Design, Synthesis, Anticancer Activity And Targets Identification Of Novel Imides Containing Pyrazole Derivatives

Objective:Malignant tumor has been a serious threat to human health. The lethality of patients with tumor is just a little lower than that of cardiovascular disease. At present, the treatments of tumor mainly include radiation therapy, surgical treatment and chemotherapy, among which chemotherapy plays a highly important role. But for most patients, chemotherapy would induce drug tolerance and serious toxicity,resulting in the failure of treatment. Therefore, we need to constantly develop novel anti-cancer agents, which are effective, safe and selective. In the early stage of the study, we have produced a class of novel imides containing pyrazole heterocyclic,and found that some compounds possessed good antitumor activity. In view of this,the compounds possessing high anti-cancer activity were used as lead compounds.Then in order to get novel anti-cancer drugs containing pyrazole heterocyclic, we retained the mother nucleus structure, modified the template molecule and studied the structure-activity relationship and anti-cancer mechanism of designed compounds.Methods: Referring to the relevant literatures and combined with the preliminary work, two series of compounds were designed. Combined with the condition of organic synthesis and other factors, the synthesis routes were determined. With phenylhydrazine, trifluoro ethyl acetoacetate and the corresponding aniline as raw material, the target molecules were obtained by multiple reaction, and their structures were confirmed by 1H-MMR, 13C-NMR and single crystal diffraction method. In vitro biological activity of these compounds was determined by MTT method to study their structure-activity relationship. Pharm Mapper web server was used to predict the potential targets of the synthetic compounds, and then filtered by Schrodinger software to find the possible targets.Results: The synthesis conditions were studied, and 24 novel compounds of two classes were obtained. These compounds were purified and confirmed through1H-NMR, 13C-NMR and single crystal diffraction method. The biological activity assays showed that most of compounds of series A possessed certain inhibition to the tumor cells of the study, among which compounds A2, A4, A11 and A14 were effictive to A-549 tumor cells and A2 was also a potential inhibitory agent of HCT-8 tumor cells, and A12 exhibited good inhibitory activity to Bel7402 cells as well.Meanwhile, few compounds of series B possessed inhibitory activity to three different tumor cells, which might due to the replacement of the pyridine ring(ring B)insulting in changes of the interactions between compounds and receptors. Further research is needed to analysis their structure-activity relationship. Aided by Pharm Mapper server, several targets associated with cancer were selected. Then the Heat Shock Protein(Hsp90 α, 1uyk) were found to be the potential target of this kind of compounds through the positive molecular docking studies.Conclusions: On the basis of the preliminary work, 24 compounds in two series were designed to study the structure characteristics, biological activity and function mechanism of imides containing pyrazole heterocyclic. The structures were confirmed by 1H-MMR, 13C-NMR and single crystal diffraction. The research progress of these compounds in the treatment of cancer might be greatly promoted by this study.