Structures of TMC-95A−D:  Novel Proteasome Inhibitors from Apiospora montagnei Sacc. TC 1093

Abstract

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.

The ubiquitin‐proteasome pathway and proteasome inhibitors

“…235 While lactacystin and epoxomicin are the best known natural product inhibitors of the 20S proteasome, there have been other potent natural product proteasome inhibitors with novel structures. For example, in the course of proteasome inhibitor screening procedure, Kohno et al 257 found a series of TMC-95 (24) from the fermentation broth of Apiospora montagnei Sacc. TC 1093 (Fig.…”

Simplified Synthetic TMC‐95A/B Analogues Retain the Potency of Proteasome Inhibitory Activity

“…These molecules are structurally characterized as novel cyclic peptides containing L-tyrosine, L-asparagine, highly oxidized L-tryptophan, (Z)-1-propenylamine (Z=benzyloxycarbonyl), and 3-methyl-2-oxopentanoic acid moieties. [30] Biological studies [29] showed that TMC-95A inhibited the CT-L, TL, and PGPH activities of 20S proteasome with IC 50 values (IC 50 =concentration required for 50% inhibition) of 5.4, 200, and 60nM, respectively. TMC-95B inhibited these activities to the same extent as TMC-95A, while TMC-95C and D were 20 -150 times weaker inhibitors.…”

A simple and eco-friendly synthesis of 3-indolyl-3-hydroxy oxindoles and 11-indolyl-11H-indeno[1,2-b]quinoxalin-11-ols in aqueous media

“…3-Substituted 3-hydroxyoxindoles are encountered in a large variety of natural products with a wide spectrum of biological activities, such as convolutamydines, 1 donaxaridines, 2 maremycins, 3 dioxibrassinines, 4 celogentin K, 5 3'-hydroxy glucoisatisin, 6 and TMC-95A. 7 3-Alkenyl-and 3-aryl-substituted 3-hydroxyindoles, 8 and their derivatives 9 have been used in a number of recent pharmaceutical studies. The formation of quaternary carbon centers via addition of nucleophiles to ketone derivatives still constitutes a major challenge for synthetic chemistry.…”