The long-term objective of this research project is to develop novel types of phosphoramidate anti tumor agents directed against specific cellular targets. Chemical mechanistic information will be utilized to guide the design, synthesis and evaluation of these new mechanism-based phosphoramidates.
Specific aims i nclude: 1) Design and synthesis of phosphoramidate analogs that undergo bioreductive activation and thus are targeted to hypoxic cells; 2) Design and synthesis of nucleoside phosphoramidate analogs that can function as prodrugs for nucleotide delivery or as irreversible enzyme inhibitors; 3) Design and synthesis of phosphoramidate analogs targeted to specific DNA sequences; 4) Evaluation of new agents both in vitro and in vivo against established tumor cell lines. Experiments to date have demonstrated that cytotoxic compounds can be prepared in each of these series. Antitumor evaluation will rely on the murine B16 system using a clonogenic assay in vitro and using regrowth delay and the lung metastasis assay in vivo. Hypoxia selective compounds will be evaluated in the HT-29 colon tumor system under aerobic and hypoxic conditions in vitro. Mass spectrometry will be required primarily for structural characterization of the synthetic products and for characterization of the covalent adducts formed between the drugs and their putative targets.
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