Linear TMC-95-Based Proteasome Inhibitors

Abstract

We have designed and evaluated 45 linear analogues of the natural constrained cyclopeptide TMC-95A. These synthetically less demanding molecules are based on the tripeptide sequence Y-N-W of TMC-95A. Structural variations in the amino acid side chains and termini greatly influenced both the efficiency and selectivity of action on a given type of active site. Inhibition constants were submicromolar (Ki approximately 300 nM) despite the absence of the entropically favorable constrained conformation that is characteristic of TMC-95A and its cyclic analogues. These linear compounds were readily prepared and reasonably stable in culture medium and could be optimized to inhibit one, two, or all three proteasome catalytic sites. Cytotoxicity assays performed on a series of human tumor cell lines identified the most potent inhibitors in cells.

Exploring the Oxidative Cyclization of Substituted N‐Aryl Enamines: Pd‐Catalyzed Formation of Indoles from Anilines

“…The formation of a brominated indole derivative (2 j) is attractive because these bromoindoles are key intermediates in the preparation of biologically active compounds by Suzuki-Miyaura cross-coupling reactions. [14] Interestingly, ortho-alkyl substituted enaminones led to comparably higher yields than para-alkyl substituted enaminones (Table 1, for example, 3 e compared to 2 k). Similarly, a bulky alkyl substituent at the ortho-position of the enaminone gave a good yield (Table 1, 3 g, 3 h).…”

Macrocyclic Proteasome Inhibitors

“…These studies have led for example to the elucidation that the C-terminal enamide moiety can be replaced by a synthetically easier accessable allyl residue without significant loss of bioactivity [83]. Interestingly, the groups of Vidal and Reboud-Ravaux have also extensively studied linearized TMC-95 analogs which despite their non-cyclic nature proved to be highly potent 20S proteasome inhibitors [84]. Again, structural studies of these compounds in complex with yeast 20S proteasome helped to clarify the structural basis of their inhibition potency.…”

TMC-95A–D and analogues: Chemistry and biology

“…The superimposition of the X-ray structures of these inhibitors with that of TMC-95A in complexes with yeast CP showed an almost identical peptide backbone display, thus suggesting similar orientations of the Leu and Nle side chains when incorporated into TMC-95A to act as P1 and P3 residues, respectively. This, however, proved to be an unfavorable approach since most inhibitory activities were considerably reduced ( (continued on next page) [25] (continued on next page) [25] (continued on next page) [25] (continued on next page) [26] (continued on next page)…”

“…These linear compounds were readily prepared and reasonably stable in culture medium and could be optimized to block one, two, or all three proteasome catalytic sites. Furthermore, cytotoxicity assays performed on a series of human tumor cell lines identified the most potent inhibitors in cells [25].…”