The goal of this study is to create molecular structures to facilitate the transport of biologically significant molecules across cell membranes. Specifically, we plan to focus on the problems of transporting nucleotides by linking them to molecules that are rapidly incorporated into cellular lipid bilayers. The problems to be solved include: 1) finding, through rational design and synthesis, amphiphilic structures that attach and anchor to the outer surface of a biological membrane, and as a consequence, simultaneously or subsequently push the nucleotide through the membrane; 2) finding the most effective linkage for attaching the nucleotide to the amphiphilic structure in order to maximize the lipophilicity of the environment around the phosphate group while at the same time facilitating cleavage to nucleotide within a cell. Initially a model membrane system will be developed to determine transport rates of 5 feet-AMP (or 5 feet-EpsilonAMP) derivatives modified to create a local lipophilic environment about the phosphate. Much of the exploratory chemistry will focus on crown-ether linked nucleotides. Once the optimum phosphate masking group is found and the best linkage to phosphorus determined a limited number of nucleoside-insertanes will be synthesized in order to test the overall concept. The development of an effective method to rapidly insert normally non-transportable nucleotides into cells could have profound implications for chemotherapy by nucleoside analogs.
| Bergstrom, D E; Abrahamson, J K; Chan, M Y (1991) Nucleoside and nucleotide transport through a model liquid membrane. Periodic-catastrophic transport of a novel amantadine phosphoramidate conjugate of 5'-AMP. Biochim Biophys Acta 1061:95-105 |
