No abstract

Synthesis and resolution of the antibiotic phosphonomycin are described. The structure is (-)(IR, 2S)-1,2-epoxypropylphosphonic acid.

of these compounds at or above 150 °C gave the previously unknown azides 16 and 17, respectively, identified by their IR spectra at -196 °C and by the fact that they reverted to 14 and 15, respectively, when warmed to -10 to 0 °C [16: IR 2140 (s), 2120 (s), 1350 (s) cm"1. 17: IR 2130 (vs), 2110 (s), 1330 (s) cm"1]. The intensities of the azide absorptions increased with the pyrolysis temperature until ca. 380 °C, when a new and strong absorption at 2000 cm"1 appeared. The latter absorption increased in intensity till ca. 500 °C; the azide absorptions decreased over the same temperature interval. Above 500 °C, the 2000-cm"1 band started disappearing again, and new nitrile absorptions at 2225-2250 cm'1 appeared in its place. The latter absorptions remained unchanged at room temperature, and isolation and chromatographic separation of the material allowed their assignment to the two nitriles 22 and 23, which had been identified previously.4An optimal pyrolysis temperature for the observation of the 2000-cm"1 absorption was found at 490 °C. Under these conditions, only traces of the azides (16 or 17) remained, and only weak bands due to the end products 22 and 23 were present. The spectra recorded at -196 °C, following pyrolysis of either 14 or 15 at 490 °C, were identical, and we therefore assign them to a common intermediate, the carbodiimide 19. When the matrix was warmed to ca. -55 °C, the carbodiimide band at 2000 cm"1 disappeared, and the nitriles 22 and 23 did not appear. Instead, a new compound, C18H12N4, corresponding to a dimer of 19 was isolated. The two dimers formed from 14 and 15 were identical.15These observations are summarized and interpreted in Scheme II. The formation of the common intermediate 19 demonstrates that both 1-isoquinolylnitrene (18) and 2-quinolylnitrene (20) undergo ring expansion under rather mild conditions, i.e., the activation energies cannot be significantly higher than those required for thermolysis of the azides 16 and 17. It would be difficult to interpret the observed spectra in terms of the fused azirines 24 and 25 (Scheme II). These molecules would be expected

The design, synthesis, and in vitro microbiological analysis of an array of forty covalently linked vancomycin dimers are reported. This work was undertaken to systematically probe the impact of linkage orientation and linker length on biological activity against susceptible and drug-resistant Gram-positive pathogens. To prepare the array, monomeric vancomycin synthons were linked through four distinct positions of the glycopeptide (C-terminus (C), N-terminus (N), vancosamine residue (V), and resorcinol ring (R)) in 10 unique pairwise combinations. Amphiphilic, peptide-based linkers of four different lengths (11, 19, 27, and 43 total atoms) were employed. Both linkage orientation and linker length were found to affect in vitro antibacterial potency. The V-V series displayed the greatest potency against vancomycin-susceptible organisms and vancomycin-resistant Enterococcus faecalis (VRE) of VanB phenotype, while the C-C, C-V, and V-R series displayed the most promising broad-spectrum activity that included VRE of VanA phenotype. Dimers bearing the shortest linkers were in all cases preferred for activity against VRE. The effects of linkage orientation and linker length on in vitro potency were not uniform; for example, (1) no single compound displayed activity that was superior against all test organisms to that of vancomycin or the other dimers, (2) linker length effects varied with test organism, and (3) whereas one-half of the dimers were more potent than vancomycin against methicillin-susceptible Staphylococcus aureus (MSSA), only one dimer was more potent against methicillin-resistant S. aureus (MRSA) and glycopeptide-intermediate susceptible S. aureus (GISA). In interpreting the results, we have considered the potential roles of multivalency and of other phenomena.

The preparation and in vitro prolyl endopeptidase (PEP) inhibitory activity of a series of alpha-keto heterocyclic compounds is described. The design is based on the introduction of alpha-keto heterocycles at the C-terminal end of substrate-like peptides. Many of the compounds including those substituted with thiazole, benzothiazole, benzoxazole, imidazole, and pyridine groups exhibit IC50 potencies of PEP inhibition at nanomolar levels. Structure-activity studies of the C-terminal heterocyclic groups indicate the importance of an sp2 nitrogen atom at a beta-position from the adjoining ketone carbonyl group. This heterocyclic nitrogen atom would provide a critical hydrogen-bond interaction with the histidine residue of the catalytic triad in PEP. Our inhibitors would extend the generality of the alpha-keto heterocycle design to another serine protease.