Study On Co-crystal Of Rosiglitazone And Berberine And Preparation And Characterization Of Rosiglitazone Derivatives

Rosiglitazone,a representative drug of thiazolidinediones,is clinically used to treat type 2 diabetes.It has full agonistic effect on PPAR-γ,which could enhance the sensitivity of tissues to insulin and control blood sugar changes for a long time in the body.However,a small number of patients have heart failure side effects after medication,which limits its clinical application.Therefore,in order to reduce its adverse drug reactions,we research on rosiglitazone from the following aspects: the drug co-crystal and the covalent modification of the structure.Drug co-crystal,a single solid state with a new supramolecular structure,is formed by non-covalent bond interaction force with active ingredients by co-crystal ligands of drugs with similar efficacy or improved side effects of drugs.Some physicochemical properties even pharmacological activities of the original drug could be changed after the original active drug are combined by the ligand.In this article,rosiglitazone was used as an API to combin with drugs of similar hypoglycemic mechanisms and curative effects on complications to prepare drug co-crystals.Subsequently,a new drug co-crystal was formed by rosiglitazone and berberine.Its structure was characterized by infrared spectroscopy and X-ray diffraction.The X-ray single crystal diffraction proved that the drug co-crystal was prepared by rosiglitazone and berberine in a molar ratio of 1∶1.The further analysis confirmed that its spatial structure was present a two-dimensional supramolecular cross-belt structure under the weak hydrogen bond of the C-H···O,the π-π conjugated stacking effect and the intermolecular interaction force such as van der Waals forces.The investigation of the dissolution rate and hygroscopicity revealed that the co-crystal of rosiglitazone-berberine improved the poor solubility of rosiglitazone while keeping the parent drug difficult to absorb moisture.Interestingly,the research on the structure and efficacy of rosiglitazone shows that its active group is a thiazolidinedione ring,and the drug does not need to fully activate PPAR-γ to exert its corresponding hypoglycemic effect.Therefore,we also used rosiglitazone as the parent structure to covalently modify the N-H bond on the thiazolidinedione ring.It is hoped that the obtained derivatives would affect on PPARγ receptors with the same activity as rosiglitazone,which are lower toxicity and fewer side effects than rosiglitazone.At present,the six derivatives have been successfully synthesized and characterized by high performance liquid chromatography,hydrogen nuclear magnetic spectroscopy,infrared spectroscopy,etc.In addition,the inhibitory effects of the first five derivatives on prostate cancer C4-2 cells were preliminarily explored by the MTT method.The results showed that the derivatives improved the proliferation of prostate cancer C4-2 cells compared with rosiglitazone.