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首页> 外文期刊>Journal of Medicinal Chemistry >Synthesis, physicochemical properties, and evaluation of N-substituted-2-alkyl-3-hydroxy-4(1H)-pyridinones.
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Synthesis, physicochemical properties, and evaluation of N-substituted-2-alkyl-3-hydroxy-4(1H)-pyridinones.

机译：N-取代的-2-烷基-3-羟基-4（1H）-吡啶酮的合成，理化性质和评价。

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The synthesis of a range of 3-hydroxy-4(1H)-pyridinones with potential for the chelation of iron(III) is described. The pKa values of respective ligands and the stability constants of their iron(III) complexes are presented. The distribution coefficient values of a range of 48 hydroxypyridinones and their corresponding iron(III) complexes between 1-octanol and MOPS buffer (pH 7.4) are reported. The range of log Dcomplex values covers 7 orders of magnitude. The results suggest the existence of a biphasic relationship between the distribution coefficient values of the chelator and the corresponding iron(III) complexes. For ligands with a log Dligand = -1, a linear relationship exists with a value of the slope 2.53, whereas with ligands with a log Dligand < -1, a linear relationship exists with a slope of 0.49. The reduced slope for the more hydrophilic molecules of the series offers some advantage for this type of hydroxypyridinone as the distribution coefficients for such complexes do not change so rapidly with increasing ligand hydrophilicity. The ability of selected 3-hydroxypyridinones to facilitate the excretion of iron in bile was investigated in non-iron-overloaded, bile duct-cannulated rats and in a [59Fe]ferritin-loaded rat model. Both systems compare the ability of chelators to remove iron from the liver, the prime target organ in thalassemia. The N-(hydroxyalkyl)-3-hydroxypyridin-4-ones are demonstrated to be orally active under the in vivo conditions adopted. Thus both 1-(hydroxyalkyl)- and 1-(carboxyalkyl)pyridinones are able to remove iron from the liver. Although 1-(carboxyalkyl)hydroxypyridinones are active, they do not demonstrate any clear advantage over Deferiprone (1,2-dimethyl-3-hydroxypyridin-4-one). Indeed 1-(hydroxyalkyl)hydroxypyridinones which are known to be rapidly converted to 1-(carboxyalkyl)hydroxypyridinones are also marginally superior to Deferiprone. In contrast, 2-ethyl-1-(2'-hydroxyethyl)-3-hydroxypyridin-4-one, which is not metabolized to the corresponding (carboxyalkyl)hydroxypyridinone, was found to be superior to Deferiprone and therefore deserves further consideration as an orally active iron chelator with potential for the treatment of iron overload associated with transfusion-dependent thalassemia.
机译：描述了一系列可能与铁（III）螯合的3-羟基-4（1H）-吡啶酮。给出了各个配体的pKa值及其铁（III）配合物的稳定性常数。报告了1-辛醇和MOPS缓冲液（pH 7.4）之间48种羟基吡啶酮及其对应的铁（III）配合物的分布系数值。对数Dcomplex值的范围涵盖7个数量级。结果表明，螯合剂的分布系数值与相应的铁（III）配合物之间存在两相关系。对于对数Dligand = -1的配体，线性关系的斜率值为2.53，而对于对数Dligand <-1的配体，线性关系的斜率为0.49。该系列中亲水性更高的分子的降低的斜率为这种类型的羟基吡啶酮提供了一些优势，因为此类配合物的分配系数不会随着配体亲水性的增加而迅速改变。在非铁超负荷，胆管插管的大鼠和负荷[59Fe]铁蛋白的大鼠模型中，研究了选定的3-羟基吡啶酮促进胆汁中铁的排泄的能力。两种系统都比较了螯合剂从肝脏（地中海贫血的主要靶器官）中去除铁的能力。 N-（羟烷基）-3-羟基吡啶-4-酮被证明在所采用的体内条件下具有口服活性。因此，1-（羟烷基）-和1-（羧烷基）吡啶酮均能够从肝脏中除去铁。尽管1-（羧烷基）羟基吡啶酮是有活性的，但它们并没有表现出优于去铁酮（1,2-二甲基-3-羟基吡啶-4-酮）的明显优势。实际上，已知能快速转化为1-（羧烷基）羟基吡啶酮的1-（羟烷基）羟基吡啶酮也略优于地氟哌酮。相反，发现未代谢为相应的（羧烷基）羟基吡啶酮的2-乙基-1-（2'-羟乙基）-3-羟基吡啶-4-酮优于酮铁酮，因此值得进一步考虑。口服活性铁螯合剂具有治疗铁依赖输血性地中海贫血的潜力。

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