Aminoferrocene-based prodrugs and their effects on human normal and cancer cells as well as bacterial cells.
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.
Department of Chemistry and Pharmacy, Friedrich-Alexander-University of Erlangen-Nürnberg , Organic Chemistry II, Henkestr. 42, 91054 Erlangen, Germany.
Paul
P
Marzenell
Helen
H
Hagen
Leopold
L
Sellner
Thorsten
T
Zenz
Ruta
R
Grinyte
Valeri
V
Pavlov
Steffen
S
Daum
Andriy
A
Mokhir
D001419:Bacteria / Q000187:drug effects*; D002460:Cell Line; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects; D005296:Ferrous Compounds / Q000737:chemistry*; D006801:Humans; D000075163:Metallocenes; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology*
D005296:Ferrous Compounds; D000075163:Metallocenes; D011355:Prodrugs; C004998:ferrocene