The synthesis of a range of 2-(1'-hydroxyalkyl)-3-hydroxypyridin-4-ones as bidentate iron(III) chelators with potential for oral administration is described. The pK(a) values of the ligands and the stability constants of their iron(III) complexes have been determined. Results indicate that the introduction of a 1'-hydroxyalkyl group at the 2-position leads to a significant improvement in the pFe(3+) values. Such an effect was found to be greater with the hydroxyethyl substituent than with the hydroxymethyl substituent, particularly in the cases of 1-ethyl-2-(1'-hydroxyethyl)-3-hydroxypyridin-4-one (pFe(3+) = 21.4) and 1,6-dimethyl-2-(1'-hydroxyethyl)-3-hydroxypyridin-4-one (pFe(3+) = 21.5) where an enhancement on pFe(3+) values in the region of two orders of magnitude is observed, as compared with Deferiprone (1, 2-dimethyl-3-hydroxypyridin-4-one) (pFe(3+) = 19.4). The ability of these novel 3-hydroxypyridin-4-ones to facilitate the iron excretion in bile was investigated using a [(59)Fe]ferritin-loaded rat model. Chelators and prodrug chelators possessing high pFe(3+) values show great promise in their ability to remove iron under in vivo conditions.

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The metabolism of 9-benzyladenine (BA) and isomeric 9-(nitrobenzyl) adenines (NBAs), i.e. 9-(2-nitrobenzyl)adenine (2NBA), 9-(3-nitrobenzyl)adenine (3NBA) and 9-(4-nitrobenzyl)adenine (4NBA), was investigated with normal hamster hepatic microsomes. Using HPLC, TLC, UV and MS techniques, it was established that metabolic N¹-oxidation occurred for all BA and NBAs. The N¹-oxidative rate was in the order 2NBA>BA>3NBA and 4NBA. The results suggest that the introduction of a nitro group may interfere with the binding between substrates and related N¹-oxidase(s). This may be the reason for the lower N¹-oxidative rates of 3NB A and 4NB A. It is also suggested that 2NBA may possess the most favourable conformation and binding characteristics for the enzymes among the substrates studied as it was metabolised even faster than BA.