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

Steffen Daum; Vasiliy F Chekhun; Igor N Todor; Natalia Yu Lukianova; Yulia V Shvets; Leopold Sellner; Kerstin Putzker; Joe Lewis; Thorsten Zenz; Inge A M de Graaf; Geny M M Groothuis; Angela Casini; Oleksii Zozulia; Frank Hampel; Andriy Mokhir

doi:10.1021/jm5019548

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

Steffen Daum, Vasiliy F Chekhun, Igor N Todor, Natalia Yu Lukianova, Yulia V Shvets, Leopold Sellner, Kerstin Putzker, Joe Lewis, Thorsten Zenz, Inge A M de Graaf, Geny M M Groothuis, Angela Casini, Oleksii Zozulia, Frank Hampel, Andriy Mokhir

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Abstract

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.

Original language	English
Pages (from-to)	2015-2024
Number of pages	10
Journal	Journal of Medicinal Chemistry
Volume	58
Issue number	4
DOIs	https://doi.org/10.1021/jm5019548
Publication status	Published - 9-Feb-2015

Keywords

chronic lymphocytic leukemia
aminoferrocene-based prodrugs
human tumor cells
cancer cell
oxidative stress
anticancer agents
hydrogen peroxide
mouse models
HL-60 Cells
in vitro

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10.1021/jm5019548

Improved Synthesis of N-Benzylaminoferrocene-Based Prodrugs and EvaluationFinal publisher's version, 802 KBLicence: Taverne

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CCDC 1011896: Experimental Crystal Structure Determination
Daum, S. (Contributor), Chekhun, V. F. (Contributor), Todor, I. N. (Contributor), Lukianova, N. Y. (Contributor), Shvets, Y. V. (Contributor), Sellner, L. (Contributor), Putzker, K. (Contributor), Lewis, J. (Contributor), Zenz, T. (Contributor), de Graaf, I. (Contributor), Groothuis, G. (Contributor), Casini, A. (Contributor), Zozulia, O. (Contributor), Hampel, F. (Contributor) & Mokhir, A. (Contributor), University of Groningen, 2-Jul-2014
DOI: 10.5517/cc12yyts
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Daum, S., Chekhun, V. F., Todor, I. N., Lukianova, N. Y., Shvets, Y. V., Sellner, L., Putzker, K., Lewis, J., Zenz, T., de Graaf, I. A. M., Groothuis, G. M. M., Casini, A., Zozulia, O., Hampel, F., & Mokhir, A. (2015). Improved Synthesis of N-Benzylaminoferrocene-Based Prodrugs and Evaluation of Their Toxicity and Antileukemic Activity. Journal of Medicinal Chemistry, 58(4), 2015-2024. https://doi.org/10.1021/jm5019548

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title = "Improved Synthesis of N-Benzylaminoferrocene-Based Prodrugs and Evaluation of Their Toxicity and Antileukemic Activity",

abstract = "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.",

keywords = "chronic lymphocytic leukemia, aminoferrocene-based prodrugs, human tumor cells, cancer cell, oxidative stress, anticancer agents, hydrogen peroxide, mouse models, HL-60 Cells, in vitro",

author = "Steffen Daum and Chekhun, {Vasiliy F} and Todor, {Igor N} and Lukianova, {Natalia Yu} and Shvets, {Yulia V} and Leopold Sellner and Kerstin Putzker and Joe Lewis and Thorsten Zenz and {de Graaf}, {Inge A M} and Groothuis, {Geny M M} and Angela Casini and Oleksii Zozulia and Frank Hampel and Andriy Mokhir",

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doi = "10.1021/jm5019548",

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Daum, S, Chekhun, VF, Todor, IN, Lukianova, NY, Shvets, YV, Sellner, L, Putzker, K, Lewis, J, Zenz, T, de Graaf, IAM , Groothuis, GMM, Casini, A, Zozulia, O, Hampel, F & Mokhir, A 2015, 'Improved Synthesis of N-Benzylaminoferrocene-Based Prodrugs and Evaluation of Their Toxicity and Antileukemic Activity', Journal of Medicinal Chemistry, vol. 58, no. 4, pp. 2015-2024. https://doi.org/10.1021/jm5019548

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T1 - Improved Synthesis of N-Benzylaminoferrocene-Based Prodrugs and Evaluation of Their Toxicity and Antileukemic Activity

AU - Daum, Steffen

AU - Chekhun, Vasiliy F

AU - Todor, Igor N

AU - Lukianova, Natalia Yu

AU - Shvets, Yulia V

AU - Sellner, Leopold

AU - Putzker, Kerstin

AU - Lewis, Joe

AU - Zenz, Thorsten

AU - de Graaf, Inge A M

AU - Groothuis, Geny M M

AU - Casini, Angela

AU - Zozulia, Oleksii

AU - Hampel, Frank

AU - Mokhir, Andriy

PY - 2015/2/9

Y1 - 2015/2/9

N2 - 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.

AB - 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.

KW - chronic lymphocytic leukemia

KW - aminoferrocene-based prodrugs

KW - human tumor cells

KW - cancer cell

KW - oxidative stress

KW - anticancer agents

KW - hydrogen peroxide

KW - mouse models

KW - HL-60 Cells

KW - in vitro

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DO - 10.1021/jm5019548

M3 - Article

C2 - 25633601

VL - 58

SP - 2015

EP - 2024

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 4

ER -

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

Abstract

Keywords

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Datasets

CCDC 1011896: Experimental Crystal Structure Determination

Cite this