Synthesis and Biochemical Evaluation of 5-Tethered Boron-Containing Pyrimidine Nucleosides for BNCT

Abstract

In order for BNCT to be successful, a major need is the development of boron compounds, which penetrate the blood-brain barrier (BBB), target tumor cells selectively, and maintain a relatively high concentration of boron-10 in the tumor, ca. 30 ug/g of tumor tissue, vis-à-vis surrounding normal tissues. Boron-containing nucleosides that use a carrier-mediated transport process for penetrating the CNS and have the potential for becoming incorporated into proliferating cells may be useful agents for BNCT.¹ This fact led to the attempts to synthesize carborane-containing nucleoside derivatives. Yamamoto² and Schinazi³ have attached the carborane moiety to the 5-position on the pyrimidine nucleosides, either directly or through a bulky substituent. Unfortunately, these compounds are very poor substrates for nucleoside kinases, and are unlikely to demontrate the requisite biological activity. This may be due to the fact that having a bulky substituent, like the carborane moiety, attached directly on the 5-position may inhibit enzymatic conversion of the 5-carboranyl-2′-deoxyuridine to their corresponding nucleotides. The formation of the latter is a necessary precondition for the incorporation of such nucleotides into DNA.