Mbongo N, Loiseau P M, Lawrence F, Craciunescu D G, Robert-Gero M
Centre National de la Recherche Scientifique, Institut de Chimie des Substances Naturelles, Gif sur Yvette, France.
Arzneimittelforschung. 1998 Aug;48(8):850-5.
Iridium (Ir)-(COD)-pentamidine tetraphenylborate (CAS 225-75-4) was selected from a primary screening to be evaluated in vitro on three Leishmania (L.) strains comparatively to pentamidine used as reference compound. The IC50 values obtained from in vitro evaluation on promastigotes of L. major CRE 26, L. donovani DD8 and L. donovani LV9 were 3.9, 23.5, and 3.3 mumol/l for Ir-(COD)-pentamidine tetraphenylborate and 1.6, 7.7, and 3.9 mumol/l for pentamidine isethionate, respectively. Cytotoxicity on mouse peritoneal macrophages led to determine a chemotherapeutic index of 1.7 for Ir-(COD)-pentamidine tetraphenylborate and 4 for pentamidine. Considering L. donovani DD8, the uptake of iridium complex by the promastigotes was shown to be saturable with a Km value of 17.4 mumol/l and Vmax of 1.3 nmol/mg protein/2 h. After 2 and 4 h incubation of treated promastigotes in drug free medium the absence of Ir-complex efflux is in favour of intracellular drug binding. As a matter of fact iridium complex was shown to bind ribosomal subunits in vitro, with no effect on macromolecular biosynthesis.
铱（Ir）-（环辛二烯）-喷他脒四苯基硼酸盐（CAS 225-75-4）是从初步筛选中选出的，与用作参考化合物的喷他脒相比，在体外对三种利什曼原虫（L.）菌株进行评估。对硕大利什曼原虫CRE 26、杜氏利什曼原虫DD8和杜氏利什曼原虫LV9前鞭毛体进行体外评估得到的铱（Ir）-（环辛二烯）-喷他脒四苯基硼酸盐的IC50值分别为3.9、23.5和3.3 μmol/L，而乙磺酸盐喷他脒的IC50值分别为1.6、7.7和3.9 μmol/L。对小鼠腹腔巨噬细胞的细胞毒性导致确定铱（Ir）-（环辛二烯）-喷他脒四苯基硼酸盐的化疗指数为1.7，喷他脒的化疗指数为4。以杜氏利什曼原虫DD8为例，前鞭毛体对铱络合物的摄取显示为可饱和，Km值为17.4 μmol/L，Vmax为1.3 nmol/mg蛋白质/2小时。在无药物培养基中处理过的前鞭毛体孵育2小时和4小时后，未观察到铱络合物的外排，这有利于细胞内药物结合。事实上，铱络合物在体外显示与核糖体亚基结合，对大分子生物合成没有影响。
