Design And Synthesis Of 9-Fibrate Substituted Berberine Derivative

Berberine（BBR）is the major alkaloid existing in the Chinese herbal medicine Coptis Rhizoma.It is a natural product with important pharmacological effects which was currently used clinically to treat gastroenteritis and anti-arrhythmia.BBR also has been proposed for the study of the pharmacological activities such as hyperglycemia and hyperlipidemia.Hyperglycemia is frequently accompanying with hyperlipidemia.To explore the potent drugs with dual-activity and dual-site effects that could reduce blood glucose and blood lipid at the same time,this paper had introduced the fibrate group with lipid-lowering effect on the 9th position of BBR using the drug design combination principle and the multi-target collaborative treatment method in order to enhance its hypoglycemic and lipid-lowering function.In the synthesis section of this experiment,we introduced microwave irradiation to synthesized dual-actively BBR derivatives with different substitution groups on 9th position.A preliminary study on the hypoglycemic effect was conducted for the synthesized compounds by animal experiments..Synthesis of BBR derivatives:The berberrubine was synthesized by the rapidly demethylation of BBR with microwave irradiation,then the 9-position regioselective demethylation of BBR was explored through quantum chemical calculation.The computations were consistent with the experimental results,which contributed to deducing the mechanism of its selective demethylation.The key intermediate,9-O-2-bromoethylberberine,was rapidly synthesized by the reaction of BBR and1,2-dibromoethane with microwave irradiation.Compared with conventional heating method,microwave radiation enhanced the reaction yield,reduced the reaction by-products,simplified the post-processing steps and the yields up to 85%.Then the intermediate 9-O-2-bromoethylberberine reacts with 4-substituted phenoxyisobutyric acid to obtain a series of products 9-（4-（2-（4-substitutedphenoxy）-2-methylpropanoic acid）-ethoxy）-O-berberine with microwave irradiation.In this paper,six 9-fibrate substituted berberine derivatives were synthesized,which five of them were not reported in the literature.The molecular structure synthesized intermediates and the final compounds were confirmed by LC-MS,¹H NMR and¹³C NMR.Animal experiment:The hypoglycemic activity of 9-fibrate substituted berberine derivatives was evaluated by preliminary experimental animals with hyperglycemia mice.The mice models with hyperglycemia was successfully established by multiple small doses of intraperitoneally injection of streptozotocin to destroy mouse pancreatic beta cells.The BBR,9-fibrate substituted berberine derivatives and metformin were respectively intraperitoneally injected to compare their hypoglycemic effects when the models were stabilized.The experimental results show that the 9-fibrate substituted berberine derivatives synthesized all have certain hypoglycemic effects,one of them named9-（4-（2-（4-fluorophenoxy）-2-methyl）propionicacid）ethoxy)-O-berberine hydrochloride shows the best effect which better than BBR,and its hypoglycemic effect close to metformin but the side effects are significantly lower than metformin.