Synthesis and evaluation of thymidine kinase 1-targeting carboranyl pyrimidine nucleoside analogues for boron neutron capture therapy of cancer

摘要

A library of sixteen 2^nd generation amino- and amido-substituted carboranyl pyrimidine nucleoside analogues, designed as substrates and inhibitors of thymidine kinase 1 (TK1) for potential use in boron neutron capture therapy (BNCT) of cancer, was synthesized and evaluated in enzyme kinetic-, enzyme inhibition-, metabolomic-, and biodistribution studies. One of these 2^nd generation carboranyl pyrimidine nucleoside analogues (>YB18A [>3]), having an amino group directly attached to a meta-carborane cage tethered via ethylene spacer to the 3-position of thymidine, was approximately 3–4 times superior as a substrate and inhibitor of hTK1 than >N5-2OH (2), a 1^st generation carboranyl pyrimidine nucleoside analogue. Both >2 and >3 appeared to be 5′-monophosphorylated in TK1(+) RG2 cells, both in vitro and in vivo. Biodistribution studies in rats bearing intracerebral RG2 glioma resulted in selective tumor uptake of >3 with an intratumoral concentration that was approximately 4 times higher than that of >2. The obtained results significantly advance the understanding of the binding interactions between TK1 and carboranyl pyrimidine nucleoside analogues and will profoundly impact future design strategies for these agents.