Radiosensitizing and cytotoxic properties of DNA targeted phenanthridine-linked nitroheterocycles of varying electron affinities.
2-Nitroimidazoles targeted to DNA via intercalation have previously been shown to be as much as 10-100 times more efficient on a molar basis than the untargeted nitroimidazole, misonidazole, in vitro as hypoxic cell selective radiosensitizers and cytotoxins based on extracellular concentrations. In this work the effect of varying the nitroaromatic group has been examined through the preparation of a DNA-targeted 4-nitroimidazole (4-MeNLP-3), a 5-nitroimidazole (5-NLP-3) and a 5-nitrofuran (FEP-2) linked to phenanthridinium ions. With the previously synthesized 2-nitroimidazoles, this provides a series of DNA targeted compounds of varying electron affinity as well as structure at the nitroaromatic position. The present series of compounds was tested for partition coefficient, DNA binding ability, reduction potentials and in vitro radiosensitizing and cytotoxic abilities. The 4-nitro compound displays good radiosensitizing ability, with an SER of approximately 2, despite its low reduction potential, -551 mV. However, hypoxia selective toxicity is lost at the lower reduction potentials presumably due to redox-independent mechanisms. The results obtained indicate that targeting such compounds to DNA diminishes the dependency of radiosensitizing and cytotoxic properties on reduction potential and may allow significant uncoupling of toxicity from radiosensitizing ability.
Cowan
D S
DS
Experimental Therapeutics Division, Ontario Cancer Institute, University of Toronto, Canada.
Matejovic
J F
JF
Wardman
P
P
McClelland
R A
RA
Rauth
A M
AM
D000818:Animals; D016466:CHO Cells / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D006224:Cricetinae; D004247:DNA / Q000187:drug effects* / Q000528:radiation effects*; D004583:Electrons; D007364:Intercalating Agents / Q000633:toxicity*; D009593:Nitroimidazoles; D010617:Phenanthridines / Q000633:toxicity*; D011836:Radiation Tolerance; D011838:Radiation-Sensitizing Agents / Q000633:toxicity*
D007364:Intercalating Agents; D009593:Nitroimidazoles; D010617:Phenanthridines; D011838:Radiation-Sensitizing Agents; C059179:NLP 1; D004247:DNA