Structures of TMC-95A-D: novel proteasome inhibitors from Apiospora montagnei sacc. TC 1093.
Four novel proteasome inhibitors, TMC-95A-D (1-4) have been isolated from the fermentation broth of Apiospora montagnei Sacc. TC 1093, isolated from a soil sample. All of the molecular formulas of 1-4 were established as C(33)H(38)N(6)O(10) by high-resolution FAB-MS. Their planar structures were determined on the basis of extensive analyses of 1D and 2D NMR, and degradation studies. Compounds 1-4 have the same planar structures to each other, and are unique highly modified cyclic peptides containing L-tyrosine, L-aspargine, highly oxidized L-tryptophan, (Z)-1-propenylamine, and 3-methyl-2-oxopentanoic acid units. The absolute configuration at C-11 and C-36 of 1-4 was determined based on chiral TLC and HPLC analyses of their chemical degradation products. The ROESY analysis along with (1)H-(1)H coupling constants clarified the absolute stereochemistry at C-6, -7, -8, and -14 of the cyclic moieties. These studies revealed the relationships of 1-4 to be diastereomers at C-7 and C-36.
Kohno
J
J
Discovery Research Laboratory, Tanabe Seiyaku Co., Ltd., 2-50 Kawagishi-2-chome, Toda-shi, Saitama 335-8505, Japan. jun-k@tanabe.co.jp
Koguchi
Y
Y
Nishio
M
M
Nakao
K
K
Kuroda
M
M
Shimizu
R
R
Ohnuki
T
T
Komatsubara
S
S
D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D005658:Fungi / Q000737:chemistry*; D008401:Gas Chromatography-Mass Spectrometry; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D009097:Multienzyme Complexes / Q000378:metabolism*; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex; D011487:Protein Conformation
D015853:Cysteine Proteinase Inhibitors; D009097:Multienzyme Complexes; D010456:Peptides, Cyclic; C408291:TMC-95A; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex