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

Abstract

The proteasome regulates diverse intracellular processes, including cell-cycle progression, antigen presentation, and inflammatory response. Selective inhibitors of the proteasome have great therapeutic potential for the treatment of cancer and inflammatory disorders. Natural cyclic peptides TMC-95A and B represent a new class of noncovalent, selective proteasome inhibitors. To explore the structure-activity relationship of this class of proteasome inhibitors, a series of TMC-95A/B analogues were prepared and analyzed. We found that the unique enamide functionality at the C-8 position of TMC-95s can be replaced with a simple allylamide. The asymmetric center at C-36 that distinguishes TMC-95A from TMC-95B but which necessitates a complicated separation of the two compounds can be eliminated. Therefore, these findings could lead to the development of more accessible simple analogues as potential therapeutic agents.

TMC‐95A Analogues with Endocyclic Biphenyl Ether Group as Proteasome Inhibitors

“…Based on these findings, it is reasonable to assume that the significantly reduced inhibition of the b2 subunit by compound 2 compared to TMC-95A [28] has to be correlated with replacement of the C-terminal (Z)-prop-1-enyl chain with the moreflexible propyl group. This conclusion is in full agreement with results obtained by similar replacements of the P1 residue in TMC analogues containing the intact core structure of the natural product [44]. Similarly, replacement of the propyl group by the larger and even more-flexible norleucine side chain leads to a further reduction in binding affinity for the b2 subunit, but concurrently also to some loss of affinity for the Fig.…”

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)…”

“…In an effort to get rid of the structural features that could render the synthesis impractical for producing amounts of materials appropriate for clinical follow-up, a set of analogues 62e71 (Fig. 9) was prepared by Danishefsky and co-workers according to the synthetic route shown for the preparation of 62 (Scheme 17) [26].…”

Total Synthesis of TMC-95A and -B via a New Reaction Leading to Z-Enamides. Some Preliminary Findings as to SAR

“…26 The inhibitory concentrations (K iapp ) of the synthetic analogues against all three catalytic activities of the proteasome are reported in Table 5 and compared with those of TMC-95A and B. Remarkably, the allylamide 47, bearing a shorter side chain at the C14 position retains full inhibition potency of all three proteasome activities.…”