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

Abstract

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 -COOH 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 μM. 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 μM. The most active compounds were found to not affect mononuclear cells and representative bacterial cells.

Induction of Cytotoxicity through Photorelease of Aminoferrocene

“…Figure S3) and in contrast to 3 (Figure S19), the multiplet in that region expands down to 4.7 ppm. This indicates that attachment of Fc-NH 2 to 3 resulted in the same electronic changes due to the carbamate bond formation.…”

“…1,2 The release of iron ions played in fact an important role in the cytotoxicity mechanism of Mokhir's complexes as catalysts for ROS generation. 1,2 To verify if the photo-decomposition of 5, 6 and Fc-NH 2 resulted in the same products, the iron release upon light irradiation was monitored in PBS buffer (pH=7.4).…”

“…1 Interestingly, the cytotoxicity of the aminoferrocene-based prodrug candidates correlates with their efficiency of ROS production in cells, showing that the aminoferrocene moiety heavily contributes to the observed cytotoxicity. 1,2 A similar concept has also been implemented by the Jacob group using ROS-activated organochalcogen compounds catalyzing ROS generation.…”

Synthesis, Structure Characterization and Antitumor Activity Study of a New Iron(III) Complex of 5-Nitro-8-hydroxylquinoline (HNOQ)

“…This is closely related to the redox activity of Fe(III)/Fe(II), which may contribute to the potential ROS generation in the cellular level. [29][30][31] In addition, according to the ESI-MS analysis for 1, both chlorides might dissociate as leaving groups in aqueous solution, which led to the changes on the charged status of 1. The conductivity experiment was thus carried out for further assessment.…”

Phosphino‐amine (PN) Ligands for Rapid Catalyst Discovery in Ruthenium‐Catalyzed Hydrogen‐Borrowing Alkylation of Anilines: A Proof of Principle

“…Our interest stemmed from the promise shown by aminoferrocenes as prodrug candidates, including their toxicity in human promyelocytic leukemia (HL-60) and human glioblastoma-astrocytoma (U373). [22] [a] In closed tubes [b] Yields of isolated product.…”