Structure-Activity Relationships of DNA-Targeted Hypoxic Cell

Radiosensitizers and CytotoxinsDr. Jan Matejovic

Presented by: Allan Nixon

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

C.1 One Electron Reduction Potentials at pH 7 – E1

7

The equilibrium constant can be determined with this data

Allows E17 to be determined for the various

compounds being studied

C.1 One Electron Reduction Potentials at pH 7 – E1

7

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

Effects of E17 on Toxicity

As E17 increases so does radiosensitization

FEP-2, with the largest value of E17 shows 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

E17 and Radiosensitization

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

C.2 Partition Coefficients

Important factor wrt aerobic toxicity◦ Unlike E1

7

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

C.2 Partition Coefficients