Synthesis of ethyleneoxide modified 3-carboranyl thymidine analogues and evaluation of their biochemical, physicochemical, and structural properties

Jayaseharan Johnsamuel, Nisha Lakhi, Ashraf Al Madhoun, Youngjoo Byun, Junhua Yan, Staffan Eriksson, Werner Tjarks

Research output: Contribution to journalArticlepeer-review

27 Citations (Scopus)

Abstract

A library of eleven 3-carboranyl thymidine analogues (3CTAs), all of which containing hydrophilic ethyleneoxide moieties, were synthesized and their biochemical and physicochemical properties were evaluated. Eleven 3-carboranyl thymidine analogues (3CTAs) containing highly hydrophilic and flexible ethyleneoxide moieties were synthesized as potential agents for boron neutron capture therapy (BNCT) and their biochemical and physicochemical properties were evaluated. Based on specific structural features, this library of 3CTAs was divided into three subgroups. The first group contained 3CTAs with 1-4 ethyleneoxide units between the thymidine (Thd) scaffold and a carborane cluster. The second group of 3CTAs contained a pentylene spacer between Thd and the carborane and 2-4 ethyleneoxide units additionally attached to the carborane cluster. The third group contained three 3CTAs all with pentylene spacers and four ethylene units but with different carborane cages. The ethyleneoxide modified 3CTAs were good substrates of thymidine kinase 1 (TK1) and poor substrates of human mitochondrial thymidine kinase 2 (TK2) as determined in phosphoryl transfer assays. In the first group of 3CTAs, all the compounds were efficiently phosphorylated regardless of varying spacer lengths (37-42% of the activity of Thd). The second group of 3CTAs was less effectively phosphorylated (17-26% of the activity of Thd) probably due to a less favorable sterical orientation of Thd within the active site of TK1 and/or an increased lipophilicity compared with the first group. In the third group of structural isomers, no significant differences in phosphorylation rates were observed (17-25%). A structure-function hypothesis explaining these results is presented.

Original languageEnglish
Pages (from-to)4769-4781
Number of pages13
JournalBioorganic and Medicinal Chemistry
Volume12
Issue number18
DOIs
Publication statusPublished - 15 Sep 2004

Keywords

  • 3-Carboranyl thymidine analogues (3CTAs)
  • Boron neutron capture therapy (BNCT)
  • Phosphorylation
  • Thymidine kinase 1
  • Thymidine kinase 2

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