Centro de Química Estrutural, Instituto Superior Técnico, Av. Rovisco Pais 1, 1049-001 Lisboa, Portugal.
Metallomics. 2010 Mar;2(3):220-7. doi: 10.1039/b914169c. Epub 2009 Nov 9.
The development of metal-containing pharmaceuticals as insulin-mimetics has been the object of recent worldwide research. We have examined a series of zinc(II) and molybdenum(VI) complexes with model O,S-donor ligands (thiomaltol and 1,2-dimethyl-3-hydroxypyridine-4-thione (DMHTP)) and the corresponding O,O-analogues (maltol and DMHP) for their insulin-mimetic activity. Aimed at getting structure-activity relationships, some physical-chemical properties were also studied, such as metal-complex formation, speciation at different pH conditions and ligand lipophilicity. The Zn-complexes exhibit considerably higher insulin-mimetic activity than the corresponding Mo-analogues. Particularly, the bis(thiomaltolato)zinc(II) complex reveals a very high activity, ascribed to the effect of the thione π character and to the soft nature of the sulfur donor atom enhancing the Zn(II)-ligand affinity and the ligand/complex lipophilicity, two determinant parameters for delivering the metal-drug into the cells. Hence, these preliminary studies indicate that the Zn(thiomaltol)₂ complex can be considered a potential drug candidate for treatment of diabetes mellitus, upon in vivo evaluations.
作为胰岛素模拟物的含金属药物的开发一直是最近全球研究的对象。我们研究了一系列具有模型 O，S-供体配体（硫代麦芽糖和 1,2-二甲基-3-羟基吡啶-4-硫酮（DMHTP））的锌（II）和钼（VI）配合物，以及相应的 O，O-类似物（麦芽糖和 DMHP）的胰岛素模拟活性。为了获得构效关系，还研究了一些物理化学性质，例如金属配合物的形成，不同 pH 条件下的形态和配体的亲脂性。锌配合物的胰岛素模拟活性明显高于相应的钼类似物。特别是，双（硫代麦芽糖）锌（II）配合物表现出非常高的活性，这归因于硫酮π 键的作用以及硫供体原子的软性质增强了 Zn（II）-配体亲和力和配体/配合物的亲脂性，这两个决定因素对于将金属药物输送到细胞中非常重要。因此，这些初步研究表明，锌（硫代麦芽糖）₂配合物可以被认为是治疗糖尿病的潜在候选药物，需要进行体内评估。
