Synthesis,Biological Activities And Fluorescence Properties Of Novel Quinolinone Derivatives

Molecules containing a quinolinone skeleton have a broad pharmacological activities and they can be used as anticancer,antibacterial,antiallergic and antituberculosis drugs.Quinolinone is also an important fluorophore,and its derivatives can be used as fluorescent probes for detecting and recognizing metal cations and biological small molecules such as biothiols.Therefore,the development of such molecules has important scientific significance.SHP2 is a member of the protein tyrosine phosphatase（PTP）family and has become an important target for anticancer therapy.In order to develop SHP2 inhibitors and novel fluorescent probes which are capable of specifically detecting metal cations and small biomolecules,on one hand,based on the excellent activities of quinolinone,triazolothiadiazole and oxadiazole,and on the other hand,based on the characteristics of quinolinone,1,8-naphthalimide and ebselen which can be used as fluorophore and biothiol recognition sites,twenty-two target molecules were synthesized in three categories for screening excellent SHP2 inhibitors and fluorescent probes with high selectivity for the detection of metal cations and amino acids.1.The first type of target molecules:Sixteen target molecules MNT（1-16）were designed and synthesized by the combination the core uint of quinolinone which had excellent biological activities and high quantum yield withα,β-unsaturated amide,triazolothiadiazole or oxadiazole.The structures of the target molecules were characterized.In order to verify the rationality of the overall design of the molecule,first,the inhibitory activities of 16 target molecules and related important intermediates against SHP2 were compared.the results show that the inhibitory activities of sixteen target molecules are more excellent than that of the intermediates.The inhibition activities of ten target molecules aer better than that of the positive reference Na₃VO₄.On this basis,in order to study the interaction mode of the target molecule with SHP2,the representative compounds were selected for molecular simulation docking.As a result,the target molecules combine with SHP2 through hydrogen bonding and van der Waals force.The results of inhibitory activity test are consistent with the results of molecular docking simulation,indicating that superposition of activities are obtained when multiple active blocks are constructed in the same molecule.The design of the overall structure of the target molecules is reasonable.This type structure molecules are expected to be a potential SHP2 inhibitors.Secondly,four representative compounds were selected to detect the fluorescence of fourteen metal cations based on their excellent fluorescence properties and multiple heteroatoms in the molecular structure.The results show that the target molecule can recognize Hg²⁺with high selectivity even thoough in the presence of the other ions.The target molecule can be used as a fluorescent probe for detecting and recognizing Hg²⁺.2.The second and third types of target molecules:In order to detect small molecule biothiols selectively,six target molecules MNQ（17-22）were synthesized through the reaction of quinolinone derivatives with ebselen and 1,8-naphthalimide derivatives respectively and their structures were characterized.The design of the target molecules was based on the nature of the reaction of the Se-N bond in the ebselen andα,β-unsaturated amide with the thiol molecule.Fluorescence detections of 15 amino acids were performed using two types of the target molecules respectively.The results show that both types all can selectively recognize GSH,which means they are expected to be a fluorescent probes for detecting GSH.