Regio-selective PEGylation of 14-deoxy-11,12-didehydroandrographolide and their biological evaluation

Poor water solubility limits the clinical use of 14-deoxy-11,12-didehydroandrographolide (DA). To develop a simple and efficient approach to improving water solubility of DA, polyethylene glycol methyl ether (mPEG350, average MW=350) as hydrophilic group is employed. Two PEGylated DA derivatives DA-1 (mPEG350 at C19-position) and DA-2 (mPEG350 at C3-position) are synthesized and evaluated to inhibit the cell proliferation of HepG-2 cells in vitro. As expected, the aqueous solubility of DA-1 and DA-2 is significantly improved (ca. 200 mg/mL, 25 °C), and both exhibit good partition coefficient (log P≥1.6). It is found that DA-1 shows tumor-inhibition activity and more than 60% cell inhibition is obtained.