Studies On The Synthesis And Preliminary Anti-tumor Pharmacological Activities Of The Sulfadiazine As FAK Inhibitors

Objective:Aim to discover more potent and selective focal adhesion kinase inhibitors,then several diphenylamine pyrimidine derivatives were designed,synthesized and their biological activity against cancer cells were evaluated.Methods:Sulfonamide structure is a kind of functional group with widely used biological activity,such as bactericidal,anticancer,weeding,anti-diabetes,insecticidal and so on.In the first section,the biological functionality,Sulfanilamide groups,was introduced to the C-2 position of the diphenylpyrimidine scaffold led by the FAK inhibitor TAE226.A total of 9 new diphenylamine pyrimidine derivatives were synthesized and characterized by NMR and HRMS.In the second section,Gemcitabine and TAE226 were used as positive drugs.In the kinase level,focal adhesion kinase were detected by quantitative analysis of the content of residual ATP in the kinase reaction.The values of half maximal inhibitory concentration(IC₅₀)were tested.In the screening of tumor cells in vitro,these 9 compounds were determined by methyl thiazolyl tetrazolium?MTT?colorimetric assay.The cell lines including Human pancreatic cancer cell line Aspc-1,Bxpc-3 and Panc-1,non-small cell lung cancer H1975,human B immunoblastic lymphomas ramos and human normal liver cell LO-2.The values of IC₅₀on tumor cells were calculated at 72h and on normal cells at 48h interactional condition.The effect of optimal compound on apoptosis induced by Aspc-1 cells was investigated by flow cytometry.Results:NMR data and high resolution mass spectrum characteristics were consistent with the target molecules structures;The preliminary results showed that the synthesized target molecules had good anti-tumor activity.Among these molecules,Q-1,Q-2,Q-5 and Q-7 have better inhibition of FAK kinase activity,and IC₅₀ is 84.6 nM,82.5 nM,84.7 nM and 86.7 nM respectively.At the same time,the compound Q-7 has good activity in human pancreatic cancer cell Aspc-1 and Bxpc-3 cells,and the IC50 is3.92?M and 0.53?M respectively.The results of flow cell apoptosis showed that,compared with the blank group,the apoptosis rate of Aspc-1 cells was 74.9%after 5?M compound Q-7 treatment.Conclusions:In this paper,a series of diphenylamine pyrimidine derivatives were synthesized and their structures were characterized.The preliminary study of anti-tumor pharmacological activity showed that most compounds had strong inhibitory effect on the proliferation of tumor cells.Several compounds,such as Q-1,Q-2,Q-5 and Q-7,displayed higher activity against FAK kinase activity than others,and compound Q-7showed better activity effect on pancreatic cancer Panc-1 and Bxpc-3 than positive control of compound TAE226.This typical molecule can be further developed as candidate compounds.The structural modification of this paper indicated that the incorporation of sulfonamides into the pyrimidine skeleton could improve the antitumor activity of the drug,and which would provide an effective structure-activity relationship theory for the further structural optimization of this template.