Structural Modification Of Thiazolidinediones And Screening Of Anti-breast Cancer Cellactivity And Molecular Docking,ADME Study

Anti-type 2 diabetes drugs thiazolidinediones,with its clinical application,in play the role of treatment at the same time,its side effects such as obesity,hypoglycemia,osteoporosis,etc.,also gradually appear,these side effects seriously hindered its clinical application.The study found that due to the complete agonistic effect of thiazolidinediones on the PPAR? receptor,its side effects were promoted.Therefore,we use the basic principles of drug design to modify the structure of a well-active thiazolidinedione to optimize PPAR modulators with fewer side effects.Among the structures of thiazolidinediones,the acidic thiazolidine-2,4-dione ring is one of the main pharmacophores for its action.In this paper,the NH bond on this part is structurally modified,and the SN alkylation reaction is used to replace the N-H of pioglitazone thiazole ring with the less active amide a-position hydrogen or enol hydrogen.which changing the conformation of the drug molecule,thereby changing the conformation of the pharmacophore of the pioglitazone derivative to the receptor.Thus,pioglitazone changes from fully agonisticPPAR? to selective agonism or partial agonism,which produces relatively less activity while also reducing the side effects of its full agonism.Then,for the known reports,the thiazolidinedione drugs have certain anti-tumor activity,so under the experimental conditions of the in vitro anti-breast cancer cell model,all the 15 thiazolidinedione derivatives were studied the activity of anti-breast cancer cell lines MCF-7,MBA-MD-231,453,CAL-120 was studied by MTT method.The experimental results showed that the thiazolidinedione derivatives tested had a relatively significant anti-breast cancer activity compared with the positive control pioglitazone,and the compound PGZ-15 was more active.Finally,based on the above two parts,the design,synthesis and anti-tumor activity screening of pioglitazone derivatives,in order to better elucidate the mechanism of action of the synthesized compounds on the PPAR? protein receptor,and the metabolic kinetics of the compounds in vivo,Molecular docking and pharmacokinetics of 15 pioglitazone derivatives with PPAR? were also studied.Molecular docking results showed that,compared with the positive control pioglitazone,except for the compound PGZ-6,PGZ-12,the scoring function was not much different from the control,the other 13 compounds had better binding ability to the receptor protein.And ADME simulation studies indicate that most of the compounds do not bind to plasma proteins in vivo,are free,and have pharmacological activity.In summary,the structural modification,structural characterization and activity screening,molecular docking and ADME simulation of thiazolidinediones have reached the preliminary goals and requirements of this paper.