The synthesis of a range of novel 3-hydroxypyridin-4-ones and 3-hydroxypyran-4-ones linked with different coumarin substituents is described. These compounds have been developed in order to provide a series of molecular probes for the quantification of intracellular labile iron pools. An evaluation of the effect of iron(III) on fluorescence intensity was undertaken. Chelation of iron(III) causes quenching of fluorescence. The relationship between iron(III) concentration and the extent of fluorescence quenching indicates that the metal is chelated in a complex with a metal-to-ligand stoichiometry of 1:3. The fluorescence of hydroxypyridinone compounds was found to be more efficiently quenched by iron(III) than were the hydroxypyranones. The metal-to-ligand stoichiometry at which maximum quenching is observed was found to depend on the site at which coumarin is attached. The efficiency of fluorescence quenching by iron(III) is markedly influenced by solvent polarity and pH. The permeability of two representative fluorescent chelators across human erythrocyte ghost membranes was investigated. The rate of permeability for a series of probes was found to be related to the corresponding ClogP values.

Design, synthesis, physicochemical properties, and evaluation of novel iron chelators with fluorescent sensors.

Pyridinium N-phenolate betaine dyes.

Cross-coupling reactions with boronic acids in water catalysed by oxime-derived palladacycles

Publisher Summary This chapter discusses the clinically useful chelators of tripositive elements. The clinical use of chelator molecules has been synonymous with the removal of toxic metals, for instance, cadmium and lead. With the realization of the central role of iron in so many physiological responses, specific ligands for iron are being widely investigated as potential therapeutic compounds. The introduction of diagnostic investigations involving γ-scintigraphy (indium), positron emission tomography (gallium) and nuclear magnetic resonance (gadolinium) has also necessitated the introduction of new chelating agents into medicine. The coordination chemistries of aluminium, iron, gallium, indium, and lanthanum (as a model of gadolinium) are compared. The design and clinical application of selective ligands for each of these metals are discussed. If chelators are to be used in the clinical situation, there are many restrictions on the chemical design of the molecule apart from that of selectivity. Both the free ligand and the complex should be water-soluble and yet, if the role of the ligand is to scavenge a metal, it must also be able to penetrate cell membranes.

Clinically useful chelators of tripositive elements.

Kojic acid derivative 2 was synthesized by joining two pyrone rings through an ethylene linkage by Horner-Emmons reaction of phosphonate 6 with aldehyde 7. The intermediates 6 and 7 were derived from kojic acid. The tyrosinase inhibitory activity of 2 was about 8 times more potent (IC(50) = 3.63 microM) than that of kojic acid (IC(50) = 30.61 microM). Compound 2 also exhibited potent melanin synthesis inhibitory activity (19.53% inhibition at 5 mug) indicating that the connection of two pyrone rings of kojic acid through a suitable linker can be an useful strategy for identification of potent tyrosinase inhibitors.

Synthesis of Tyrosinase Inhibitory Kojic Acid Derivative

3-Acetyltropolone (1) was synthesized from 3-isopropenyltropolone by treatment with sodium azide in concentrated sulfuric acid. Methylation of 1 by diazomethane gave two isomers, 3-acetyl-2-methoxytropone (2a) and 2-acetyl-7-methoxytropone (2b). 1, 2a, and 2b reacted with hydrazine to give some 1,8-dihydrocycloheptapyrazol-8-one derivatives.

Reactions of 3-acetyltropolone and its methyl ethers with hydrazine.

5-Hydroxy-2-hydroxymethyl-4-pyridone and its N-methyl, N-ethyl, and N-phenyl derivatives were prepared from kojic acid. The UV spectra in neutral, acid, and alkaline solutions showed that the neutral species and the conjugate acids existed in the pyridone and the pyridine form, respectively. The conjugate bases may exist in both forms. The acid dissociation constants and the halochromism have been measured and discussed.

Structure of 5-Hydroxy-2-hydroxymethyl-4-pyridones

Alkaline condensation of 3-acetyltropolone (1) with benzaldehydes gave 3-cinnamoyltropolones (2 a-d), which were cyclized with concentrated orthophosphoric acid to afford 2-aryl-2, 3, 4, 9-tetra-hydrocyclohepta [b] pyran-4, 9-diones (3a-d) and oxidized with selenium dioxide to give 2-aryl-4, 9- dihydrocyclohepta [b] pyran-4, 9-diones (4a-d).

Synthesis and Cyclization of 3-Cinnamoyltropolones

Acid dissociation constants and UV and NMR spectra of a series of 6-substituted 3-hydroxy-1-methyl-4-pyridones have been measured. The acid dissociation constants have been analyzed in terms of the Hammett equation to give linear relationships, with ρ=1.16 for the conjugate acids and ρ=1.06 for the neutral compounds. Halochromism in the UV spectra gave the equation: Δ\ ildeν=689 pKa−9399, and the Hammett plots of the chemical shifts of the 2-H, 5-H, and CH3 protons gave linear relationships, with ρ=1.78, 2.56, and 1.39, respectively.

Hisashi Matsumura

Papers

Reactions of 3-acetyltropolone and its methyl ethers with hydrazine.

Structure of 5-Hydroxy-2-hydroxymethyl-4-pyridones

Synthesis and Cyclization of 3-Cinnamoyltropolones

Substituent Effects on 6-Substituted 3-Hydroxy-1-methyl-4-pyridones

Reactions of 3-acetyltropolone and its methyl ethers with hydroxylamine. Formation of 8H-cyclohept[d]isoxazol-8-one and 8H-cyclohept[c]isoxazol-8-one