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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 7 1. 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 – E71 • One electron reduction potentials are determined by pulse radiolysis • Solution with drug is pulsed (30ns) with 4MeV electrons • The radical that is formed gives up an electron to an indicator • Equilibrium observed with time resolved spectrophotometry • Change in absorbance is due to change in the concentration of the indicator

  3. C.1 One Electron Reduction Potentials at pH 7 – E71 • The equilibrium constant can be determined with this data • From the equilibrium constant E71 can be determined for the various compounds being studied

  4. Effects of E71on 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

  5. Effects of E71 on Toxicity • As E71increases, drug toxicity increases under hypoxic conditions

  6. E71 and Radiosensitization • As E71 increases so does radiosensitization • In general the DNA-targeted compounds (dashed line) are better radiosensitizers than the un-targeted compounds (solid line)

  7. E71 and Radiosensitization • FEP-2, with the largest value of E71for the DNA-targeted compounds shows a decrease in radiosensitization (outlier) • Compounds that are so electron affinic may not be suitable for targeting DNA for radiosensitization

  8. C.2 Partition Coefficients • Partition coefficient: a measure of the difference in solubility of a compound between two immiscible phases • In this study the partition coefficients (P*) were 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 non-polar membranes

  9. C.2 Partition Coefficients • Important factor wrtaerobic toxicity • Unlike E17 • Decreased lipophilicity is desired • Compounds unable to cross cellular membranes • Blood-brain barrier etc. • Results in decreased aerobic toxicity

  10. 2-NLP-4, A Standout Compound? • Low partition coefficient • Low chronic and acute aerobic toxicity • Good hypoxic toxicity • Good radiosensitizing capabilities

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