Aminoferrocene-Based Prodrugs and Their Effects on Human Normal and Cancer Cells as Well as Bacterial Cells

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• 作者：Paul Marzenell ; Helen Hagen ; Leopold Sellner ; Thorsten Zenz ; Ruta Grinyte ; Valeri Pavlov ; Steffen Daum ; Andriy Mokhir
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：September 12, 2013
• 年：2013
• 卷：56
• 期：17
• 页码：6935-6944
• 全文大小：383K
• 年卷期：v.56,no.17(September 12, 2013)
• ISSN：1520-4804

文摘

Aminoferrocene-based prodrugs are activated under cancer-specific conditions (high concentration of reactive oxygen species, ROS) with the formation of glutathione scavengers (p-quinone methide) and ROS-generating iron complexes. Herein, we explored three structural modifications of these prodrugs in an attempt to improve their properties: (a) the attachment of a 鈭扖OOH function to the ferrocene fragment leads to the improvement of water solubility and reactivity in vitro but also decreases cell-membrane permeability and biological activity, (b) the alkylation of the N-benzyl residue does not show any significant affect, and (c) the attachment of the second arylboronic acid fragment improves the toxicity (IC₅₀) of the prodrugs toward human promyelocytic leukemia cells (HL-60) from 52 to 12 渭M. Finally, we demonstrated that the prodrugs are active against primary chronic lymphocytic leukemia (CLL) cells, with the best compounds exhibiting an IC₅₀ value of 1.5 渭M. The most active compounds were found to not affect mononuclear cells and representative bacterial cells.