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

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

Research output: Contribution to journalArticlepeer-review

60 Citations (Scopus)

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
Pages (from-to)1188-1198
Number of pages11
JournalJournal of Medicinal Chemistry
Volume48
Issue number4
DOIs
Publication statusPublished - 24 Feb 2005

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