Hydrophilically enhanced 3-carboranyl thymidine analogues (3CTAs) for boron neutron capture therapy (BNCT) of cancer

Five novel 3-carboranyl thymidine analogues (3CTAs) were designed and synthesized for boron neutron capture therapy (BNCT) of cancer. Phosphorylation of all five 3CTAs was catalyzed by recombinant human thymidine kinase (hTK1) using adenosine triphosphate (ATP) as the phosphate donor. The obtained phosphorylation rates ranged from 4% to 64.5% relative to that of thymidine. The compound with the most favorable hTK1 binding properties had a kcat/KM value of 57.4% relative to that of thymidine and an IC50 of inhibition of thymidine phosphorylation by hTK1 of 92 μM. Among the five synthesized 3CTAs, this agent had also the overall most favorable physicochemical properties. Therefore, it may have the potential to replace N5–2OH, the current lead 3CTA, in preclinical studies. An in silico model for the binding of this compound to hTK1 was developed.

Several 3-carboranyl thymidine analogues (3CTAs), all of which are containing hydrophilicity-enhancing groups, were synthesized and their biochemical and physicochemical properties were evaluated.Figure optionsDownload as PowerPoint slide