The Drugs

1. The Drugs Laura Duffin

2. Introduction • Four different series of compounds were synthesized • Each compound had a phenanthridinium DNA-targeting moiety at one end • Active compounds also contained an electron affinicheteroaromatic moiety at the other end

3. Series One • First series of compounds was prepared to test whether targeting to DNA changed the relationship between radiosensitizing ability and electron affinity

4. Series Two • Second series examined the length of the spacer arm separating the DNA binding group from the active portion of the drug

5. Series Three • Third series was designed to examine the properties of the DNA-binding group alone

6. Series Four • Fourth series, non-radiosensitizingbioreductive agent, and the non-bioreductive, radiosensitizingnitrotriazolemoiety

7. Overall • Generally you tried to first attach an electrophilic spacer arm to the bioreduccible portion of the drug which was either purchased or synthesized from alicyclic precursors • Then functional group manipulation and phenanthridine was alkylated by the side chain

8. Drugs Used • 2-Nitroimidazoles • 1-(2-Methyl-5-nitro-1H-imidazolyl)-2-bromoethane • 4- and 5-Nitroimidazoles • 5-Nitrofurans • 3-Nitropyrroles • 1-Substituted-3- and 5-nitro-1,2,4-triazoles • N3-Substrituted-3-amino-1,2,4-triazine-1,4-dioxides

9. 2-Nitroimidazoles • Synthesis was tedious and expensive but could be scaled up to give the large quantities of the microbial agent required to make several different 2-nitroimidazole based compounds • Very good yield • The best yields and shorter reaction times were obtain when DMSO was used as a solvent

11. 1-(2-Methyl-5-nitro-1H-imidazolyl)-2-bromoethane • Using metronidazole treated with triphenylphosphine-Br2 in acetonitrile produced a yield of 95% but the triphenylphosphine could not be separated from the product using chromatography • Could have used extremely pyrophoric triethylphosphine to give a more easily separated oxide

13. 4- and 5-Nitroimidazoles • It was found that 4-nitroimidazoles would be the favoured tautomer in polar solvents and 5-nitroimidazole in the gas phase • Low yields were produced for both due to the decomposition caused by longer reflux periods

14. 5-Nitrofurans • Convenient attachment of a spacer arm to the 5-nitro-2-furoic acid • Phenanthridine was then added to the arm • Good yields

15. 3-Nitropyrroles • Several routes of synthesis were tried but all of them showed unimpressive yields

16. Summary of Yields

17. Summary of Yields