Design of Carborane‐Based Hypoxia‐Inducible Factor Inhibitors

Research on 3-carboranyl thymidine analogs (3CTAs) has been initiated about 20 years ago. These compounds were designed as boron delivery agents for boron neutron capture therapy (BNCT) of brain tumors. The tumor selective uptake of these compounds presumably is caused by thymidine kinase 1 (TK1)-mediated trapping via 5′-monophosphorylation. Overall, a library of about seventy 3CTAs was synthesized. A critical perspective of design concepts, synthetic strategies, enzymatic and metabolic properties, cellular influx and efflux mechanisms, toxicological features, in vitro uptake and in vivo biodistribution characteristics, efficacy in preclinical BNCT studies with tumor bearing rodents, and potential non-BNCT applications for 3CTAs is given in this review.