Multi-component assembly of the bicyclic core associated with the tRNA synthetase inhibitors SB-203207 and SB-203208. Application to the synthesis of biologically active analogues.

The ketone (+/-)-5, which embodies the bicyclic core associated with the title tRNA synthetase inhibitors 1 and 2, has been prepared via a three-component coupling reaction involving 2-(hydroxymethyl)cyclopent-2-enone (15), methylamine (6) and propiolamide (10); straightforward elaboration of the readily derived acetates (-)-21 and (+)-21 has provided the biologically active analogues 23 and 24, respectively, of the title compounds.

Analogues of SB-203207 as inhibitors of tRNA synthetases.

SB-203207 and 10 analogues have been prepared, by elaboration of altemicidin, and evaluated as inhibitors of isoleucyl, leucyl and valyl tRNA synthetases (IRS, LRS, and VRS, respectively). Substituting the isoleucine residue of SB-203207 with leucine and valine increased the potency of inhibition of LRS and VRS, respectively. The leucine derivative showed low level antibacterial activity, while several of the compounds inhibited IRS from Staphylococcus aureus WCUH29 more strongly than rat liver IRS.

Leucine-phenylalanine dipeptide-based N-mesyloxysuccinimides: synthesis of all four stereoisomers and their assay against serine proteases.

The four stereoisomers of 3-(N-acetylleucylamino)-3-benzyl-1-[(methylsulfonyl)oxy]succinimid e have been prepared and shown to inhibit alpha-chymotrypsin and human neutrophil elastase. The structural and stereochemical features that affect the potency and selectivity of inhibition are discussed.