Ruth J. Mayer

Hydroxamate-based inhibitors of low affinity IgE receptor (CD23) processing

A series of hydroxamic acids related to the non-selective matrix metalloprotease inhibitor Batimastat is described, which inhibits the proteolytic cleavage of the low affinity IgE receptor from cell membrane preparations. Limited SAR studies suggest that the structural requirements for effective inhibition are distinct from those required for the inhibition of collagenase.

Inhibition of 3-hydroxy-3-methylglutaryl coenzyme A synthase by antibiotic 1233A and other β-lactones

3-Hydroxy-3-methylglutaryl CoA synthase was shown to be inhibited in a time-dependent, irreversible manner by compounds containing the substituted beta-lactone functionality found in the natural product 1233A. The rate of inactivation (kinact) was found to approach the rate of catalysis (kcat). The inactivation was irreversible over several hours. A related compound lacking the hydroxymethyl substituent on the beta-lactone ring is a reversible inhibitor and is competitive with respect to acetylCoA. The results are consistent with beta-lactone ring opening by the active site Cys to form an enzyme bound thioester.

Involvement of superoxide in the reactions of the catechol dioxygenases

Abstract The effect of copper salicylate on the rates of reaction of protocatechuate 3,4-dioxygenase (intradiol cleavage) and 3,4-dihydroxyphenylacetate 2,3-dioxygenase (extradiol cleavage) was monitored. The data obtained is consistent with the dismutation of superoxide by the copper complex resulting in the uncoupling of the oxygen reduction step from the product formation step. Mechanistic interpretations are presented.

The therapeutic potential for phospholipase A2 inhibitors

Modulation of pro-inflammatory lipid mediator production by inhibition of phospholipase A2 (PLA2) activity remains a potential target for development of new drugs for the treatment of rheumatoid arthritis or other inflammatory diseases. Evidence now exists that more than one isoform of PLA2, including types IIa and V 14 and 85 kDa PLA2, is required for production of lipid mediators. Specific isoforms may be associated with production of either the prostaglandin or leukotriene class of lipid mediators in different cell types such as monocytes and neutrophils. Characterisation of isoform-selective inhibitors in models of inflammatory disease, such as rat adjuvant arthritis or phorbol myristate acetate (PMA)-induced mouse ear oedema, suggests that both 14 kDa and 85 kDa PLA2 may contribute to the development of the disease state and that both forms of PLA2 may be targets for modulation of inflammatory disease. Much work remains to clarify fully the relative roles of different PLA2 in the aetiology of inflamm...

Section Review: Pulmonary-Allergy, Dermatological, Gastrointestinal & Arthritis: Therapeutic regulation of 14 kDa phospholipase A2(s)

Phospholipases A2(s) (PLA2), which catalyse the hydrolysis of the sn-2 fatty acyl chain of phospholipid substrates to yield fatty acids and lysophospholipids, have over the last few years become a broad group of structurally and mechanistically diverse enzymes. The importance and respective functions of the various PLA2 isoforms are only now beginning to be appreciated. The type II 14 kDa PLA2 is clearly implicated in disease states and, as such, has been a prime target for therapeutic intervention; while the biological function of the 85 kDa PLA2 is not fully understood. The 14 and 85 kDa PLA2 enzymes are structurally and mechanistically distinct and, as such, development of selective 14 kDa PLA2 inhibitors has been achieved. Herein, the structural aspects and biological role of the type II 14 kDa PLA2 are reviewed and compared with the 85 kDa PLA2 to define better their respective roles. Further, the more recent chemical strategies for designing 14 kDa PLA2 inhibitors are reviewed and key compounds summ...

Novel frameworks for trifluoromethyl ketone and phosphonate tsa inhibitors of type II PLA2

Abstract Design and synthesis of some TSA inhibitors on novel molecular frameworks is described. This TSA analog design culminates in the preparation of the phosphonate 18.

Phosphinic acid inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme a reductase

Abstract Compound 3 was designed as a prototype for a new class of phosphorus-based inhibitors of 3-hydorxy-3-methylglutaryl-coenzyme A reductase. The synthesis and biochemical evaluation of compound 3 are described.