2型糖尿病(T2DM)患病率较高,缺乏有效的治疗方法,确定是否需要新的治疗方案。本研究集中于NO供体药物类别作为有效的抗糖尿病药物。由于许多生物系统参与了T2DM的发病和进展,开发用于治疗T2DM的有效药物的最有希望的方法是寻找对T2DM及其并发症的许多治疗靶标具有选择性的药理活性化合物:氧化应激,非酶蛋白糖基化,多元醇途径。在这项工作中研究了具有硫代硫酸盐配体的亚硝基铁配合物。双核亚硝基铁络合物是NO的调节蛋白天然储库中[2Fe-2S]中心的合成类似物。由于它们在生理条件下无需额外活化即可释放NO的能力,这些化合物对于潜在药物的开发具有相当大的意义。本研究探讨了四硝基铁配合物与硫代硫酸盐配体(TNIC-ThS)对T2DM及其并发症的影响,以及它结合脂质体膜的能力,抑制脂质过氧化(LPO),和牛血清白蛋白(BSA)的非酶糖基化,以及醛糖还原酶,催化多元醇途径中葡萄糖还原为山梨醇的酶。采用荧光探针法,已经显示TNIC-ThS分子与模型膜的亲水和疏水区域相互作用。TNIC-ThS抑制脂质过氧化,由于释放NO而表现出抗自由基活性(IC50=21.5±3.7µM)。发现TNIC-ThS显示醛糖还原酶的非竞争性抑制,Ki值为5.25×10-4M。TNIC-ThS被证明是体外非酶蛋白糖基化过程的有效抑制剂(IC50=47.4±7.6µM)。因此,TNIC-ThS可能被认为对T2DM和糖尿病并发症的治疗有重要贡献。
The high prevalence of type 2 diabetes mellitus (T2DM), and the lack of effective therapy, determine the need for new treatment options. The present study is focused on the NO-donors drug class as effective antidiabetic agents. Since numerous biological systems are involved in the pathogenesis and progression of T2DM, the most promising approach to the development of effective drugs for the treatment of T2DM is the search for pharmacologically active compounds that are selective for a number of therapeutic targets for T2DM and its complications: oxidative stress, non-enzymatic protein glycation, polyol pathway. The nitrosyl iron complex with thiosulfate ligands was studied in this work. Binuclear iron nitrosyl complexes are synthetic analogues of [2Fe-2S] centers in the regulatory protein natural reservoirs of NO. Due to their ability to release NO without additional activation under physiological conditions, these compounds are of considerable interest for the development of potential drugs. The present study explores the effects of tetranitrosyl iron complex with thiosulfate ligands (TNIC-ThS) on T2DM and its complications regarding therapeutic targets in vitro, as well as its ability to bind liposomal membrane, inhibit lipid peroxidation (LPO), and non-enzymatic glycation of bovine serum albumin (BSA), as well as aldose reductase, the enzyme that catalyzes the reduction in glucose to sorbitol in the polyol pathway. Using the fluorescent probe method, it has been shown that TNIC-ThS molecules interact with both hydrophilic and hydrophobic regions of model membranes. TNIC-ThS inhibits lipid peroxidation, exhibiting antiradical activity due to releasing NO (IC50 = 21.5 ± 3.7 µM). TNIC-ThS was found to show non-competitive inhibition of aldose reductase with Ki value of 5.25 × 10-4 M. In addition, TNIC-ThS was shown to be an effective inhibitor of the process of non-enzymatic protein glycation in vitro (IC50 = 47.4 ± 7.6 µM). Thus, TNIC-ThS may be considered to contribute significantly to the treatment of T2DM and diabetic complications.