Speciation 98: Abstracts

Aspirin (O-acetylsalicylic acid) is a widely used analgesic, antipyretic,anti-inflammatory and anti-thrombotic agent. The effects of aspirin aredue to inhibition of the haem-containing enzyme prostaglandin-H-synthase(PGHS). It has however several side effects sometimes resulting in fatalities and hence there is a search foralternative drugs with equivalent beneficial therapeutic effects butlacking the side effects. We therefore attempted to synthesise ahydroxamic acid analogue of aspirin by acetylating salicylhydroxamic acid (I). This however resulted inthe acetylated product (II) in which the hydroxamic acid group rather than the phenolic group isacetylated. Nevertheless this compound was found to have a ten-foldgreater inhibitory effect on PGHS than aspirin. The attempted acetylationof anthranilic hydroxamic acid (III) resulted in the formation of the cyclic hydroxamic acid (IV). Since PGHS is a haem enzyme compound (II) may exert its inhibitoryeffect by binding to the metal ion. We therefore decided to investigatethe metal binding properties of (II) and the related hydroxamic acid ligands, (I), (III) and (IV) as well as benzohydroxamic acid (V) for comparison. Where solubility permitted studies were carried out inaqueous solution by pH-metry and in some cases by visiblespectroscopy.

The species in solution are CuA, CuAH; NiAH, NiAH_-1, NiA₂H₂, NiA, NiA₂H, NiA₂; ZnAH, ZnA₂H₂, ZnA₂, ZnA, ZnA₂H, ZnA₂H_-1; FeA, FeAH, FeA₂, FeA₂H₂, FeA₃, where HA represents the hydroxamic acid. Anthranilichydroxamic acid (III) and benzohydroxamic acid (V) produce similar species with comparable stability constants indicatingthat the amino group has little effect on complex formation. The cyclichydroxamic acid (IV) forms less stable complexes than the acyclicones.

Acknowledgement: We thank the Research Committee of the Royal College of Surgeons in Ireland and Forbairt Ireland (Programme on International Collaboration) for financial support.

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