Boron neutron capture therapy (BNCT) is a binary therapeutic strategy for cancer treatment based on combination of cancer-specific drug containing … 10B and the radiation with thermal neutron. The boron neutron capture reaction generates α particles and lithium ions having destructive effect and short path lengths in 5~10 μm. Therefore, cancer cells containing 10B species are selectively destroyed without affecting healthy tissues. For the development of efficient BNCT agents, the following criteria must be satisfied: (i) low toxicity and a higher uptake in tumor tissue than health normal tissue; (ii) 10B has to be accumulated in tumor tissues, and be rapidly cleared from the blood and normal tissues; and (iii) the concentrations of boron inside or near tumor cells must be ≥ 109 10B atoms/cell (20−35 g 10B/gram of tumor tissue). To date, however, only two BNCT agents have been used as a clinically test compounds, sodium mercaptoborate (BSH) and L-4-boronophenylalanine (BPA). Although design and synthesis of various boron-containing analogues such as amino acids, biochemical precursors of nucleic acids, carbohydrates, amines, porphyrin derivatives and monoclonal antibodies, most of these agents do not satisfy the requirement for clinical application.
It is known that D-Glucose is taken up as the main carbon and energy source for cells via membrane-bound glucose transporters. Tumor cells metabolize D-glucose by anaerobic glycolysis and their rapid growth and proliferation require a drastic increase in D-glucose uptake and metabolite flux, known as the Warburg effect. It is also known that polyamines such as spermidine and spermine are crucial for chromatin structure maintenance, DNA replication and protein synthesis.
This background has prompted us to design and synthesize new BNCT agents based on glucose and macrocyclic polyamine scaffolds. First, 2-boryl-2-deoxy-D-glucose derivatives were designed and synthesized via the hydroboration of D-glucal and their cytotoxicity and cellular uptake activity to cancer cells were examined (Itoh, T. et al. Bioorg. Med. Chem. 2018, 26, 5922). Second, phenylboronic acid-pendant macrocyclic polyamine derivatives and their corresponding metal complexes were designed and synthesized and their cytotoxicity and intracellular uptake activity in cancer cells and BNCT effect were assessed (Kitamura, M. et al. Inorg. Chem. 2011, 50, 11568 and Ueda, H. et al. Submitted for publication). In this paper, these results will be reported.