Evaluation of Carboranyl 2′-Deoxyuridine Derivatives as Substrates for Human Thymidine Kinases 1 and 2

Cellular nucleoside kinases play a pivotal role in the use of nucleosides for cancer and antiviral therapy.1 For BNCT, the cytosolic thymidine kinase (TK1) may be a particularly important target enzyme. TK1 activity is present in proliferating cells but is virtually absent from all quiescent cells.2 Boron-containing thymidine derivatives, that are good substrates for TK1, may be entrapped in proliferating neoplastic cells after conversion to the monophosphate. Therefore, such agents may be excellent vehicles for the selective delivery of boron-10 to those compartments of a tumor consisting of viable cells. A substantial number of nucleosides modified with various boron moieties at different positions have been synthesized and evaluated biologically for use in BNCT.3 Some thymidine derivatives were found to be phosphorylated in vitro 4 and in phos-phoryl transfer assays with purified human thymidine kinases.5 In these experiments, the observed rates of phosphorylation were generally low compared to natural nucleosides and did not distinguish between phosphorylation by TK1 and mitochondr-ial thymidine kinase (TK2) which appears to be equally active in proliferating and non-proliferating cells, thus providing no basis for selective uptake of boronated nucleosides in tumor cells.6