Chaves Sílvia, Gil Marco, Canário Sónia, Jelic Ratomir, Romão Maria João, Trincão José, Herdtweck Eberhardt, Sousa Joana, Diniz Carmen, Fresco Paula, Santos M Amélia
Centro de Química Estrutural, Complexo I, Instituto Superior Técnico, Av. Rovisco Pais, 1049-001, Lisboa, Portugal.
Dalton Trans. 2008 Apr 7(13):1773-82. doi: 10.1039/b717172b. Epub 2008 Feb 20.
Two O,S-donor ligands, hydroxythiopyrone and hydroxythiopyridinone derivatives, were developed and studied, as well as the corresponding O,O-derivatives, with a view to their potential pharmacological applications as xanthine oxidase (XO) inhibitors. The biological assays revealed that the O,S-ligands present high inhibitory activity towards XO (nanomolar order, close to that of the pharmaceutical drug allopurinol), in contrast to the corresponding O,O-analogues. Due to the biomedical relevance of this molybdenum-containing enzyme, the corresponding Mo(VI) complexes were studied both in solution and in the solid state, aimed at identifying the source of the biological properties. The solution studies showed that, in comparison with the O,O-analogues, the Mo(VI) complexes with the O,S-ligands present some stabilization, which is even more pronounced for the reduced Mo(IV) species. The crystal structures of the Mo(VI) complexes with the hydroxythiopyrone revealed good flexibility of the coordination modes, with two structural isomers and two polymorphic forms for a mononuclear and a binuclear species, respectively. These results give some support to mechanistic proposals for the XO inhibition involving the interaction of the thione group with the molybdenum cofactor, thus indicating a role of the sulfur atom in the XO inhibition.
开发并研究了两种含O、S的供体配体，即羟基硫代吡喃酮和羟基硫代吡啶酮衍生物，以及相应的O、O - 衍生物，旨在探索它们作为黄嘌呤氧化酶（XO）抑制剂的潜在药理应用。生物学测定表明，与相应的O、O - 类似物相比，O、S - 配体对XO具有高抑制活性（纳摩尔级，接近药物别嘌呤醇）。由于这种含钼酶在生物医学方面的相关性，对相应的Mo(VI)配合物进行了溶液和固态研究，旨在确定其生物学特性的来源。溶液研究表明，与O、O - 类似物相比，含O、S - 配体的Mo(VI)配合物具有一定的稳定性，对于还原态的Mo(IV)物种而言更为明显。含羟基硫代吡喃酮的Mo(VI)配合物的晶体结构显示出配位模式具有良好的灵活性，单核和双核物种分别有两种结构异构体和两种多晶型形式。这些结果为涉及硫酮基团与钼辅因子相互作用的XO抑制作用机制提供了一些支持，从而表明硫原子在XO抑制中发挥了作用。
