Data from Evaluation of Human Thymidine Kinase 1 Substrates as New Candidates for Boron Neutron Capture Therapy

Abstract

<div>Abstract<p>Thymidine analogs containing <i>o</i>-carboranylalkyl groups at the 3-position were screened as potential substrates for human thymidine kinase 1 (TK1), an enzyme that is selectively expressed in a variety of rapidly proliferating cells, including tumor cells. On the basis of previous studies, 12 of these were identified as potential delivery agents for boron neutron capture therapy, a therapeutic method used for the treatment of high-grade brain tumors. Compound 4 with a pentylene spacer between the <i>o</i>-carborane cage and the thymidine scaffold and compound 10, which has an additional dihydroxypropyl substituent at the <i>o</i>-carborane cage, were the best substrates for TK1 with <i>k<sub>cat</sub>/K</i><sub>m</sub> values of 27% and 36% relative to that of thymidine, respectively. These compounds showed partial competitive inhibition for thymidine phosphorylation by TK1. Neither compound was a substrate of recombinant human thymidine phosphorylase nor were their respective 5′-monophosphates substrates of 5′-deoxynucleotidase 1, thereby indicating potential <i>in vivo</i> stability. The octanol/water partition coefficient for compound 10 was 2.09, suggesting that it has excellent physiochemical properties for crossing the blood brain barrier and penetrating brain tissue. The <i>in vitro</i> cytotoxic effect of the 12 analogs was moderate to low in mammalian cell cultures with IC<sub>50</sub> values between 10 and 160 μmol/L. Compounds 4 and 10 were taken up selectively and retained by the murine fibroblast L929 cell line, in contrast to its TK1-deficient variant. These findings suggest that compound 10 is a promising candidate for selective delivery of boron-10 to malignant cells, and additional in vivo studies are planned to evaluate it for boron neutron capture therapy of brain tumors.</p></div>