A unique category of basic side chain containing amino acid derived sulfonyl fluorides (SFs) has been synthesized for incorporation into new proteasome inhibitors targeting the trypsin-like site of the 20S proteasome. Masking the former α-amino functionality of the amino acid starting derivatives as an azido functionality allowed an elegant conversion to the corresponding amino acid derived sulfonyl fluorides. The inclusion of different SFs at the P site of a proteasome inhibitor resulted in 14 different peptidosulfonyl fluorides (PSFs) having a high potency and an excellent selectivity for the proteolytic activity of the β2 subunit over that of the β5 subunit. The results of this study strongly indicate that a free N-terminus of PSFs inhibitors is crucial for high selectivity toward the trypsin-like site of the 20S proteasome. Nevertheless, all compounds are slightly more selective for inhibition of the constitutive over the immunoproteasome.

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COMMUNICATIONS filtered and cirr-drieci 10 yield 2-2 PF, (232 mg. 95 %)as a yellow powder: m.p. 282 C (dscomp.). FAB-MS 171;: 531 ( M -PF,)'. 386 ( M -2PF,)': ' H NMR (CD,CN). d = 6.75 (4H. s). 7.51 ~ 7.55 (6H. m). 7.62-7.67 (4H. m). 8.81 (4H. s).

A facile synthesis of 4,6-dideoxy-3-O-methyl-D-xylo-hexose (D-chalcose) is described, which involves the preparation of methyl 4,6-dichloro-4,6-dideoxy-3-O-methyl-D-galactopyranoside (2) by a reaction with sulfuryl chloride, and its reduction to the dideoxy sugar by hydrogenation over Raney nickel.

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