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

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.

• Authors: 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
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 100 Pg. 197-209 (Jul 15 2015) ISSN: 1768-3254 [Electronic] France
• PMID: 26087030 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Chemical References

• Boron Compounds
• Protein Kinase Inhibitors
• Pyrimidine Nucleosides
• Thymidine Kinase
• thymidine kinase 1

Topics

• Animals
• Boron Compounds (therapeutic use)
• Boron Neutron Capture Therapy
• Cell Line, Tumor
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• Glioma (metabolism, radiotherapy)
• Molecular Structure
• Protein Kinase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Pyrimidine Nucleosides (chemical synthesis, chemistry, pharmacology)
• Rats
• Structure-Activity Relationship
• Thymidine Kinase (antagonists & inhibitors, metabolism)