Department of Chemistry and Pharmacy, Organic Chemistry II, Friedrich-Alexander-University of Erlangen-Nürnberg , Henkestraße 42, 91054 Erlangen, Germany.
J Med Chem. 2015 Feb 26;58(4):2015-24. doi: 10.1021/jm5019548. Epub 2015 Feb 9.
We report on an improved method of synthesis of N-benzylaminoferrocene-based prodrugs and demonstrate its applicability by preparing nine new aminoferrocenes. Their effect on the viability of selected cancer cells having different p53 status was studied. The obtained data are in agreement with the hypothesis that the toxicity of aminoferrocenes is not dependent upon p53 status. Subsequently the toxicity of a selected prodrug (4) was investigated ex vivo using rat precision cut liver slices and in vivo on hybrid male mice BDF1. In both experiments no toxicity was observed: ex vivo, up to 10 μM; in vivo, up to 6 mg/kg. Finally, prodrug 4 was shown to extend the survival of BDF1 mice carrying L1210 leukemia from 13.7 ± 0.6 days to 17.5 ± 0.7 days when injected daily 6 times at a dose of 26 μg/kg starting from the second day after injection of L1210 cells.
我们报告了一种改进的 N-苄基氨基二茂铁基前药的合成方法，并通过制备 9 种新的氨基二茂铁证明了其适用性。研究了它们对具有不同 p53 状态的选定癌细胞存活能力的影响。所得数据与以下假设一致，即氨基二茂铁的毒性不依赖于 p53 状态。随后，使用大鼠精密肝切片在体研究了选定前药（4）的体外毒性，并在杂交雄性 BDF1 小鼠体内进行了研究。在这两项实验中均未观察到毒性：体外实验中，浓度高达 10 μM；体内实验中，剂量高达 6 mg/kg。最后，当每天注射 L1210 细胞后第二天开始以 26 μg/kg 的剂量注射 6 次时，前药 4 可将携带 L1210 白血病的 BDF1 小鼠的存活期从 13.7 ± 0.6 天延长至 17.5 ± 0.7 天。
