Ikuko I. Ohtani

Dimerumic acid as an antioxidant of the mold, Monascus anka.

We previously reported that the mold Monascus anka, traditionally used for fermentation of food, showed antioxidant and hepatoprotective actions against chemically induced liver injuries. In the present study, the antioxidant component of M. anka was isolated and identified. The antioxidant was elucidated to be dimerumic acid. DPPH (1,1-diphenyl-2-picrylhydrazyl) radical was significantly scavenged by the antioxidant whereas hydroxyl radical and superoxide anion were moderately scavenged. When the antioxidant (12 mg/kg) was given to mice prior to carbon tetrachloride (CCl(4), 20 microl/kg, ip) treatment, the CCl(4)-induced liver toxicity in mice seen in an elevation of serum aspartate aminotransferase and alanine aminotransferase activities was depressed, suggesting the hepatoprotective action of the antioxidant. The liver microsomal glutathione S-transferase activity, which is known to be activated by oxidative stress or active metabolites, was increased by CCl(4) treatment and the increase was also depressed by pretreatment with the mold antioxidant. Thus these data confirmed that the dimerumic acid isolated from M. anka is the potential antioxidant and protective against CCl(4)-induced liver injury.

New polyoxygenated steroids exhibiting reversal of multidrug resistance from the gorgonian Isis hippuris

Abstract Eleven new ( 5–15 ) and one known ( 4 ) polyoxygenated steroids have been isolated from two collections of the gorgonian Isis hippuris and their structures determined by spectroscopic analysis and X-ray diffraction study. Except for 15 all others were polyoxygenated gorgosterols. X-Ray study of the previously reported compound 4 demonstrated the stereochemistry of the side chain moiety to be identical with that of gorgosterol. Compound 15 was a deacetyl derivative of the known steroid 16 having a spiroketal and a lactone function. The stereochemistry of 15 was confirmed by X-ray analysis, which also established the C-22 configuration of 16 which had remained unsolved. These compounds have been tested for reversal of multidrug resistance (MDR) with cancer cells expressing P-glycoprotein (P-gp). Some of them showed moderate activity.

New Cyclic Peptides from the Indonesian Sponge Theonella swinhoei

Abstract Three new cyclic peptides, barangamides B, C, and D and a new depsipeptide, theonellapeptolide IIe as well as known theonellapeptolides Ia, Id, Ie, IId have been isolated from the sponge Theonella swinhoei collected in Baranglompo Island, Indonesia. The structures of barangamides were elucidated by interpretation of NMR data and application of Marfeys method. The structure of theonellapeptolide IIe, a mixture of several conformers showing complex NMR spectra, was determined by MS analysis of a ring-opened product and by chemical reaction. Some of the theonellapeptolides showed mild immunosuppressive activity, while barangamide A was inactive.

Molecular shape analysis and activity of tautomycin, a protein phosphatase inhibitor

Abstract Tautomycin, a well-known protein phosphatase inhibitor, exists in two forms (acid anhydride and diacid). We successfully isolated them and proved that diacid is the real active form of tautomycin. The molecular shape-activity relationship of tautomycin and its conformational analysis are also described.

Biosynthesis of anatoxin-a(s). Origin of the carbons

Abstract C-2, C-4, C-5 and C-6 of the potent anticholinesterase, anatoxin-a(s), in Anabaena flosaquae NRC 525-17 are derived from the guanido carbon, C-5, C-4 and C-3 of L-arginine, respectively, and the three O,N -methyl groups originate from the tetrahydrofolate C 1 pool. Erythro -4-Hydroxy- l -arginine, a minor constituent of the cyanophyte, may be a precursor in the biosynthesis.

Iheyamines, new cytotoxic bisindole pigments from a colonial ascidian, Polycitorella sp.

Abstract A new class of bisindole pigments, iheyamines A and B, have been isolated from an ascidian, Polycitorella sp. and their structures elucidated by interpretation of spectral data. Both compounds exhibited moderate cytotoxicity.

Structure of cereulide, a cyclic dodecadepsipeptide toxin from Bacillus cereus and studies on NMR characteristics of its alkali metal complexes including a conformational structure of the K+ complex

The structure and stereochemistry of cereulide 1 or 1a, an emetic toxin produced by Bacillus cereus, have been determined through spectral analysis and chemical methods. It is a 36-membered cyclic depsipeptide with the sequence of cyclo(D-O-Leu-D-Ala-L-O-Val-L-Val)3. The outstanding property of cereulide is a Rb+-and K+-ion-selective ionophore, the same as in valinomycin 2. Cereulide forms a 1:1 complex with alkali metal ions. Owing to its structural similarity to valinomycin 2 and our well established conformational knowledge about compound 2, the NMR data of cereulide–alkali metal complexes in chloroform gave us a partial view of the conformational structure in solution and a calculated modelling of the complex with K+ is proposed. The main chain shows a hexagonal cyclinder-like framework which is similar to the known bracelet-like structure of the valinomycin–K+ complex. All amide carbonyls arrange along the cylindrical side-wall planes so that they can form β-turn hydrogen bonds with NH protons. Every alpha carbon is located at a corner in both the top and the bottom planes, enabling alpha protons of oxy acids to turn inwards towards the cavity and those of the amino acids turn outwards. The K+ is centrally situated in the cavity of the host cereulide by the ion–dipole interactions with three carbonyl oxygens of L-Val in the top plane and the three carbonyls of D-Ala in the bottom plane. The experimental coupling constant and NOE data of the K+ complex had conformity with the calculated dihedral angle and distance measured from the proposed conformational structure. Partial views of the conformations of cereulide complexed with Li+ and Na+ are analysed as follows: The frameworks of the Li+ complex main chain lose their compactness, becoming more linearly extended, which results in a bigger cavity diameter, have fewer hydrogen bonds, and all the residual side-chains can freely rotate whereas the conformation(s) of the Na+ complex takes the intermediate conformation(s) between those of the highly stable (the K+ and Rb+) and that of the less stable (the Li+) complexes.

ECHINOCLATHRINES A-C : A NEW CLASS OF PYRIDINE ALKALOIDS FROM AN OKINAWAN SPONGE, ECHINOCLATHRIA SP.

Abstract Echinoclathrines A–C ( 3–5 ) have been isolated from an Okinawan sponge, Echinoclathria sp. and the structures elucidated by interpretation of spectral data. These compounds are a new class of pyridine alkaloids possessing an 4-aryl-2-methylpyridine moiety as a common structural element. Echinoclathrines A and B exhibited weak immunosup-pressive activity in a mixed lymphocyte reaction assay.

Ptilomycalin A, a novel Na+,K+-or Ca2+-ATPase inhibitor, competitively interacts with ATP at its binding site

Ptilomycalin A inhibited the brain Na+, K(+)-ATPase and Ca2(+)-ATPase from skeletal sarcoplasmic reticulum with an IC50 value of 2 microM and 10 microM, respectively. Kinetic analysis of the inhibitory effects of ptilomycalin A suggests that the inhibition of Na+, K(+)-ATPase is a competitive-, an uncompetitive- and an anticompetitive-type with respect to ATP, Na+ and K+, respectively. The inhibition of Ca2(+)-ATPase by ptilomycalin A is a competitive- or an uncompetitive-type with respect to ATP or Ca2+, respectively. These results suggest that ptilomycalin A interacts with ATP at the ATP binding site of Na+, K(+)-ATPase or Ca2(+)-ATPase. Ptilomycalin A has become a useful biochemical tool for clarifying the ATP binding site in both enzymes.

BARANGAMIDE A, A NEW CYCLIC PEPTIDE FROM THE INDONESIAN SPONGE THEONELLA SWINHOEI

Abstract Barangamide A has been isolated from the sponge Theonella swinhoei , collected at Baranglompo Island, Indonesia, and the structure elucidated by interpretation of spectral data and application of Marfeys method. Barangamide A is a cyclic undecapeptide possessing three N -methylated amino acids, three β-alanine and the same amino acid sequence with the ring portion of the known theonellapeptolide IId isolated also in the present work. The theonellapeptolides have been reported to have moderate cytotoxicity, whereas barangamide A was inactive at the same concentration.