Improved Synthesis of N-Benzylaminoferrocene-Based Prodrugs and Evaluation of Their Toxicity and Antileukemic Activity

被引：79

作者：

Daum, Steffen ^{[1
]}

Chekhun, Vasiliy F. ^{[2
]}

Todor, Igor N. ^{[2
]}

Lukianova, Natalia Yu ^{[2
]}

Shvets, Yulia V. ^{[2
]}

Sellner, Leopold ^{[3
,4
,5
]}

Putzker, Kerstin ^{[7
]}

Lewis, Joe ^{[7
]}

Zenz, Thorsten ^{[3
,4
,5
]}

de Graaf, Inge A. M. ^{[6
]}

Groothuis, Geny M. M. ^{[6
]}

Casini, Angela ^{[6
]}

Zozulia, Oleksii ^{[1
]}

Hampel, Frank ^{[1
]}

Mokhir, Andriy ^{[1
]}

机构：

[1] Univ Erlangen Nurnberg, Dept Chem & Pharm, Organ Chem 2, D-91054 Erlangen, Germany

[2] Natl Acad Sci Ukraine, RE Kavetsky Inst Expt Pathol Oncol & Radiobiol, UA-03022 Kiev, Ukraine

[3] Natl Ctr Tumor Dis NCT, Dept Translat Oncol, D-69120 Heidelberg, Germany

[4] German Canc Res Ctr DKFZ Heidelberg, D-69120 Heidelberg, Germany

[5] Univ Heidelberg Hosp, Dept Med 5, D-69120 Heidelberg, Germany

[6] Univ Groningen, Groningen Res Inst Pharm, Dept Pharmacokinet Toxicol & Targeting, NL-9713 AV Groningen, Netherlands

[7] European Mol Biol Lab Heidelberg, Chem Biol Core Facil, D-69117 Heidelberg, Germany

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2015年 / 58卷 / 04期

关键词：

AMINOFERROCENE-BASED PRODRUGS; CANCER-CELLS; HYDROGEN-PEROXIDE; OXIDATIVE STRESS; MOUSE MODELS; TUMOR CELLS; ANTICANCER; EXPRESSION; SLICES;

D O I：

10.1021/jm5019548

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

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 mu M; 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 mu g/kg starting from the second day after injection of L1210 cells.

引用

页码：2015 / 2024

页数：10

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