Design And Synthesis Of CDC25 Inhibitors Based On 4-thiazolidone Scaffold

Objective : Since 90 years ago, as the first factor of death surpassing heart disease,cancer has brought much threaton to human. Though it comes in many forms, their common theme is a disordered cell cycle, which is characterized by rapid and uncontrolled cell growth. Cdc25(cell division cycle 25) phosphatases are cell cycle control proteins and their overexpression is closely linked with many kinds of cancer. Cdc25 phosphatases serve as key activators of the cyclin-dependent kinases(Cdk/cyclins), which are the critical regulators of the eukaryotic cell cycle and are responsible for controlling each phase of cell division.Methods:Based on fragments of docking, active fragments stitching, such as skeleton growth principle of molecular design,We designed two series of new compounds containing 4-thiazolidone scaffold. Considering the particularity of active site of CDC25 protein crystal, we use the drug design method based on Fragment(FBDD). According to the structure of reported 117 effective CDC25 inhibitors, we adopt the means of computer-aided Drug Design(CADD) by using the Discovery Studio 3.0- De Novo Design module respectively in the two active sites and connected region selected matching molecular fragments, connected the fragment, then optimized by scaffold growth and positive compound control, screened the compounds of higher score. Combined with the difficulty of organic synthesis and other factors, methods of synthesis route were determined. Starting from carboxyl substituted phenol and nitro substituted phenol as the raw material, the target compounds were obtained by chemical synthesis and their structures were confirmed by 1H-MMR and MS.Results: Two series of new compounds containing 4-thiazolidone scaffold were obtained by screening, whose docking score(CDOCKER ENERGY) are ranging from 55.2904 to 61.4375, significantly higher than the control group(33.0918、38.7936). The optimum synthesis conditions of 4-thiazolidone derivatives were studied, and 17 novel compounds are obtained through the cyclization reaction, esterification reaction, etherification reaction and nucleophilic substitution, with a high level of product purity and yield. The target compounds were purified and then confirmed by 1H-NMR and MS. And the activity detection is on going.Conclusion: Selecting CDC25 as the target enzyme,the 4-thiazolidone scaffold based CDC25 inhibitors were designed by fragment based drug design. The designed compounds were screened using the CADD technology, and some potencial compounds were identified. By chemical synthesis, 17 4-thiazolidone class CDC25 inhibitors were obtained and confirmed by 1H-MMR and MS. Further activity studies were underway.