Synthesis and Biological Evaluation of Neutral and Zwitterionic 3-Carboranyl Thymidine Analogues for Boron Neutron Capture Therapy

Novel 3-carboranyl thymidine analogues (3CTAs) were synthesized as potential boron delivery agents for boron neutron capture therapy (BNCT). This library includes six zwitterionic NH<INF>3</INF>⁺-nido-m-carborane-substituted thymidine analogues (Thds) and the corresponding neutral NH<INF>2</INF>-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-NH<INF>3</INF>⁺-nido-m-carboran-1-yl)propan-1-yl]thymidine (<BO>19b</BO>), showed selective retention in TK1-expressing murine L929 wild-type tumors versus L929 TK1 (−) tumors in biodistribution studies. The biological evaluation of the zwitterionic NH<INF>3</INF>⁺-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. <BO>2004</BO>, 64, 6280−6286 and 6287−6295). To complete previous structure−activity relationship (SAR) studies, 3-[(closo-o-carboranyl)methyl]thymidine (<BO>4</BO>) was also synthesized and evaluated.