TMC-95A, B, C, and D, Novel Proteasome Inhibitors Produced by Apiospora montagnei Sacc. TC 1093. Taxonomy, Production, Isolation, and Biological Activities.

Abstract

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Facile Creation of 3-Substituted-3-Hydroxy-2-Oxindoles by Arginine-Catalyzed Aldol Reactions of α,β-Unsaturated Ketones with Isatins

“…Generally, α,β-unsaturated ketones with electron-donating groups gave higher yields than those with electron-withdrawing groups (Table 2, entries 2, 10 vs. [3][4][5][6][7][8]. Ortho-and meta-substituted α,β-unsaturated ketones gave higher yields than para-substituted α,β-unsaturated ketones ( Table 2, entries 2-5 vs. [8][9][10][11]. α,β-Unsaturated ketones bearing naphthyl and heterocyclic substituents participated in smooth aldol reactions in 81% and 88% yield, respectively (Table 2, entries 13,14).…”

“…This kind of compounds have become important synthetic targets as these structural frameworks form the core units of many natural products and pharmaceutically active compounds [1]. Convolutamydines [2], arundaphine [3], donaxaridine [4], dioxibrassinine [5], maremycins [6], paratunamide [7], celogentin K [8], TMC-95A-D [9], flustraminol [10], 3-hydroxy welwitindolinones [11] and CPC-1 [12] are some examples of a growing list of bioactive 3-substituted-3-hydroxy-2-oxindole natural products (Figure 1). …”

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

“…Selective inhibitors of the proteasome show great promise as novel anticancer agents since tumor cells are more sensitive than normal cells to proteasome-inhibition-induced apoptosis. [26][27][28] TMC-95A (1) and its diastereoisomers TMC-95B -D(2 -4), recently isolated as fermentation products of Apiospora montagnei, [29] represent a new class of selective proteasome inhibitors (Scheme 1). 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.…”

“…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 concise, total synthesis of the TMC-95A/B proteasome inhibitors

“…In early 2000, Kohno and coworkers (5) reported the isolation of novel cyclic tripeptides TMC-95A-D (1-4) (Fig. 1).…”