Synthesis and biological evaluation of neutral and zwitterionic 3-carboranyl thymidine analogues for boron neutron capture therapy

Youngjoo Byun, Junhua Yan, Ashraf S. Al-Madhoun, Jayaseharan Johnsamuel, Weilian Yang, Rolf F. Barth, Staffan Eriksson, Werner Tjarks

Research output: Contribution to journalArticle

Abstract

Novel 3-carboranyl thymidine analogues (3CTAs) were synthesized as potential boron delivery agents for boron neutron capture therapy (BNCT). This library includes six zwitterionic NH3+-nido-m-carborane- substituted thymidine analogues (Thds) and the corresponding neutral NH 2-closo-m-carborane-substituted counterparts. All compounds of this library were good substrates for recombinant human thymidine kinase 1 (TK1) with phosphorylation rates up to 89% relative to that of Thd. One compound out of this library, 3-[3-(7-NH3+-nido-m-carboran-1-yl)propan-1- yl]thymidine (19b), showed selective retention in TK1-expressing murine L929 wild-type tumors versus L929 TK1 (-) tumors in biodistribution studies. The biological evaluation of the zwitterionic NH3+-nido-/n- carborane-substituted Thds indicated improved aqueous solubility and similar or even superior potential as BNCT agents compared with different classes of 3CTAs (Cancer Res. 2004, 64, 6280-6286 and 6287-6295). To complete previous structure-activity relationship (SAR) studies, 3-[(closo-o-carboranyl)methyl] thymidine (4) was also synthesized and evaluated.

Original languageEnglish (US)
Pages (from-to)1188-1198
Number of pages11
JournalJournal of Medicinal Chemistry
Volume48
Issue number4
DOIs
StatePublished - Feb 24 2005
Externally publishedYes

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Boron Neutron Capture Therapy
Boron
Thymidine
Neutrons
Libraries
Tumors
Neoplasms
Phosphorylation
Structure-Activity Relationship
Solubility
Substrates
thymidine kinase 1

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Synthesis and biological evaluation of neutral and zwitterionic 3-carboranyl thymidine analogues for boron neutron capture therapy. / Byun, Youngjoo; Yan, Junhua; Al-Madhoun, Ashraf S.; Johnsamuel, Jayaseharan; Yang, Weilian; Barth, Rolf F.; Eriksson, Staffan; Tjarks, Werner.

In: Journal of Medicinal Chemistry, Vol. 48, No. 4, 24.02.2005, p. 1188-1198.

Research output: Contribution to journalArticle

Byun, Y, Yan, J, Al-Madhoun, AS, Johnsamuel, J, Yang, W, Barth, RF, Eriksson, S & Tjarks, W 2005, 'Synthesis and biological evaluation of neutral and zwitterionic 3-carboranyl thymidine analogues for boron neutron capture therapy', Journal of Medicinal Chemistry, vol. 48, no. 4, pp. 1188-1198. https://doi.org/10.1021/jm0491896
Byun, Youngjoo ; Yan, Junhua ; Al-Madhoun, Ashraf S. ; Johnsamuel, Jayaseharan ; Yang, Weilian ; Barth, Rolf F. ; Eriksson, Staffan ; Tjarks, Werner. / Synthesis and biological evaluation of neutral and zwitterionic 3-carboranyl thymidine analogues for boron neutron capture therapy. In: Journal of Medicinal Chemistry. 2005 ; Vol. 48, No. 4. pp. 1188-1198.
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