1. Dr. Jan Matejovic Presented by: Allan Nixon
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 E71 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

5. Effects of E71 on Toxicity
As E71 increases, 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 E71 for 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 wrt aerobic 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