A phosphate prodrug of pyrazinib: Improved solubility and antiproliferative activity

Pyrazinib [(E)-2-(2-(pyrazin-2-yl)vinyl)phenol] is a novel small molecule with anti-angiogenic and anti-metabolic activity. It significantly enhances radiosensitivity in cellular models of oesophageal adenocarcinoma and is under development as a radiosensitizer. However, pyrazinib is limited by extremely poor aqueous solubility. To overcome this limitation, a phosphate prodrug of pyrazinib was synthesised. The aqueous solubility, partition co-efficient and stability of pyrazinib phosphate were determined by HPLC. Pyrazinib phosphate had 600-fold greater water solubility than pyrazinib. In agreement with this, the partition coefficient, LogP, was found to be higher for pyrazinib (1.53) than pyrazinib phosphate (-1.72). Both pyrazinib and its phosphate prodrug were stable in phosphate buffers of pH 4, 7.4 and 9 over 8 weeks. Pyrazinib phosphate was completely converted to pyrazinib by alkaline phosphatase in < 5 sec. The antiproliferative activity of pyrazinib phosphate in MCF-7 human breast cancer cells was significantly better than that of the parent compound. Pyrazinib phosphate successfully overcomes some of the physiochemical limitations of pyrazinib and will be further evaluated as a radiosensitizer for the treatment of oesophageal adenocarcinoma.