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

被引：61
作者：
Byun, Y
Yan, JH
Al-Madhoun, AS
Johnsamuel, J
Yang, WL
Barth, RF
Eriksson, S
Tjarks, W [1 ]
机构：
[1] Ohio State Univ, Dept Med Chem & Pharmacognosy, Coll Pharm, Columbus, OH 43210 USA
[2] Ohio State Univ, Dept Pathol, Columbus, OH 43210 USA
[3] Swedish Univ Agr Sci, Dept Mol Biosci, Ctr Biomed, SE-75123 Uppsala, Sweden
来源：
JOURNAL OF MEDICINAL CHEMISTRY | 2005年 / 48卷 / 04期
关键词：
D O I：
10.1021/jm0491896
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
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 NH2-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-m-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.
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页码：1188 / 1198
页数：11
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