PDF(Pubmed)
Abstract：
Organometallic compounds, including Ruthenium complexes, have been widely developed as anti-cancer chemotherapeutics, but have also attracted much interest as potential anti-parasitic drugs. Recently hybrid drugs composed of organometallic Ruthenium moieties that were complexed to different antimicrobial agents were synthesized. One of these compounds, a trithiolato-diRuthenium complex (RU) conjugated to sulfadoxine (SDX), inhibited proliferation of Toxoplasma gondii tachyzoites grown in human foreskin fibroblast (HFF) monolayers with an IC50 < 150 nM, while SDX and the non-modified RU complex applied either individually or as an equimolar mixture were much less potent. In addition, conjugation of SDX to RU lead to decreased HFF cytotoxicity. RU-SDX did not impair the in vitro proliferation of murine splenocytes at concentrations ranging from 0.1 to 0.5 μM but had an impact at 2 μM, and induced zebrafish embryotoxicity at 20 μM, but not at 2 or 0.2 μM. RU-SDX acted parasitostatic but not parasiticidal, and induced transient ultrastructural changes in the mitochondrial matrix of tachyzoites early during treatment. While other compounds that target the mitochondrion such as the uncouplers FCCP and CCCP and another trithiolato-Ruthenium complex conjugated to adenine affected the mitochondrial membrane potential, no such effect was detected for RU-SDX. Evaluation of the in vivo efficacy of RU-SDX in a murine T. gondii oocyst infection model comprised of non-pregnant outbred CD1 mice showed no effects on the cerebral parasite burden, but reduced parasite load in the eyes and in heart tissue.
摘要：
有机金属化合物,包括钌配合物，已经被广泛开发为抗癌化疗药物，但作为潜在的抗寄生虫药物也引起了极大的兴趣。最近合成了由与不同抗微生物剂络合的有机金属钌部分组成的杂合药物。其中一种化合物，与磺胺多辛（SDX）共轭的三硫醇-二钌络合物（RU），抑制人包皮成纤维细胞（HFF）单层中生长的弓形虫速殖子的增殖，IC50<150nM，而单独或作为等摩尔混合物应用的SDX和未修饰的RU复合物的效力低得多。此外,SDX与RU的缀合导致HFF细胞毒性降低。RU-SDX在0.1至0.5μM的浓度范围内不会损害小鼠脾细胞的体外增殖，但在2μM时具有影响，并在20μM诱导斑马鱼胚胎毒性，但不是2或0.2μM。RU-SDX具有抗寄生虫作用，但不具有杀寄生虫作用，并在治疗早期诱导速殖子线粒体基质的瞬时超微结构变化。虽然其他靶向线粒体的化合物，如解偶联剂FCCP和CCCP以及与腺嘌呤缀合的另一种三硫代钌复合物影响线粒体膜电位，RU-SDX未检测到这种效应.评估RU-SDX在由非妊娠近交CD1小鼠组成的鼠弓形虫卵囊感染模型中的体内功效，显示对脑寄生虫负荷没有影响，但减少了眼睛和心脏组织中的寄生虫负荷。
