ABSTRACT
Cinatrins A, B, C1, C2 and C3, a family of phospholipase A2 inhibitors were isolated from the fermentation broth of Circinotrichum falcatisporum RF-641. They were found to be novel spiro-gamma-dilactones and gamma-lactones derived from 1,2,3,5-tetra or 1,2,3(or 1,2,4)-trihydroxypentadecane-1,2,3-tricarboxylic acids. Structures were elucidated by MS and NMR studies and chemical transformations. The structure of cinatrin C3 was confirmed by X-ray crystallographic analysis, and its absolute configuration was determined by comparison of the CD spectra with related compounds.
Subject(s)
Lactones/isolation & purification , Mitosporic Fungi/metabolism , Phospholipases A/antagonists & inhibitors , Chromatography , Chromatography, High Pressure Liquid , Chromatography, Thin Layer , Fermentation , Lactones/chemistry , Magnetic Resonance Spectroscopy , Mass Spectrometry , Mitosporic Fungi/classification , Molecular Conformation , Molecular Structure , Phospholipases A2 , Solubility , Spectrophotometry, Infrared , Spectrophotometry, Ultraviolet , X-Ray DiffractionABSTRACT
Cinatrins A, B and C3 inhibited phospholipase A2 purified from rat platelets in a dose-dependent manner. Cinatrin C3, the most potent component (IC50 70 microM), was noncompetitive with a Ki value of 36 microM. Cinatrins B and C3 also inhibited both porcine pancreas and Naja naja venom phospholipase A2. Inhibition of rat platelet phospholipase A2 by cinatrin C3 was independent of Ca2+ and substrate concentration. Comparison with duramycin, another phospholipase A2 inhibitor, displayed inhibition dependent on substrate concentration when phosphatidylethanolamine was the substrate. These results indicate that the inhibition of phospholipase A2 by cinatrin C3 may result from direct interaction with the enzyme.
Subject(s)
Anti-Bacterial Agents , Lactones/pharmacology , Phospholipases A/antagonists & inhibitors , Animals , Anti-Bacterial Agents/pharmacology , Bacteriocins , Blood Platelets/enzymology , Elapid Venoms/chemistry , Lactones/chemistry , Molecular Structure , Pancreas/enzymology , Peptides/pharmacology , Phospholipases A2 , Rats , Regression Analysis , SwineABSTRACT
C34H42N4O6, Mr = 602.73, triclinic, P1, a = 14.707 (2), b = 15.559 (2), c = 13.026 (1) A, alpha = 112.23 (1), beta = 97.25 (1), gamma = 60.67 (1) degree, V = 2399.1 (6) A3, Z = 3, Dx = 1.251 Mg m-3, lambda(Cu K alpha) = 1.54178 A, mu = 0.71 mm-1, F(000) = 966, T = 295 K, R = 0.042 for 7802 observed reflections [Fo greater than 3 sigma (Fo)]. The structure of trapoxin A was determined as cyclo[-(S)-phenylalanyl-(S)-phenylalanyl-(R)-pipecolinyl- (2S,9S)-2-amino-8-oxo-9,10-epoxydecanoyl-]. There are three crystallographically independent molecules in the cell. These molecules are linked to each other by NH...O hydrogen bonds to form an infinite chain extending along the a axis.
Subject(s)
Anti-Bacterial Agents , Peptides , Amino Acid Sequence , Antibiotics, Antineoplastic/chemistry , Molecular Sequence Data , Molecular Structure , Peptides, Cyclic/chemistry , Protein Conformation , X-Ray DiffractionABSTRACT
New cyclotetrapeptides, trapoxins A and B were isolated from the culture broth of Helicoma ambiens RF-1023. These compounds exhibit detransformation activities against v-sis oncogene-transformed NIH3T3 cells (sis/NIH3T3) as antitumor agents. The structures were found to be new cyclotetrapeptides, cyclo[(S)-phenylalanyl-(S)-phenylalanyl-(R)-pipecolinyl- (2S,9S)-2-amino-8-oxo-9,10-epoxydecanoyl-] for trapoxin A and cyclo[(S)-phenylalanyl-(S)-phenylalanyl-(R)-prolyl-2- amino-8-oxo-9,10-epoxydecanoyl-] for trapoxin B, by X-ray analysis, mass spectrometric, NMR and chemical studies.
Subject(s)
Anti-Bacterial Agents , Antibiotics, Antineoplastic/chemistry , Cell Transformation, Neoplastic/drug effects , Mitosporic Fungi/metabolism , Peptides , Amino Acid Sequence , Antibiotics, Antineoplastic/biosynthesis , Antibiotics, Antineoplastic/isolation & purification , Antibiotics, Antineoplastic/pharmacology , Cell Line, Transformed , Chromatography, High Pressure Liquid , Fermentation , Intercellular Signaling Peptides and Proteins , Magnetic Resonance Spectroscopy , Mass Spectrometry , Molecular Sequence Data , Molecular Structure , Peptide Fragments/chemistry , Peptides, Cyclic/chemistry , Protein Conformation , Spectrophotometry, Infrared , Spectrophotometry, Ultraviolet , X-Ray DiffractionABSTRACT
PA48009, a lanthionine-containing peptide antibiotic was isolated from the culture broth of Streptoverticillium griseoverticillatum PA-48009, and identified as duramycin. Determination of the structure using both Edman degradations and 2D NMR spectroscopy showed the need to revise the structure of duramycin given in literature. Duramycin (PA48009) was different from lanthiopeptin (Ro 09-0198, cinnamycin) only by a Lys/Arg exchange at position 2.
