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5-Halogeno-6-amino-2′-deoxyuridines were synthesized from 2′-deoxyuridine as potential thymidine phosphorylase (ThdPase) inhibitors. Among the compounds synthesized, 5-bromo-6-amino-2′-deoxyuridine (6) and 5-iodo-6-amino-2′-deoxyuridine (9) were found to inhibit ThdPase activity with IC50 values of 1.3 μM and 6.5 μM, respectively. In vitro cell culture studies showed that compound (6) can significantly enhance the cytotoxic effects of 5-fluoro-2′-deoxyuridine against a human colon cancer HCT-8 cell line.

A series of 5′-halogenated formycins, including the chloro-, bromo- and iodo- derivatives, were synthesized. These compounds are competitive inhibitors of 5′-deoxy-5′-methylthioadenosine phosphorylase (MTAPase) with Ki values in the range of 10−7 M, making them the most potent inhibitors of MTAPase reported to date. These compounds protect cells from the growth-inhibitory action of 5′-halogenated adenosines, which must be activated by MTAPase. The syntheses of 5′-halogenated formycin B derivatives, which inhibit purine nucleoside phosphorylase, are also described.

Furanosyl analogs of BAU (5-benzylacyclouridine) and BBAU (5-benzyloxybenzylacyclouridine), two potent inhibitors of uridine phosphorylase, were synthesized and evaluated as potential cancer chemotherapeutic agents. The analogs included ribosides, 2,2′-anhydro nucleosides, arabinosides and deoxyribosides. The anhydrouridine intermediates were potent inhibitors of uridine phosphorylase and good potentiators of FdUrd activity in human tumor cells in culture.

Hydroxymethyl analogs of 5-benzylacyclouridine (BAU) and 5-benzyloxybenzylacyclouridine (BBAU) were synthesized by the condensation of appropriately blocked 2-(chloromethyl)glycerols with substituted 2, 4-dimethoxypyrimidines. The HM derivatives were found to be potent inhibitors of the enzyme uridine phosphorylase and to potentiate significantly the growth-inhibiting action of FdUrd in cell culture.