Alan G. Sutherland

Mechanism of Action of the Mannopeptimycins, a Novel Class of Glycopeptide Antibiotics Active against Vancomycin-Resistant Gram-Positive Bacteria

ABSTRACT The naturally occurring mannopeptimycins (formerly AC98-1 through AC98-5) are a novel class of glycopeptide antibiotics that are active against a wide variety of gram-positive bacteria. The structures of the mannopeptimycins suggested that they might act by targeting cell wall biosynthesis, similar to other known glycopeptide antibiotics; but the fact that the mannopeptimycins retain activity against vancomycin-resistant organisms suggested that they might have a unique mode of action. By using a radioactive mannopeptimycin derivative bearing a photoactivation ligand, it was shown that mannopeptimycins interact with the membrane-bound cell wall precursor lipid II [C55-MurNAc-(peptide)-GlcNAc] and that this interaction is different from the binding of other lipid II-binding antibiotics such as vancomycin and mersacidin. The antimicrobial activities of several mannopeptimycin derivatives correlated with their affinities toward lipid II, suggesting that the inhibition of cell wall biosynthesis was primarily through lipid II binding. In addition, it was shown that mannopeptimycins bind to lipoteichoic acid in a rather nonspecific interaction, which might facilitate the accumulation of antibiotic on the bacterial cell surface.

Chemoenzymatic synthesis of (–)-carbovir utilizing a whole cell catalysed resolution of 2-azabicyclo[2.2.1]hept-5-en-3-one

The resolution of (±)-2-azabicyclo[2.2.1]hept-5-en-3-one (3), a versatile intermediate in the synthesis of carbocyclic nucleosides, is described; both optical forms of the lactam have been obtained in very high optical purity (> 98% enantiomeric excess) in rapid, facile, large-scale biotransformation processes using whole cell catalysts and the laevorotatory enantiomer has been converted into (–)-carbovir.

Structure-based design of carboxybiphenylindole inhibitors of the ZipA–FtsZ interaction

Structural features of two weak inhibitors of the ZipA-FtsZ protein-protein interaction which were found to bind to overlapping but different areas of the key binding site were combined in one new series of carboxybiphenyl-indoles with improved inhibitory activity.

Whole cell catalysed kinetic resolution of 6-azabicyclo[3.2.0]hept-3-en-7-one: synthesis of (–)-cispentacin (FR 109615)

Enantioselective hydrolysis of the β-lactam (±)-2 using Rhodococcus equi provided (1R,5S)-6azabicyclo[3.2.0] hept-3-en-7-one (+)-2, a precursor of the antifungal agent cispentacin.

The first isolation of an episulphone intermediate from a Ramberg-Bäcklund reaction

Abstract Episulphone 6 was isolated as a crystalline solid in 69% yield from the low temperature Ramberg-Backlund reaction of α-iodosulphone 5. The expected cyclopentene 7 was obtained when episulphone 6 was heated or treated with base and when the Ramberg-Backlund reaction was carried out under more forcing conditions.

Design and SAR of macrocyclic Hsp90 inhibitors with increased metabolic stability and potent cell-proliferation activity.

A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. A basic nitrogen within the tether linking the aniline nitrogen atom to a tetrahydroindolone moiety allowed access to compounds with good physical properties. Important structure-activity relationship information was obtained from this series which led to the discovery of a soluble and stable compound which is potent in an Hsp90 binding and cell-proliferation assay.

Isolation of episulfones from the Ramberg–Bäcklund rearrangement. Part 2. X-Ray molecular structure of 2,3-epithio-8,8-dimethyl-6,10- dioxaspiro[4.5]decane S,S-dioxide and of r-6-benzyl-t-7,t-8-epithio-1,4-dioxaspiro[4.4]nonane S,S-dioxide

For the first time, episulfones have been isolated by the treatment of α-halogeno sulfones with base under the conditions of the Ramberg–Backlund reaction. 3,3-Dialkoxy-6-thiabicyclo[3.1.0]hexane dioxides 3a-c and 11a, b have been fully characterised, X-ray crystal structures having been obtained for compounds 3c and 11a. Attempts to prepare episulfones with substituents at the bridgehead position were unsuccessful, however. The thermal stabilities of some of these episulfones have been studied, as have their reactions with base.

Enzymatic resolution of sterically demanding bicyclo[3.2.0]heptanes: evidence for a novel hydrolase in crude porcine pancreatic lipase and the advantages of using organic media for some of the biotransformations

Sterically demanding 7,7-dimethylbicyclo[3.2.0]hept-2-en-6-one 1 was enzymatically resolved via the exo-acetate 11a using crude porcine pancreatic lipase. By employing different fractions of hydrolases from the crude enzyme, evidence was obtained that an enzymatic ‘impurity’ was responsible for the highly selective reaction (E > 300). Alternatively, 7,7-dimethyl and 7,7-diphenyl derivatives 1 and 2 were equally well resolved, via bromohydrins 12b and 13b, by lipases from Pseudomonas cepacia and Candida cylindracea but only when acylations were conducted in organic media.

Synthesis of either enantiomer of cis-3-aminocyclopentanecarboxylic acid from both enantiomers of racemic 2-azabicyclo[2.2.1]hept-5-en-3-one

(–)-2-Azabicyclo[2.2.1]hept-5-en-3-one (–)-1 was converted into (–)-cis-3-aminocyclopentanecarboxylic acid (–)-2 in two steps and into the enantiomeric amino-acid (+)-2 in three steps.

Ring–Chain Tautomerism of the 1,4-Oxathiane S,S-Dioxide Anion

The ring-chain tautomer of the α-sulfonyl anion of 1,4-oxathiane S,S-dioxide can be trapped by addition of alkoxides to the vinyl sulfone; the scope of this reaction is explored.