Synthesis of a small library of 3-(carboranylalkyl)thymidines and their biological evaluation as substrates for human thymidine kinases 1 and 2

J Med Chem. 2002 Aug 29;45(18):4018-28. doi: 10.1021/jm020047q.


A small library consisting of two series of thymidine derivatives containing o-carboranylalkyl groups at the N-3 position was prepared. In both series, alkyl spacers of 2-7 methylene units were placed between the o-carborane cage and the thymidine scaffold. In one series, an additional dihydroxypropyl substituent was introduced at the second carbon atom of the carborane cage. In the series of N-3-substituted carboranyl thymidines without additional dihydroxypropyl substituent, three steps were required to obtain the target compounds in overall yields as high as 75%, while in the series of N-3-substituted carboranyl thymidines with additional dihydroxypropyl substituent, 9-10 steps were necessary with significantly lower overall yield. All target compounds were good substrates of human cytosolic thymidine kinase 1 while they were, if at all, poor substrates of the mitochondrial thymidine kinase 2. There was only a minor difference in phosphorylation rates between N-3-substituted carboranyl thymidines with additional dihydroxypropyl substituents with thymidine kinase 1 (range: 13-49% relative to thymidine) and their counterparts lacking this group (range: 11-57% relative to thymidine). Tether lengths of two and five methylene groups in both series gave the highest enzyme activities in the present study. A hypothesis for this result is presented.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Boron Compounds / chemical synthesis*
  • Boron Compounds / chemistry
  • Combinatorial Chemistry Techniques
  • Humans
  • Structure-Activity Relationship
  • Substrate Specificity
  • Thymidine / analogs & derivatives*
  • Thymidine / chemical synthesis*
  • Thymidine / chemistry
  • Thymidine Kinase / chemistry*


  • Boron Compounds
  • thymidine kinase 2
  • Thymidine Kinase
  • thymidine kinase 1
  • Thymidine