Study on development of anti-septic zinc(II) complex with immune-enhancing activity

脓毒性休克伴发热甚至死亡是一种生物反应，它是由革兰氏阴性菌高度保守的外膜化合物LPS（脂多糖，内毒素）触发的。小鼠和人类巨噬细胞对内毒素表现出特别强烈的反应，内毒素诱导多种炎症调节剂的产生，如一氧化氮（NO）、活性氧（ROS）、几种细胞因子（IL-1β、TNF-α、IL-6、INF-γ）和前列腺素。锌（Zn）是所有生物系统中必需的微量元素。它有四个配位键，在许多蛋白质和酶中起结构作用。据报道，它在体外和体内实验中都表现出胰岛素模拟活性。在模拟胰岛素剂的开发中，合成低分子量锌配合物，如二麦芽糖酸锌（II）、锌（mal）_2及其衍生物，在模拟胰岛素活性方面比离子锌更有前景。锌具有较强的抗氧化作用，并能抑制脂多糖诱导的NO和ROS的产生。因此，锌具有广泛的药理活性，可能通过抑制炎症刺激来保护机体免受lps诱导的感染性休克。本研究考察了麦芽糖酸锌衍生物作为一种潜在的肝保护剂，对lps诱导的离体大鼠原代肝细胞体外肝毒性和人败血症模型大鼠体内内毒素休克的抑制作用。结果表明：LPS （30 mg/kg）腹腔注射和Zn(mal)_2 （10 mg/kg）腹腔注射后96 h内大鼠的存活率分别接近100%和70%。5和20 mg Zn/kg低剂量和高剂量组的存活率均降低。此外，药代动力学分析表明，具有S_2O_2配位模式的锌配合物在口服后可能比苹果酸锌衍生物表现出更强的抗菌活性，这主要是由于锌（S_2O_2）配合物在胃肠道中的生物利用度更高，并分布到器官中。少

Septic shock with fever and even death is induced as one of the biological responses, which are triggered by LPS (lipopolysaccharide, endotoxin), a highly conserved outer membrane compound of gram-negative bacteria. Murine and human macrophages exhibit a particularly vigorous response to endotoxin, which induces production of a variety of inflammatory modulators such as nitric oxide (NO), reactive oxygen species (ROS), several cytokines (IL-1β, TNF-α, IL-6, INF-γ), and prostaglandins.Zinc (Zn) is an essential trace element in all-living systems. It has four coordinating bonds and plays a structural role in many proteins and enzymes. It has been also reported to exhibit insulinomimetic activity in both in vitro and in vivo experiments. In the development of insulinomimetic agents, synthetic low-molecular weight Zn complexes such as bis(maltolato)zinc(II), Zn(mal)_2, and its derivatives exhibited more promise in insulinomimetic activity than ionic zinc species. While, Zn is known to exhi … More bit antioxidative effects and inhibit LPS-induced NO and ROS production. Then, Zn has extensive pharmacological activity and may protect the body against the LPS-induced septic shock with suppressing inflammatory stimulation.In the present study, we examined the suppressive effect of zinc-maltolate derivatives as a potential liver-protecting agent on the LPS-induced in vitro hepatotoxicity in isolated rat primary hepatocytes and in vivo endotoxin shock in rats, which is a model of human septicemia. The results indicated that the survival rate of rats, who were intraperitoneally (ip) administered with LPS (30 mg/kg) and ip pre- or post-treated with Zn(mal)_2 injection at a dose of 10 mg Zn/kg, was almost 100% or approximately 70% within 96 hours after LPS injection, respectively. While, the survival rates was decreased in both cases at lower and higher doses of 5 and 20 mg Zn/kg. In addition, pharmacokinetic analysis suggested that Zn complexes with S_2O_2 coordination mode may exhibit more potent anti-septic activity than zinc-maltolate derivatives after oral administration, mainly due to the higher bioavailability from the gastrointestine and distribution to organs of Zn(S_2O_2) complexes. Less