The overall goal of the Biochemical Pharmacology program will be the further investigation of mechanistic hypotheses for selective toxicity to TdT positive cells, attempting to define, at the molecular level, how selective toxicity occurs. We will begin with the further study of dideoxyadenosine, the prototypic inhibitor from whose study much of our mechanistic hypotheses have sprung. We will then proceed to similar investigations of 2-chlorodideoxyadenosine, a considerably more potent analog already uncovered as part of our medicinal chemistry program. As further candidate compounds are synthesized, they will be screened as part of the cell biology program for selective toxicity to TdT positive cells in culture and in vivo. Those that show promise, i.e. greater potency will be fully investigated with respect to their biochemical pharmacology. Specific areas to be investigated include: 1. Determination of the degree of conversion of candidate compounds to active metabolites, their 5' triphosphates. 2. Determination of the kinetics of utilization by TdT and other cellular polymerases. 3. Determination of sensitivity toward removal by 3'-5' exonuclease activities. 4. Investigation of effects on ribonucleotide and deoxyribonucleotide pools. 5. Measurement of the degree of misincorporation into cellular DNA.
| Kim, H O; Schinazi, R F; Nampalli, S et al. (1993) 1,3-dioxolanylpurine nucleosides (2R,4R) and (2R,4S) with selective anti-HIV-1 activity in human lymphocytes. J Med Chem 36:30-7 |
| Kim, H O; Ahn, S K; Alves, A J et al. (1992) Asymmetric synthesis of 1,3-dioxolane-pyrimidine nucleosides and their anti-HIV activity. J Med Chem 35:1987-95 |
