Synthesis Of Diphenylurea And Phthalimide Derivatives And Preliminary Evaluation Of The Activity Of Inhibiting ROCK1

Malignant tumor is a complex disease caused by multiple factors,which is characterized by the unrestricted proliferation of malignant cells and metastasize to other parts of the body,causing organ failure and ultimately death.According to the WHO survey,the high mortality rate of cancer has seriously affected the quality of human life.Currently,among many cancer treatment methods,targeted therapy has become a research hotspot for its high selectivity,small toxic side effects on normal cells and good safety.As an member of serine/threonine kinase,ROCK contains two subtypes,ROCK 1 and ROCK 2.A lot of studies have been verified that ROCK plays a critical role in multiple links of tumor occurrence and development,which is considered to be an effective target to intervene and treat tumors.Compared with ROCK 2,the over-expression of ROCK 1 is more closely related to the proliferation and migration of tumors.Therefore,the development of ROCK 1 inhibitors is expected to become potential anti-tumor drugs.In the present work,three series of diphenylurea and phthalimide derivatives based on the characteristics of the three-dimensional structure of active binding domain of ROCK 1,together with the molecular hybridization strategy,were herein designed,synthesized and bioevaluated as ROCK 1 inhibitors.As a result,21 diphenylurea derivatives(series I and II)and 8 phthalimide derivatives(series III)have been obtained.All compounds were initially submitted to the enzymatic inhibitory assessment at the concentration of 10 μM and it resulted that some compounds,MJ-6-3 and MJ-D1-MJ-D8,gave comparable ROCK 1 inhibition with the positive control fasudil.Their inhibition rates against ROCK 1 were 64.9%,99.4%,98.0%,93.9%,100%,100%,100%,96.5%,100%,respectively.The anitproliferative evaluation on these derivatives were performed on three ROCK 1-sensitive tumor cell lines,viz.gastric cancer cells(AGS),liver cancer cells(HepG2),and lung cancer cells(A549).The results showed compounds MJ-5-3,MJ-6-3 and MJ-15-3 presented significantly improved antiproliferative activities against AGS than the reference drug fasudil,with IC50 values of 2.73,3.58,8.80 μM in comparison with control(IC50=33.24 μM).Compounds MJ-5-3,MJ-6-3 and MJ-D5 gave better antiproliferative activities against A549,with IC50 values of 4.21,8.36,13.12 μM,respectively,than fasudil(IC50=138.0 μM).Compounds MJ-5-3,MJ-6-3 and MJ-13-3 displayed elevated anti-proliferative activities against HepG2,with IC50 values of 6.29,4.25,8.04 μM,respectively,compared with fasudil(IC50=45.31 μM).Finally,given the ability of cell migration is directly related to tumor metastasis,compound MJ-6-3,which exhibited a decent ROCK 1 inhibition and also the most potent antiproliferative activity against AGS and HepG2 cell lines,was selected to investigate its ability to inhibit tumor migration on AGS and HepG2 cells.It resulted that MJ-6-3 demonstrated obvious inhibition on the migration of two tumor cells at the concentrations of 7.8 and 15.6 μM,respectively.The inhibition rate increased in a concentration-dependent manner.Specifically,MJ-6-3 showed migration inhibition rate of 70%against AGS and 62%against HepG2 at 15.6 μM.The results of this thesis might lay the foundation for further development of more potent ROCK inhibitors as anti-tumor candidates.