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

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 h...

Full description

Saved in:
Bibliographic Details
Published in:Journal of medicinal chemistry 2015-02, Vol.58 (4), p.2015-2024
Main Authors: Daum, Steffen, Chekhun, Vasiliy F, Todor, Igor N, Lukianova, Natalia Yu, Shvets, Yulia V, Sellner, Leopold, Putzker, Kerstin, Lewis, Joe, Zenz, Thorsten, de Graaf, Inge A. M, Groothuis, Geny M. M, Casini, Angela, Zozulia, Oleksii, Hampel, Frank, Mokhir, Andriy
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Antineoplastic Agents - toxicity
Carbamates - chemical synthesis
Carbamates - chemistry
Carbamates - pharmacology
Carbamates - toxicity
Cell Proliferation - drug effects
Cell Survival - drug effects
Crystallography, X-Ray
Dose-Response Relationship, Drug
Ferrous Compounds - chemical synthesis
Ferrous Compounds - chemistry
Ferrous Compounds - pharmacology
Ferrous Compounds - toxicity
HL-60 Cells
Humans
In Vitro Techniques
Injections, Intraperitoneal
Leukemia - drug therapy
Liver - drug effects
Male
Mice
Mice, Inbred C57BL
Mice, Inbred DBA
Models, Molecular
Molecular Structure
Prodrugs - chemical synthesis
Prodrugs - chemistry
Prodrugs - pharmacology
Prodrugs - toxicity
Rats
Rats, Wistar
Structure-Activity Relationship
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm5019548