Vanadium compounds are promising anti-diabetic agents. However, reducing the metal toxicity while keeping/improving the hypoglycemic effect is still a big challenge towards the success of anti-diabetic vanadium drugs. To improve the therapeutic potency using the anti-oxidative strategy, we synthesized new N,N-dimethylphenylenediamine (DMPD)-derivatized nitrilotriacetic acid vanadyl complexes ([VO(dmada)]). The in vitro biological evaluations revealed that the DMPD-derivatized complexes showed improved antioxidant capacity and lowered cytotoxicity on HK-2 cells than bis(maltolato)oxidovanadium (IV) (BMOV). In type II diabetic mice, [VO(p-dmada)] (0.15 mmol kg^− 1/day) exhibited better hypoglycemic effects than BMOV especially on improving glucose tolerance and alleviating the hyperglycemia-induced liver damage. These insulin enhancement effects were associated with increased expression of peroxisome proliferator-activated receptor α and γ (PPARα/γ) in fat, activation of Akt (v-Akt murine thymoma viral oncogene)/PKB (protein kinase-B) in fat and liver, and inactivation of c-Jun NH₂-terminal protein kinases (JNK) in liver. Moreover, [VO(p-dmada)] showed no tissue toxicity at the therapeutic dose in diabetic mice and the oral acute toxicity (LD50) was determined to be 1640 mg kg^− 1. Overall, the experimental results indicated that [VO(p-dmada)] can be a potent insulin enhancement agent with improved efficacy-over- toxicity index for further drug development. In addition, the results on brain Tau phosphorylation suggested necessary investigation on the effects of vanadyl complexes on the pathology of the Alzheimer's disease in the future.

钒化合物是有希望的抗糖尿病药。然而，在保持/改善降血糖作用的同时降低金属毒性仍然是抗糖尿病钒药物成功的一大挑战。为了使用抗氧化策略提高治疗效果，我们合成了新的N，N-二甲基苯二胺（DMPD）-衍生的次氮基三乙酸钒基复合物（[VO（dmada）]）。体外生物学评估表明，与双（麦芽糖基）氧化钒（IV）（BMOV）相比，DMPD衍生的复合物对HK-2细胞显示出更高的抗氧化能力，并降低了细胞毒性。在II型糖尿病小鼠中，[VO（p-dmada）]（0.15 mmol kg ^{− 1}/日）显示出比BMOV更好的降血糖作用，尤其是在改善葡萄糖耐量和减轻高血糖引起的肝损害方面。这些胰岛素增强作用与脂肪中过氧化物酶体增殖物激活受体α和γ（PPARα/γ）的表达增加，脂肪和肝中Akt（v-Akt鼠胸腺瘤病毒致癌基因）/ PKB（蛋白激酶B）的激活有关以及肝中c-Jun NH ₂末端蛋白激酶（JNK）的失活。此外，[VO（p-dmada）]在糖尿病小鼠的治疗剂量下无组织毒性，口服急性毒性（LD50）被确定为1640 mg kg ^-1。总体而言，实验结果表明，[VO（p-dmada）]可以是一种有效的胰岛素增强剂，具有更高的药效比毒性指数，可用于进一步的药物开发。此外，有关脑Tau磷酸化的结果表明，将来有必要对钒基复合物对阿尔茨海默氏病病理的影响进行研究。