Design, Synthesis, and Biological Activity of Boron-Bearing Sugar Derivatives for Boron Neutron Capture Therapy (BNCT).

Radiotherapy is one of the conventional methods for the treatment of cancers. Boron neutron capture therapy (BNCT) has emerged as a promising and well-recognized modality for treating certain types of cancers. BNCT is a binary radiotherapy that largely depends on neutron beams and 10B carriers. Although an "ideal" boron carrier should fulfill multiple criteria, high tumor/normal tissue ratio (T/N > 5) and high tumor uptake of boron (>20 μg/g) are critically important. First-generation (boric acid and derivatives) and second-generation (BPA and BSH) boron carriers suffer from poor T/N and extremely high dose in clinical use (500 mg/kg and usually >30 g for each patient). Glucose transporter 1 (GLUT1) is overexpressed on the membrane surface of multiple tumors and is a potential target for third-generation boron carrier to achieve high T/N and high tumor uptake of boron. However, the boron-bearing sugar derivatives designed in the last few decades have suffered from suboptimal T/N values and significant cytotoxicity. In the present study, a total of two categories comprising 6 series (28 in total) of boron-bearing sugar derivatives were designed and synthesized and their cellular boron uptake, T/N, and cytotoxicity were evaluated. The structure-activity relationship (SAR) of these target compounds was analyzed, and one of the target compounds, B3, a phenyl C-mannoside with an o-carborane moiety, exhibited the best boron-carrying profile, which featured 10.6-fold higher boron uptake by the SCC-9 cell line and a largely improved T/N (3.3 for B3 vs. 1.4 for BPA) compared with the current clinical gold standard BPA. Therefore, the chemical structure of B3 represents a privileged candidate structure for the future design of "ideal" boron carriers for BNCT.