Synthesis of 5-S-Alkylcarboranyl-2′-Deoxyuridines
Since glioma cells are more mitotically active than normal brain cells, they have an increased demand for nucleic acids to synthesize DNA. Several boronated nucleosides have been synthesized to take advantage of this differential to selectively target boron to brain tumors for treatment by BNCT.1 5-Methylmercapto-2′-deoxyuridine has been reported to be phosphorylated2 and incorporated into DNA3 at comparable, if not greater, levels than thymidine. On this basis, we have designed the 5-S-alkyl carboranyl deoxyuridines 1–5 (Figure 1). Our objective was to not only synthesize boron-containing nucleosides but compounds that would use the enzyme systems that act on the natural nucleoside, thymidine. If the nucleoside portion of these compounds undergoes normal cellular metabolism, a triphosphate will be produced that can ultimately become incorporated into the cell’s DNA. Such subcellular localization of boron within the cell’s nucleus would increase the RBE of the neutron capture reaction by at least two fold.4 The nucleosides 1–5 were designed with a long, flexible hydrocarbon tether between the carborane and nucleoside portions unlike other boronated nucleosides which have positioned the carborane immediately next to nucleoside component.1 The positioning of such bulky groups immediately attached to the nucleoside may interfere with proper binding to kinases, the enzymes that phosphorylate the nucleoside. Addition of the tether, however, projects the bulky boron moiety away from the nucleoside component thereby decreasing steric interference and allowing better binding. The concept of using a tether has proven useful in the application of affinity chromatography in which the binding of enzymes to substrates covalently linked to a solid support was increased when an appropriate tether length between the ligand and support matrix was used.5 The synthesis of 1–3 and a preliminary in vitro evaluation of 1 is presented in this paper. It is our objective to use the in vitro phosphorylation assay presented to direct our synthetic efforts. The assay also serves as a screening method to select the best nucleoside candidate for future cell culture studies and in vivo assays.
KeywordsThymidine Kinase Boron Neutron Capture Therapy Sodium Hydride Phosphorylation Assay Synthetic Effort
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- 1.I. M. Wyzlic, W. Tjarks, A. H. Soloway, A. K. M. Anisuzzaman, F.-G. Rong and R. F. Barth, Strategies for the Design and Synthesis of Boronated Nucleic Acid and Protein Components as Potential Delvery Agents for Neutron Capture Therapy, International Journal of Radiation Oncology, Biology, Physics 28: 1203–1213, 1994.Google Scholar