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

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

Research output: Contribution to journalArticle

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 (US)
Pages (from-to)4769-4781
Number of pages13
JournalBioorganic and Medicinal Chemistry
Volume12
Issue number18
DOIs
StatePublished - Sep 15 2004
Externally publishedYes

Fingerprint

Thymidine
Structural properties
Libraries
Boron Neutron Capture Therapy
Phosphorylation
Boron
Substrates
Scaffolds
Isomers
Assays
Catalytic Domain
Neutrons

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

Cite this

Synthesis of ethyleneoxide modified 3-carboranyl thymidine analogues and evaluation of their biochemical, physicochemical, and structural properties. / Johnsamuel, Jayaseharan; Lakhi, Nisha; Al-Madhoun, Ashraf S.; Byun, Youngjoo; Yan, Junhua; Eriksson, Staffan; Tjarks, Werner.

In: Bioorganic and Medicinal Chemistry, Vol. 12, No. 18, 15.09.2004, p. 4769-4781.

Research output: Contribution to journalArticle

Johnsamuel, Jayaseharan ; Lakhi, Nisha ; Al-Madhoun, Ashraf S. ; Byun, Youngjoo ; Yan, Junhua ; Eriksson, Staffan ; Tjarks, Werner. / Synthesis of ethyleneoxide modified 3-carboranyl thymidine analogues and evaluation of their biochemical, physicochemical, and structural properties. In: Bioorganic and Medicinal Chemistry. 2004 ; Vol. 12, No. 18. pp. 4769-4781.
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AU - Byun, Youngjoo

AU - Yan, Junhua

AU - Eriksson, Staffan

AU - Tjarks, Werner

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AB - 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.

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