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

Hitesh K. Agarwal, Ahmed Khalil, Keisuke Ishita, Weilian Yang, Robin J. Nakkula, Lai Chu Wu, Tehane Ali, Rohit Tiwari, Youngjoo Byun, Rolf F. Barth, Werner Tjarks

Research output: Contribution to journalArticle

Abstract

Abstract A library of sixteen 2nd generation amino- and amido-substituted carboranyl pyrimidine nucleoside analogs, 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 2nd generation carboranyl pyrimidine nucleoside analogs (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 1st generation carboranyl pyrimidine nucleoside analog. 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 analogs and will profoundly impact future design strategies for these agents.

Original languageEnglish (US)
Article number7921
Pages (from-to)197-209
Number of pages13
JournalEuropean Journal of Medicinal Chemistry
Volume100
DOIs
StatePublished - Jun 16 2015
Externally publishedYes

Keywords

  • Boron neutron capture therapy (BNCT)
  • Carborane
  • Carboranyl pyrimidine nucleoside analog
  • Thymidine kinase 1 (TK1)

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Pharmacology

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    Agarwal, H. K., Khalil, A., Ishita, K., Yang, W., Nakkula, R. J., Wu, L. C., Ali, T., Tiwari, R., Byun, Y., Barth, R. F., & Tjarks, W. (2015). Synthesis and evaluation of thymidine kinase 1-targeting carboranyl pyrimidine nucleoside analogs for boron neutron capture therapy of cancer. European Journal of Medicinal Chemistry, 100, 197-209. [7921]. https://doi.org/10.1016/j.ejmech.2015.05.042