| Abstract
| - Novel 3-carboranyl thymidine analogues (3CTAs) were synthesized as potential boron deliveryagents 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 substratesfor recombinant human thymidine kinase 1 (TK1) with phosphorylation rates up to 89% relativeto 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-typetumors versus L929 TK1 (−) tumors in biodistribution studies. The biological evaluation ofthe zwitterionic NH3+-nido-m-carborane-substituted Thds indicated improved aqueous solubilityand 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−activityrelationship (SAR) studies, 3-[(closo-o-carboranyl)methyl]thymidine (4) was also synthesizedand evaluated.
|
