New carboxylate and hydroxamate inhibitors of prostaglandin-H-synthase and their metal complexes
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The thesis describes new carboxylate and hydroxamate inhibitors of prostaglandin-H-synthase (PGHS) as well as the synthesis and structures of metal complexes of the hydroxamates which were synthesised. This enzyme, also called cyclooxygenase (COX), has two active sites a cyclooxygenase (COX) active site which is the target for aspirin and a peroxidase (POX) active site, upon which the COX site depends.
The thesis is divided in to three chapters. The first chapter describes the attempted synthesis of aspirin derivatives, specifically designed by molecular modelling to fit better into the COX active site of PGHS. These derivatives possess O-acetylsalicylate moieties with an additional alkylcarboxylate substituent which allows simultaneous interaction with Arg120 and Tyr385 at the COX site whilst locating the acetyl group in close proximity to Ser530. The most active compound synthesised was an O-acetylsalicylate ester with an alkylcarboxylate ester substituent which is non-acidic and may act as a lead for further research. An introduction to platelets, thrombosis, prostaglandins and PGHS is given in this chapter prior to a description and discussion of the compounds synthesised.
Chapter 2 describes acetylated salicylhydroxamic acids as PGHS inhibitors. Previous work in our laboratory led to mono- and tri-acetylated salicyhydroxamate derivatives as inhibitors of the COX site of PGHS. The first of these, N-acetoxy-2-hydroxybenzamide (SalAc, 2), is less potent than aspirin while N-acetoxy-N-acetyl 2-acetoxybenzamide (SalAc3, 4) is 4-fold more potent. A mechanism of action for SalAc, 2, similar to that of aspirin and for SalAc3, 4, involving N-deacetylation followed by transfer of an acetyl group to Ser530 from the diacetylated metabolite N-acetoxy-2-acetoxybenzamide, SalAc2, 3. The synthesis, crystal structure and PGHS inhibitory activity of 3, which is 6-fold more active than aspirin, is reported in Chapter 2. The crystal structure of 2 is also reported as well as improved synthesis of 2 and 3.
Chapter 3 describes the attempted synthesis of acetylated antbranilic hydroxamic acid as a dual COX and POX site inhibitor of PGHS. Unfortunately the product was the cyclic hydroxamic acid, 3-hydroxy-2-methyl-3H-quinazoIin-4-one (ChaH). The formation and structure of this and of the complexes Fe(Cha)2(Cl)(H2O).7/2H2O, Co(Cha)2(C2H5OH)2, Ni(Cha)2(C2H5OH)2, Cu(Cha)H2O(CI) and [Zn(Cha)2].2H20 are described. The synthesis and structure of the 4-aminophenylhydroxamic acid complex [FeIII(4-Apha)3].C2H5OH is also described here.