Design,Synthesis And Applications Of Small Molecules Based On Saturated Six-Membered Ring Structure

In organic chemistry,saturated six-membered rings participate in numerous reactions and have a wide range of applications.Among them,the research on the structure of 1,4-benzodioxane has been widely attracted in various fields such as chemistry,medicine and pharmacy.1,3-dithiane has been developed and applied by many researchers in organic synthetic chemistry and chemical biology due to its special structure,high reactivity,wide application field and easy availability.The classical mitogen-activated protein kinase(MAPK)pathway is involved in critical cellular processes such as cell proliferation and survival.A large number of data reports indicate that its overactivation is associated with up to 30%of human cancer.The most involved in the report is the activation mutation involved in RAF through its RAS-RAF-MEK-ERK cascade pathway.Therefore,inhibition of RAF is considered to be an effective solution for the treatment of cancer.Currently,RAF kinase inhibitors which have been approved by FDA include sorafenib,vemurafenib,dabrafenib and encorafenib.They are used alone to treat liver tumor cells,renal tumor cells,melanoma patients that cannot be surgically removed,or in combination with other drugs for the treatment of metastatic non-small cell lung cancer and melanoma patients with BRAFV600E mutations.Mercury is one of the most dangerous metal elements and is a major hazard to the environment and humans.There are many traditional quantitative methods for the analysis of mercury(?),including atomic absorption spectroscopy,cold vapor atomic fluorescence spectroscopy,gas chromatography,high performance liquid chromatography and electrochemistry.These methods require complex sample preparation steps or instruments and are not suitable for rapid detection of mercury ion in actual water samples or in vivo studies of mercury ion biology and toxicology.Recently,mercury(?)-responsive probes have made significant progress in design,synthesis and characterization.In addition to probes based on biomolecules and materials,new mercury(?)small molecule fluorescence based on coumarin,rhodamine,benzothiazole,1,8-naphthalene amide,pyrene,BODIPY,hydrazine and other structures colorimetric detectors are designed and synthesized.Based on the saturated six-membered ring structure,this project designed specific inhibitors of BRAFV600E and mercury(?)highly selective fluorescent probes from the medicinal chemistry and chemical biology.In the previous research work,we designed a series of compounds of the ABC tricyclic structure,in which the ICs50 value of optimal compound is0.11?M.In this paper,we carefully rotated the ABC ring and made fine adjustments to designe and synthesize 16 triarylpyrazoline derivatives of 1,4-benzodioxane structur,and compound 12 showed good inhibitory activity and excellent selectivity for BRAFV600E over BRAFWT at both kinase and cellular levels.Flow cytometry data analysis confirmed the mechanism of apoptosis induced by this compound,and western blot also showed the effect of the compound on kinase inhibitory activity.At the same time,molecular docking simulations show that binding to the PHE594 of BRAFV600E while avoiding binding to the HIS573 of BRAFWT may be an important trend to increase selectivity.This work may provide important clues for the future development of selective BRAF inhibitors and related safety drugs.On the other hand,we used a specific mercury(?)-promoted thioacetal deprotection reaction to construct a xanthene-based fluorescent probe XL-1 and XL-2,which was used for mercury(?)detection.After preliminary screening,XL-1 with better optical stability was selected for subsequent fluorescence properties determination and bioimaging experiments.Compared with the mercury(?)probes reported in recent years,XL-1 shows better performance in terms of selectivity,interference,time stability,etc.The most characteristic of which is the wide range of pH applications.It can be stably present at pH 3-11 and the detection effect is undisturbed,which shows the potential of the probe in acid-base environment.Moreover,it has been shown by fluorescence confocal imaging experiments that the probe can conveniently detect mercury(?)by changing the fluorescence intensity in living cells.Therefore,XL-1 provided an applicable tool for mercury(?)detection and had potential value for further applications.