Molenda J J, Jones M M, Johnston D S, Walker E M, Cannon D J
Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37235.
J Med Chem. 1994 Dec 9;37(25):4363-70. doi: 10.1021/jm00051a014.
In the search for 3-hydroxypyrid-4-ones with enhanced iron-mobilizing ability, seven chiral, anionic amino acid derivatives of maltol (3-hydroxy-2-methyl-4-pyrone) have been synthesized, utilizing L-methionine, L-serine, L-leucine, L-phenylalanine, L-glutamic acid, and the D- and L-isomers of alanine. Two achiral, aromatic compounds were also synthesized and compared with the phenylalanine derivative. The biliary iron excretion following iv injection and the urinary iron excretion following po administration were measured using female Sprague-Dawley rats and compared to that of the standard, 1,2-dimethyl-3-hydroxypyrid-4-one (L1). While none of the compounds was as effective as L1 in enhancing the urinary excretion of iron, all monoanionic chelators increased excretion relative to the controls. All monoanionic compounds were at least equivalent to L1 in enhancing the biliary excretion of iron, with the methionine, leucine, and benzoate derivatives surpassing the standard and the other aromatic compounds also showing strong activity. The dianionic glutamate derivative showed low activity relative to the controls for both urinary and biliary iron excretion. No significant difference in iron excretion was observed due to variation in chirality; molecular weight and the number of negative charges appeared to have the greatest influence on the ability of the various derivatives to enhance iron excretion. In order to evaluate the relative purity of the stereoisomers, the alanine derivatives were analyzed by circular dichroism. Further characterization was provided by UV/vis spectroscopy for all compounds and X-ray crystallography for the novel dianionic derivative.
为了寻找具有增强铁动员能力的3-羟基吡啶-4-酮，利用L-甲硫氨酸、L-丝氨酸、L-亮氨酸、L-苯丙氨酸、L-谷氨酸以及丙氨酸的D-和L-异构体，合成了麦芽酚（3-羟基-2-甲基-4-吡喃酮）的七种手性阴离子氨基酸衍生物。还合成了两种非手性芳香化合物，并与苯丙氨酸衍生物进行比较。使用雌性Sprague-Dawley大鼠测量静脉注射后的胆汁铁排泄量和口服给药后的尿铁排泄量，并与标准品1,2-二甲基-3-羟基吡啶-4-酮（L1）进行比较。虽然没有一种化合物在增强尿铁排泄方面像L1那样有效，但所有单阴离子螯合剂相对于对照组都增加了排泄量。所有单阴离子化合物在增强胆汁铁排泄方面至少与L1相当，甲硫氨酸、亮氨酸和苯甲酸盐衍生物超过了标准品，其他芳香化合物也表现出很强的活性。二阴离子谷氨酸衍生物在尿铁和胆汁铁排泄方面相对于对照组表现出低活性。由于手性的变化未观察到铁排泄有显著差异；分子量和负电荷数量似乎对各种衍生物增强铁排泄的能力影响最大。为了评估立体异构体的相对纯度，通过圆二色性分析了丙氨酸衍生物。通过紫外/可见光谱对所有化合物进行了进一步表征，并通过X射线晶体学对新型二阴离子衍生物进行了表征。
