Boron neutron capture therapy (BNCT) is a non-invasive potential treatment for locally invasive malignant brain tumors. It involves the use drugs, also called boron delivery agents, that contain the non-radioactive isotope boron-10 (10B) which has a high propensity to capture slow neutrons. Neutron beam irradiation of the site to which 10B has been introduced results in the degradation of the boron delivery agent which subsequently emits high energy particles that kill the cancer cells. One approach to the design of biocompatible 10B-containing agents that might have therapeutic efficacy for this treatment is to incorporate 10B into scaffolds found in nature, for example, amino acids, in order to introduce boron into molecules that are likely to be taken up into the cells. Towards this goal, the boron-rich moiety m-carborane was appended to the amino acid cysteine to form 2-acetamido-3-(1,7-dicarba-closo-dodecacarboranyl-1-thio)propanoic acid. The installation of the carborane moiety into the cysteine scaffold improved the bioavailability of the boron delivery agent, as demonstrated by its rapid uptake into U87 neuronal cells within 5 minutes of exposure, and intracellular retention of the compound after 48 h, as indicated by fluorescence microscopy. A cytostatic effect was observed at 1 μM to 1000 μM relative to the control, while no change was observed at 1 μM to 0.01 μM. Microarray studies revealed that exposure of cells to the compound resulted in the downregulation of several genes associated with cell cycle. These results were validated by qPCR studies. The percentage of cells in S phase was substantially reduced compared to the control, indicating that cellular DNA synthesis was adversely affected. Although the compound was designed for BNCT, the distinct gene regulation results and the low systemic toxicity observed in this study suggest the possibility that this compound might be therapeutic in the absence of applied radiation

Synthesis and biological effects of a novel carborane-based α-amino acid for the treatment of glioblastoma

255th National Meeting (2018)

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