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 C8 position of TMC-95s can be replaced with a simple allylamide. The asymmetric center at C36 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.

Scheme 1

Structures of TMC-95s.

Scheme 2

Final steps in the synthesis of TMC-95A and B. Reagents and conditions: a) Pd/C, H₂, EtOH, RT, 19 h; b) (+)-3-methyl-2-oxopentanoic acid, EDC/HOAT, CH₂Cl₂/DMF, RT, 2 h, 0°C → RT, 2 h, 85% (two steps); c) HF/Py; d) TESOTf, 2,6-lutidine, CH₂Cl₂, 0°C → RT, 15 h; then NaHCO₃ ; then citric acid, EtOAc/H₂O; e) Jones reagent, acetone, 0 °C, 2 h; f) 9, EDC/HOAT, CH₂Cl₂/DMF, RT, 13 h, 33% (four steps); g) o-xylene, 140 °C, 3 d; then H₂O; h) HF/Py, THF/Py; then Me₃SiOMe, 49% (two steps). Bn, benzyl; TIPS, triisopropylsilyl, TES, trimethylsilyl; Tf, trifluoromethanesulfonyl; EDC, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride; HOAT, 1-hydroxyl-7-azabenzotriazole; DMF, N,N-dimethylformamide; THF, tetrahydrofuran; Py, pyridine.

Scheme 3

Structures of designed TMC-95A analogues.