2002 IRISH SCIENTIST YEAR BOOK

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ROYAL COLLEGE OF SURGEONS IN IRELAND
CELINE J. MARMION & KEVIN B. NOLAN
Hydroxamic Acids – Iron chelators, aspirin analogues, nitric oxide donors and structurally diverse metal complexes

Salicylhydroxamic Salicylic acid

What are they? – Hydroxamic acids are a family of organic acids of general formula RC(=O)N(R’)OH. They are much weaker acids than the structurally related carboxylic acids RC(=O)OH. The structures of simple acids are shown in Figure 1.

 What do they do? – Hydroxamic acids fulfil a variety of roles in biology and medicine. They have antibacterial and anti-fungal properties and are inhibitors of enzymes such as prostaglandin H synthase, peroxidases, ureases, and matrix metallo-proteinases (MMP) which degrade the barriers holding cells in place and are involved in tumour growth. Their ability to inhibit enzymes makes them ideal as drug candidates – e.g. Marimastat is a hydroxamic acid which is an MMP inhibitor and is at an advanced stage of clinical development as an anticancer drug.

 Hydroxamate ions are powerful metal binding agents (chelators) and some are siderophores which are compounds produced by microorganisms for the abstraction of iron from iron-deficient environments. One such siderephore, desferrioxamine B (Desferal) is also used in medicine to treat potentially fatal iron overload resulting from regular blood transfusion of patients with thalassaemia – a genetic blood disease, affecting 100,000 babies annually, characterised by the decreased production of normal haemoglobin and resulting in anaemia (see Figures 2 & 3).

Figure 2. Structure of the iron(III)-Desferal complex excreted in bile and urine following administration of Desferal to treat iron overload.


Figure 3. Nearly all untreated thalassaemic patients die within the first few years but, with regular blood transfusions, many live into their 20s when mortality due to iron overload occurs. Treatment with Desferal leads to normal life expectancy. From Chemistry in Britain, 1990, 26, 565-568.

Hydroxamic acids as alternatives to aspirin and as nitric oxide donors – We, in collaboration with Professor Des Fitzgerald and Dr Caroline Sharkey, Department of Clinical Pharmacology, are developing hydroxamic acids as alternatives to aspirin (O-acetylsalicylic acid), which acts by inhibiting the enzyme, prostaglandin H synthase (PGHS). This enzyme has two isoforms, PGHS-1 and PGHS-2, each of which has two catalytic sites, a peroxidase site and a cyclooxygenase site, only the latter of which is inhibited by aspirin (which delivers its acetyl group to the site) (Figure 4).

Figure 4. The active sites of PGHS showing the peroxidase (red, top left) and cyclooxygenase (mauve) sites.

The side effects of aspirin – e.g. irritation of the gastric mucosa – are due to inhibition of PGHS-1, whilst its anti-inflammatory effects are due to inhibition of PGHS-2. Aspirin does not inhibit the peroxidase site and this can lead to the production of damaging free radicals even after inhibition of the cyclooxygenase site. Acetylated salicyl-hydroxamic acids are attractive candidates as aspirin substitutes since they, like aspirin, should inhibit the cyclooxygenase site of PGHS by acetylation. The hydroxamic acid group is a much weaker acid than the carboxylic acid group which is present in aspirin and should cause less topical irritation, and the hydroxamic acid metabolites, unlike that of aspirin, should inhibit the peroxidase site of the enzyme.

 We have recently found that hydroxamic acids are nitric oxide donors (they can transfer nitric oxide to ruthenium(III), forming nitrosyl complexes, and physiologically can cause vascular relaxation in rat aorta). This NO-releasing capability offers an additional advantage in the present context, since nitric oxide counteracts some of the side effects of aspirin by exerting a protective defensive ability on the gastric mucosa.

 We have synthesised O-acetylsalicyl-hydroxamic acid and found that it inhibits PGHS as effectively as aspirin, and does so by a similar mechanism. Triacetylsalicyl-hydroxamic acid, another of our compounds, is a much better inhibitor of the enzyme than aspirin, and we are using this as a lead to synthesise more potent inhibitors.

 Structural diversity in metal-hydroxamate complexes – Although hydroxamate ions usually bind to metal ions through the two oxygen atoms (i.e. as O,O-bidentate chelating agents), other binding modes are also possible, and this range can be greatly increased if the hydroxamate ligand contains secondary binding groups, resulting in many diverse and intriguing structures. This we have found in the complexes formed between the isomeric amino-phenylhydroxamic acids (AphaH 2 ) and CuSO 4 .5H 2 O. Whilst 4-aminophenylhydroxamic acid (4-AphaH2 ) gives the simple square planar complex Cu(4-AphaH)2 .2H 2 O, 2-aminophenylhydroxamic acid (2-AphaH 2 ) gives a complex of formula [Cu5 (2-Apha)4 SO 4 .(H2 O)2 ] 2 , in which the metal ions display extensive magnetic coupling (with potential applications in the field of magnetoelectronics) and 3-aminophenylhydroxamic acid (3-AphaH 2 ) gives a trinuclear helical polymer of formula [Cu3 (3-AphaH)4 SO 4 .(H 2 O)]n .8H2 O, which has a supramolecular structure with large open cavities (Figure 5), which can be useful in trapping guest molecules.

Figure 5. The structure of the copper(II) complex with 3-aminophenylhydroxamic acid has large cavities.

The above areas are currently under investigation by ourselves and Declan Gaynor in collaboration with Professor David Brown at University College Dublin and other EU research groups.

Contact: Professor Kevin B. Nolan;
E-mail: kbnolan@rcsi.ie ; or
Dr Celine J. Marmion;
E-mail: cmarmion@rcsi.ie ;
Royal College ofSurgeons in Ireland, St Stephen’s Green,Dublin 2;
Web: http://www.rcsi.ie/research/research_by_department/Chemistry_&_Physics/