Synthesis of 5-(carboranylallkylmercapto)-2 '-deoxyuridines and 3-(carboranylalkyl)thymidines and their evaluation as substrates for human thymidine kinases 1 and 2

Derivatives of thymidine containing o-carboranylalkyl groups at the N-3 pos ition and derivatives of 2'-deoxyuridine containing o-carboranylalkylmercap to groups at the C-5 position were synthesized. The alkyl spacers consist o f 4-8 methylene units. The synthesis of the former compounds required 3-4 r eaction steps in up to 75% overall yield and that of the latter 9-10 reacti on steps with significantly lower overall yield. Derivatives of thymidine s ubstituted with carboranylalkyl substituents at the N-3 position and short spacers were phosphorylated by both recombinant and purified cytosolic thym idine kinase (TK1) to a relatively high degree. None of the tested 2'-deoxy uridine derivatives possessing carboranyl substituents at the C-5 position were phosphorylated by either recombinant or purified TK1. The amounts of p hosphorylation product detected for some of the C-5-substituted nucleosides with recombinant mitochondrial thymidine kinase (TK2) were low but signifi cant and decreased with increasing lengths of the alkyl spacer. The data ob tained in this study do not seem to support the tether concept applied in t he synthesis of the new C-5- and N-3-substituted carboranyl nucleosides int ended to reduce possible steric interference in the binding of carboranyl n ucleosides with deoxynucleoside kinases. Instead, it appeared that a closer proximity of the bulky carborane moiety to the nucleoside scaffold resulte d in better substrate characteristics.