Synthesis, conformation and antiproliferative activity of isothiazoloisoxazole 1,1-dioxides.

Sixteen new isothiazoloisoxazole 1,1-dioxides, one new isothiazolotriazole and one new isothiazolopyrazole have been synthesised by using 1,3-dipolar cycloadditions to isothiazole 1,1-dioxides. One sub-set of these isothiazoloisoxazoles showed low µM activity against a human breast carcinoma cell line, whilst a second sub-set plus the isothiazolotriazole demonstrated an interesting restricted rotation of sterically hindered bridgehead substituents. A thiazete 1,1-dioxide produced from one of the isothiazole 1,1-dioxides underwent conversion into an unknown 1,2,3-oxathiazolin-2-oxide upon treatment with Lewis acids, but was inert towards 1,3-dipoles and cyclopropenones. Six supporting crystal structures are included.

Cysteinyl peptide inhibitors of Bacillus cereus zinc beta-lactamase.

Several cysteinyl peptides have been synthesised and shown to be reversible competitive inhibitors of the Bacillus cereus metallo-beta-lactamase. The pH dependence of pKi indicates that the thiol anion displaces hydroxide ion from the active site zinc(II). D,D-Peptides bind to the enzyme better than other diastereoisomers, which is compatible with the predicted stereochemistry of the active site.

The reactivity of beta-lactams, the mechanism of catalysis and the inhibition of beta-lactamases.

Four membered b-lactam rings do not show unusual reactivity compared with their acyclic amide analogues and there is no evidence of concerted mechanisms for nucleophilic substitution reactions at the carbonyl centre. The identity of the general base/acid catalyst in the serine b-lactamases, which catalyse the hydrolysis of b-lactams, is unknown. There are no ideal transition state analogue inhibitors for these enzymes which involve several intermediates and transition states. The class C serine b-lactamase enhances the rate of phosphonylation of its active site serine residue by a similar magnitude to the enzyme rate enhancement factor for the hydrolysis of b-lactams. Comparisons are made between the stereochemical consequences of tetrahedral and trigonal bipyramidal intermediates for hydrolysis and phosphonylation respectively. Class B zinc b-lactamases are inhibited by thiol dipeptides with a D configuration at the cysteine centre analogous to the L configuration at C6 in penicillins. The mechanism of hydrolysis catalysed by the metallo-b-lactamases probably involves a di-anionic tetrahedral intermediate stabilised by zinc(II).

Clinical significance of extreme elevation of the erythrocyte sedimentation rate.

Charts of 1006 consecutive outpatients were reviewed to ascertain the cause of extreme elevation of the erythrocyte sedimentation rate (ESR) (greater than or equal to 100 mm/h) and the sensitivity of marked ESR elevation in patients with disorders commonly reported to cause ESR elevation. Prevalence of ESRs of 100 mm/h or more was 4.2%. Infection was the most common cause (33%), with malignant neoplasms and renal disease each responsible for 17% and inflammatory disorders for 14%. Only 1% of all other patients had ESRs of 100 mm/h or more. An ESR of 100 mm/h or more had low sensitivity: 36% among patients with infection, 25% among those with malignant neoplasms, and 21% among patients with noninfectious inflammatory disorders. Specificity was high, both for individual disease categories (96% for malignant neoplasms and 97% for infection) and as a "sickness" index (greater than 99%). The positive predictive value for an identifiable cause of marked ESR elevation was 90%.