TA-3037A, a new inhibitor of glutathione S-transferase, produced by actinomycetes. II. Structure determination.

TA-3037A, a new inhibitor of glutathione S-transferase, has been isolated from the culture broth of Streptomyces sp. TA-3037. The structure of TA-3037A was defined as (Z)-3-benzylidene-3,4-dihydro-2-oxo-2H-1,4-benzoxazine-5-carboxylic acid by an analysis of spectral properties and chemical studies of TA-3037A and its derivatives.     

Vanoxonin, a new inhibitor of thymidylate synthetase. II. Structure determination and total synthesis

Acid hydrolysis of vanoxonin yielded one mol each of 2,3-dihydroxybenzoic acid, L-threonine, L-N omega-hydroxyornithine. Presence of acetyl group in vanoxonin was suggested by the 1H NMR. Periodate oxidation of vanoxonin liberated one mol of acetic acid suggesting that the acetyl group bound to the omega-nitrogen of N omega-hydroxyornithine. The sequence of three components was determined to be L-N-(2,3-dihydroxybenzoyl)threonyl-L-(N omega-acetyl-N omega-hydroxy)ornithine by mass spectrometric analysis. This structure was confirmed by the total synthesis of vanoxonin.     

beta-Galactosidase-inhibiting new isoflavonoids produced by actinomycetes.

Six isoflavonoids having beta-galactosidase inhibiting activity were isolated from the culture filtrate of Streptomyces xanthophaeus. Their structures were determined by spectral analyses to be daidzein, daidzein 7-alpha-L-rhamnoside, daidzein 4',7-di-alpha-L-rhamnoside, genistein, genistein 7-alpha-L-rhamnoside and genistein 4',7-di-alpha-L-rhamnoside.     

Sapurimycin, new antitumor antibiotic produced by Streptomyces. Structure determination

The structure of a new anthra-gamma-pyrone antitumor antibiotic sapurimycin was determined by the spectral studies of its methyl ester. Sapurimycin has the same anthra-gamma-pyrone skeleton as pluramycin, but is distinctly different because of the absence of sugars on the D ring and possessing a carboxylmethyl group on C-5.     

Probestin, a new inhibitor of aminopeptidase M, produced by Streptomyces azureus MH663-2F6. II. Structure determination of probestin

Probestin, a new inhibitor of aminopeptidase M, has been isolated from the culture broth of Streptomyces azureus MH663-2F6. The 1H and 13C NMR studies and amino acid analysis confirmed the presence of one 3-amino-2-hydroxy-phenylbutanoic acid, leucine and two proline residues in the molecule. Stereochemistries of these amino acids were determined by HPLC analysis. The fragmentation pattern shown in the mass spectrum and the chemical analysis on probestin clarified the amino acid sequence. Thus the structure of probestin was defined as (2S,3R)-3-amino-2-hydroxy-4-phenylbutanoyl-L-leucyl-L-prolyl-L-pro line.     

Leuhistin, a new inhibitor of aminopeptidase M, produced by Bacillus laterosporus BMI156-14F1. II. Structure determination of leuhistin.

Leuhistin, a new inhibitor of aminopeptidase M, has been isolated from the culture broth of Bacillus laterosporus BMI156-14F1. The structure of leuhistin was determined by NMR studies. X-Ray and chemical analysis confirmed the absolute structure to be (2R,3S)-3-amino-2-hydroxy-2-(1H-imidazol-4-ylmethyl)-5-methylhe xanoic acid.     

SB-219383, a novel tyrosyl tRNA synthetase inhibitor from a Micromonospora sp. II. Structure determination

A novel tyrosyl tRNA synthetase inhibitor, SB-219383, has been isolated from a Micromonospora sp. The structure of SB-219383 has been elucidated by a combination of derivatisation, spectroscopic and other analytical techniques and found to be N-(L-tyrosyl)-2-amino[1(S*),3(S*),4(S*),5(R*),8(R*)-2,4,5,8-tetrahydroxy -7-oxa-2-azabicyclo[3.2.1]oct-3-y1]acetic acid (1).     

Inhibition of poly(ADP-ribose) synthetase (PARS) and protection against peroxynitrite-induced cytotoxicity by zinc chelation

Peroxynitrite, a potent oxidant formed by the reaction of nitric oxide and superoxide causes thymocyte necrosis, in part, via activation of the nuclear enzyme poly(ADP-ribose) synthetase (PARS). The cytotoxic PARS pathway initiated by DNA strand breaks and excessive PARS activation has been shown to deplete cellular energy pools, leading to cell necrosis. Here we have investigated the effect of tetrakis-(2-pyridylmethyl)-ethylenediamine (TPEN) a heavy metal chelator on peroxynitrite-induced cytotoxicity. TPEN (10 microM) abolished cell death induced by authentic peroxynitrite (25 microM) and the peroxynitrite generating agent 3-morpholinosidnonimine (SIN-1, 250 microM). Preincubation of TPEN with equimolar Zn2+ but not Ca2+ or Mg2+ blocked the cytoprotective effect of the chelator. TPEN (10 microM) markedly reduced the peroxynitrite-induced decrease of mitochondrial transmembrane potential, secondary superoxide production and mitochondrial membrane damage, indicating that it acts proximal to mitochondrial alterations. Although TPEN (1 - 300 microM) did not scavenge peroxynitrite, it inhibited PARS activation in a dose-dependent manner. The cytoprotective effect of TPEN is only partly mediated via PARS inhibition, as the chelator also protected PARS-deficient thymocytes from peroxynitrite-induced death. While being cytoprotective against peroxynitrite-induced necrotic death, TPEN (10 microM), similar to other agents that inhibit PARS, enhanced apoptosis (at 5-6 h after exposure), as characterized by phosphatydilserine exposure, caspase activation and DNA fragmentation. In conclusion, the current data demonstrate that TPEN, most likely by zinc chelation, exerts protective effects against peroxynitrite-induced necrosis. Its effects are, in part, mediated by inhibition of PARS.     

Poststatin, a new inhibitor of prolyl endopeptidase, produced by Streptomyces viridochromogenes MH534-30F3. II. Structure determination and inhibitory activities

Poststatin, a new inhibitor of prolyl endopeptidase, has been isolated from the culture broth of Streptomyces viridochromogenes MH534-30F3. The structure of poststatin was defined as L-valyl-L-valyl-3-amino-2-oxovaleryl-D-leucyl-L-valine by analysis of spectral properties and chemical studies of poststatin and its derivatives. The alpha-keto group of postine in poststatin plays the most important role on the inhibitory mechanism.