Targeting radiosensitizers to DNA by attachment of an intercalating group: Nitroimidazole-linked phenanthridines

Journal Article · Mon Jul 01 00:00:00 EDT 1991 · Radiation Research; (United States)

DOI:https://doi.org/10.2307/3578092· OSTI ID:5389604

Cowan, D S; Panicucci, R; McClelland, R A; Rauth, A M ^[1]

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1. Experimental Therapeutics Division, Ontario Cancer Institute, University of Toronto (Canada)

The nitroimidazole-linked phenanthridine series of compounds (NLP-1, 2, and 3) were synthesized under the assumption that it should be possible to enhance the molar efficiency of 2-nitroimidazoles as hypoxic cell radiosensitizers and cytotoxins by targeting them to their likely site of action, DNA. The targeting group chosen was the phenanthridine moiety, the major component of the classical DNA intercalating compound, ethidium bromide. The sole difference between the compounds is the length of the hydrocarbon chain linking the nitroimidazole to the phenanthridine. The phenanthridine group with a three-carbon side chain, P-1, was also synthesized to allow studies on the effect of the targeting group by itself. The ability of the compounds to bind to DNA is inversely proportional to their linker chain length with binding constant values ranging from approximately 1 {times} 10(5) mol-1 for NLP-2 to 6 {times} 10(5) mol-1 for NLP-3. The NLP compounds show selective toxicity to hypoxic cells at 37 degrees C at external drug concentrations 10-40 times lower than would be required for untargeted 2-nitroimidazoles such as misonidazole in vitro. Toxicity to both hypoxic and aerobic cells is dependent on the linker chain: the shorter the chain, the greater the toxicity. In addition, the NLP compounds radiosensitize hypoxic cells at external drug concentrations as low as 0.05 mM with almost the full oxygen effect being observed at a concentration of 0.5 mM. These concentrations are 10-100 times lower than would be required for similar radiosensitization using misonidazole. Radiosensitizing ability is independent of linker chain length. The present compounds represent prototypes for further studies of the efficacy and mechanism of action of 2-nitroimidazoles targeted to DNA by linkage to an intercalating group.

• OSTI ID: 5389604
• Journal Information: Radiation Research; (United States), Journal Name: Radiation Research; (United States) Vol. 127:1; ISSN RAREA; ISSN 0033-7587
• Country of Publication: United States
• Language: English

Related Subjects

560152* -- Radiation Effects on Animals-- Animals
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ANIMALS
ANOXIA
CHEMICAL PREPARATION
DNA
DRUGS
EFFICIENCY
MAMMALS
NUCLEIC ACIDS
ORGANIC COMPOUNDS
RADIOSENSITIZERS
RATS
RODENTS
STRUCTURE-ACTIVITY RELATIONSHIPS
SYNTHESIS
TOXICITY
VERTEBRATES