Synthesis and anti-inflammatory effects of a series of novel 9-O-substituted berberine derivatives

Berberine owns multiple pharmacological activities, especially anti-inflammatory activity. To enhance the anti-inflammatory therapeutic efficiency of berberine, a series of novel 9- O -substituted berberine derivatives ( 5a – 5d ) were synthesized and their anti-inflammatory activities were evaluated. 13 C-NMR, 1 H-NMR, IR and high resolution mass spectrum (HRMS) results indicated that these derivatives were successfully synthesized. The xylene-induced inflammatory mice model demonstrated that these derivatives showed dose-dependent inhibition of ear inflammatory swelling. Comparing to berberine, ibuprofen and naproxen-modified berberine derivatives enhanced anti-inflammatory activities, while aspirin and nicotinic acid-modified berberine derivatives showed lower anti-inflammatory effects at the same dosages. This could be attributed to the enhanced inhibition of secretion of cytokines, including interleukin-6 and tumor necrosis factor-α, by ibuprofen and naproxen berberine derivatives, while aspirin and nicotinic acid berberine derivatives showed lower inhibition of tumor necrosis factor-α than berberine. These results suggest that ibuprofen and naproxen-modified berberine derivatives are promising new anti-inflammatory drug candidates.