Institute of Medicinal Chemistry, School of Pharmacy of Lanzhou University, China.
Institute of Medicinal Chemistry, School of Pharmacy of Lanzhou University, China.
Eur J Med Chem. 2018 Nov 5;159:339-356. doi: 10.1016/j.ejmech.2018.10.004. Epub 2018 Oct 4.
A series of HSCO dual-donors [Mn(CO)CSNRR] was synthesized, and evaluated from toxicity and bioactivity. The COHS measuring test showed all the complexes not only released CO, but released HS. The resulting data of cytotoxicity showed all the complexes had activities against the cell proliferation; among them, complexes 1, 2 and 7 displayed higher activities than the others, and their potencies were close to cis-platinum (DDP); whereas the precursors A-A had almost no activities against all five tumor cell lines and W138 cell line proliferation. It is worth noting that complex 1 displayed the highest activity to MCF-7, complex 2 displayed the highest activity to HePG2, and complex 7 showed selectivity inhibition to both A549 and HeLa. The developmental toxicities of the complex were assessed using zebrafish embryos. The results showed complexes 1 and 2 had effect on the mortality and hatching rate of zebrafish embryos in dose-dependent manner. They caused zebrafish malformations when they were over 10 μM. Meanwhile, they displayed dose-dependent toxicities to larval zebrafish. In the test of bio-activities, complexes 1 and 2 had strong anti-inflammatory activities; they not only down-regulated the expression levels of iNOS and TNF-α, up-regulated the expression of HO-1 and IL-10, but also up-regulated COX-2 levels. In contrast, the precursor compound (A or A) displayed lower anti-inflammatory activity than the corresponding complex, which suggests both the CO and HS from the complex took synergistic effects in the process of anti-inflammation. In addition, the complex showed antihypertensive effect and myocardial protection. This effect also possibly resulted from this synergistic effect. All these suggest the complexes have potential to be candidate medicines.
一系列 HSCO 双供体 [Mn(CO)CSNRR] 被合成，并从毒性和生物活性方面进行了评估。COHS 测量试验表明，所有配合物不仅释放 CO，还释放 HS。细胞毒性的结果表明，所有配合物都对细胞增殖有活性；其中，配合物 1、2 和 7 的活性高于其他配合物，其效力接近顺铂（DDP）；而前体 A-A 对所有五种肿瘤细胞系和 W138 细胞系的增殖几乎没有活性。值得注意的是，配合物 1 对 MCF-7 的活性最高，配合物 2 对 HePG2 的活性最高，配合物 7 对 A549 和 HeLa 均有选择性抑制作用。利用斑马鱼胚胎评估了配合物的发育毒性。结果表明，配合物 1 和 2 以剂量依赖的方式影响斑马鱼胚胎的死亡率和孵化率。当浓度超过 10 μM 时，它们会导致斑马鱼畸形。同时，它们对幼鱼斑马鱼也表现出剂量依赖性毒性。在生物活性测试中，配合物 1 和 2 具有很强的抗炎活性；它们不仅下调了 iNOS 和 TNF-α 的表达水平，上调了 HO-1 和 IL-10 的表达水平，还上调了 COX-2 水平。相比之下，前体化合物（A 或 A）的抗炎活性低于相应的配合物，这表明配合物中的 CO 和 HS 在抗炎过程中具有协同作用。此外，该配合物具有降压作用和心肌保护作用。这种作用也可能是由于这种协同作用。所有这些都表明这些配合物具有成为候选药物的潜力。
