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Structure-Activity Relationships of DNA-Targeted Hypoxic Cell Radiosensitizers and Cytotoxins

Structure-Activity Relationships of DNA-Targeted Hypoxic Cell Radiosensitizers and Cytotoxins. Dr. Jan Matejovic Presented by: Allan Nixon. C.1 One Electron Reduction Potentials at pH 7 – E 1 7. One electron reduction potentials are determined by pulse radiolysis

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Structure-Activity Relationships of DNA-Targeted Hypoxic Cell Radiosensitizers and Cytotoxins

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  1. Structure-Activity Relationships of DNA-Targeted Hypoxic Cell Radiosensitizers and Cytotoxins Dr. Jan Matejovic Presented by: Allan Nixon

  2. C.1 One Electron Reduction Potentials at pH 7 – E17 • One electron reduction potentials are determined by pulse radiolysis • Solution with drug is pulsed (30ns) with 4MeV electrons • Equilibrium observed with time resolved spectrophotometry • The radical that is formed gives up an electron to an indicator • Change in absorbance is due to this process

  3. C.1 One Electron Reduction Potentials at pH 7 – E17 • The equilibrium constant can be determined with this data • Allows E17 to be determined for the various compounds being studied

  4. Effects of E17 on Toxicity • No correlation between aerobic toxicity and one electron potentials at pH 7 was observed for the DNA-targeted hypoxic cell cytotoxins • This is not the case for untargeted hypoxic cell specific cytotoxins • As E17 increases toxicity increases under hypoxic conditions

  5. E17and Radiosensitization • As E17increases so does radiosensitization • FEP-2, with the largest value of E17shows a decrease in radiosensitization (outlier) • Compounds that are so electron affinic may not be suitable for target DNA for radiosensitization • In general the DNA-targeted compounds are better radiosensitizers than the un-targeted compounds

  6. C.2 Partition Coefficients • Partition coefficients measured using 1-octanol and phophate buffer-saline • Used to determine lipophilicity • The greater the value, the more lipophilic the compound • Lipophilicity is important to cellular uptake • Crossing membranes

  7. C.2 Partition Coefficients • Important factor wrt aerobic toxicity • Unlike E17 • Decreased lipophilicity is desired • Compounds unable to cross cellular membranes • Blood-brain barrier etc. • Results in decreased aerobic toxicity • 2-NLP-4 showed a low partition coefficient but still maintained good hypoxic and radiosensitizing capabilities

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