Download The Drugs - chem4520

The Drugs
Laura Duffin
Introduction
• Four different series of compounds were
synthesized
• Each compound had a phenanthridinium DNAtargeting moiety at one end
• Active compounds also contained an electron
affinic heteroaromatic moiety at the other end
Series One
• First series of compounds was prepared to test
whether targeting to DNA changed the
relationship between radiosensitizing ability and
electron affinity
Series Two
• Second series examined the length of the spacer
arm separating the DNA binding group from the
active portion of the drug
Series Three
• Third series was designed to examine the
properties of the DNA-binding group alone
Series Four
• Fourth series, non-radiosensitizing bioreductive
agent, and the non-bioreductive,
radiosensitizing nitrotriazole moiety
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
Drugs Used
• 2-Nitroimidazoles
• 1-(2-Methyl-5-nitro-1H-imidazolyl)-2bromoethane
• 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-1,4dioxides
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
1-(2-Methyl-5-nitro-1H-imidazolyl)-2bromoethane
• 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
4- and 5-Nitroimidazoles
• It was found that 4-nitroimidazoles would be the
favoured tautomer in polar solvents and 5nitroimidazole in the gas phase
• Low yields were produced for both due to the
decomposition caused by longer reflux periods
5-Nitrofurans
• Convenient attachment of a spacer arm to the 5nitro-2-furoic acid
• Phenanthridine was then added to the arm
• Good yields
3-Nitropyrroles
• Several routes of synthesis were tried but all of
them showed unimpressive yields
Summary of Yields
Summary of Yields