE2 levels in the stomach. Addnl., bolinaquinone inhibited inducible nitric oxide synthase expression and reduced the degree of bone resorption, soft tissue swelling, and osteophyte formation

Dysidotronic acid, a new and selective human phospholipase A2 inhibitor from the sponge Dysidea sp.

A new bioactive sesquiterpenoid, named dysidotronic acid (I), with a rearranged drimane skeleton has been isolated from the sponge Dysidea sp. from Vanuatu islands, along with bolinaquinone. The chem. structure of I was detd. on the basis of spectroscopic data. Dysidotronic acid (I) significantly inhibited human synovial phospholipase A2 (PLA2) at 10 mM, with an IC50 value of 2.6 mM and a higher selectivity and potency towards this enzyme than the ref. inhibitor manoalide