Proteasome inhibitor TMC

Albrecht and Wilhams [132,133] developed an interesting synthetic approach to macrocyclic proteasome inhibitors TMC-95A/B, involving reaction of BT sulfone 297 with activated ketone 298 (Scheme 96). The reaction was carried out using LHMDS, in DMF containing DMPU as the co-solvent, at 0 °C. The olefination product 299 was obtained in 79% yield, E/Z 5/1. 

The syn addition, rotation, and syn elimination rule is valid even for reaction of congested molecules. Hirama applied HR of 20 to the stereocontrolled synthesis of the northern part of a potent proteasome inhibitor TMC-95A, and found that the Z isomer of the cyclized product 21 was obtained selectively in 86% yield... 

Total synthesis of proteasome inhibitor TMC-95A was achieved by smooth coupling of e functionalized boronate 37 with the iodide 38 without touching labile functional groups to give 39 in 75 % yield in the presenee of PdCl2(dppf) as a key reaction [52]. 

Williams has reported the synthesis of biaryl moiety of proteasome inhibitors TMC-95/A/B by Suzuki cross-coupling of boronic ester 68 with indolyl iodide 69 to give precursor 70 in 90% yield [49]. The boronic ester 68 was obtained from the tyrosine derivative 71 with i)is(pinacol)diborane (37), Pd(dppf)Cl2 and KOAc via the Miyaura protocol (Scheme 3.31). 

The biaryl moiety of proteasome inhibitor TMC-95 has been prepared via a ligandless Pd(OAc)2-catalyzed Suzuki-coupling reaction of 7-iodoisatin with steri-cally hindered tyrosine-derived aryl boronic acid using potassium fluoride as a... 

Koguchi, Y., Kohno, J., Nishio, M., Takahashi, K., Okuda, T., Ohnuki, T., and Komatsubaea, S. TMC-95A, B, C, and D, novel proteasome inhibitors produced by Apiospora montagnei Sacc. TC 1093. Taxonomy, production, isolation, and biological activities. J Antibiot (Tokyo) 2000, 53, 105-109. 

Groll, M., Koguchi, Y., Huber, R., Kohno, j.. Crystal structure of the 20 S proteasome TMC-95A complex a non-covalent proteasome inhibitor. J. Mol. 

The total synthesis of the proteasome inhibitor cyclic peptide TMC-95A was accomplished by. S.J. Danishefsky and co-workers. The biaryl linkage in the natural product was constructed by a Suzuki cross-coupling between an aryl iodide and an arylboronic ester derived from L-tyrosine. The required arylboronic pinacolate substrate was prepared using the Miyaura boration. The aryl iodide was exposed to b/s(pinacolato)diboron in the presence of a palladium catalyst and potassium acetate in DMSO. The coupling proceeded in high yield and no symmetrical biaryl by-product was observed. 

Recently, more selective noncovalent inhibitors of proteasome have been developed. TMC-95A 15 is a potent and reversible selective inhibitor of the chymotrypsin-like, trypsinlike, and caspaselike activities of the 20S proteasome. Comparatively, TMC-95A shows no inhibition of calpain, cathepsin, or trypsin. 

Structures of TMC-95A-D novel proteasome inhibitors from Apiospora montagnei sacc. TC 1093,/. Org. 

In recent years, a number of structurally distinct compounds targeting the proteasome have reached the clinic, amongst others the covalent and irreversible inhibitor carfilzomib [5]. The structure of carfilzomib is based on that of the natural product, epoxomicin, that also features the epoxyketone electrophilic trap. Indeed, numerous natural product proteasome inhibitors with a distinguishing electrophile grafted onto a peptidic core have been described over the years, including lactacystin, syringolin A (SylA), and fellutamide B. An important class of synthetic covalent proteasome inhibitors is represented by the peptide vinyl sulfones, whereas numerous noncovalent proteasome inhibitors have been discovered as well (e.g., TMC 95A). 

TMC-95A, a cydic peptide metabolite from Apiospra montagnei, is a potent competitive inhibitor of all active sites and forms characteristic hydrogen bonds with the protein backbone. The crystal structure of the yeast 20S proteasome in complex with TMC-95A indicates a non-covalent linkage to the active y -subunits the N-terminal threonine residues are not modified. The TMC-95A backbone adopts a -conformation and extends the -strand SI by the generation of an antiparallel P-sheet. This stmcture is similar to that seen with the aldehyde and epoxyketone inhibitors. An interactions of TMC-95A are formed with main-chain atoms and strictly conserved residues of the 20S proteasome. 

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