Design,Synthesis And Applications Of Novel Heterocyclic Compounds Containing Sulfur And Nitrogen

With the constantly development of modern synthetic technologies,such as multi-component reactions(one-pot method),coupled reactions and cyclization/cycloaddition reactions,a growing number of novel heterocyclic compounds have been reported.Heterocyclic organic compounds are the most abundant compounds in organic compounds and the heterocyclic chemistry has already become one of the most concerned research fields.in organic chemistry.Heterocyclic compounds containing sulfur and nitrogen is a key component of heterocyclic compounds which possess various biological activities and could widely found in natural products,drugs and dyes.Among them,rhodamine and 1,5-benzothiazepine are the five-membered and seven-membered heterocycles containing sulfur and nitrogen,respectively.They are commonly used as molecular blocks in drug discovery because of their various pharmacological activities.Moreover,quinoline derivatives are the benzo six-membered heterocycles containing nitrogen,were often selected as fluorophore in fluorescent sensors due to its excellent photophysical properties.On this basis,the applications of heterocyclic compounds containing sulfur and nitrogen in chemical biology(small-molecule fluorescent sensors for humari serum albumin(HSA))and drug discovery(tubulin inhibitors)were studied in this work.Thus,this thesis deals with two parts of work,as follows:1.Design,synthesis and applications of quinoline derivatives containing rhodanine as HSA fluorescent sensorsHSA,the most abundant transport protein in human plasma,takes part in various physiological and pathological processes.As an adjuvant drug,HSA also widely used for therapeutic in clinic and was described as "golden life-saving drug".Meanwhile,the abnormal level of HSA in body fluids are the diagnostic index for many diseases and plays a vital role in the pre-clinical diagnosis of diseases.In addition,bovine serum albumin(BSA)was often used as a substitute of HSA because of its similar structure but different functions with HSA.The abuse of HSA and BSA could cause fatal harm to patients and the discrimination of HSA over BSA is a big challenge.Thus,the precise sensing of HSA in various biofluids have victal clinical significance.Based on the unique properties of heterocycles such as rhodanine,quinoline and 1,8-dinaphthalimide,we designed and synthesized four fluorescent sensors NJUP1-NJUP4.Among them,compound NJUP1 exhibited the best selectivity which could distinguish HSA from BSA,and showed anti-interference from other proteins,carbohydrates,amino acids and ions.The limit of detection(LOD)for HSA was determined to be 1.23 ?g/mL(18.1 nM).In the range of 0-1.0 mg/mL,the fluorescence intensity increased linearly,and could be available to cover the detection requirements of human blood samples.Subsequently,a series of experiments demonstrated that NJUP1 binding to the warfarin binding site(domain ?a)of HSA.In addition,sensor NJUP1 was successfully used for sensing HSA in rat urine andhuman blood serum samples that provides a potential approach for pre-clinicaldiagnosis of HSA.2.Design,synthesis and biological evaluation of 1,5-benzothiazepine analogues as tubulin polymerization inhibitorsCancer is remained a main leading cause of death in the world and anti-cancer drugs are the hotspot of drug discovery.Microtubules(MTs)plays an essential role in various intracellular processes such as eukaryotic cell division.Hence,microtubule/tubulin is one of the most commonly used targets in the development of anti-cancer drug.In particular,the anti-tubulin agents binding to colchicine site have attracted the highly attention in recent years,such as the CA-4 analogues.Based on the CA-4 analogues possess three vital structural units and 1,5-benzothiazepine scaffolds exhibits superior pharmacological properties,we maintained the TMP moiety and introduced the seven-membered heterocyclic 1,5-benzothiazepine.Two series of 36 compounds were screened,designed and synthesized,all compounds were characterized by 1H-NMR?13C-NMR?HR-MS,and their biological activities were preliminarily evaluated.As the results of bioactivity tests showed,most compounds exhibited some inhibitory effects and compound D08 exhibited the most activity against HeLa,MCF-7,HT29 and A549 cancer cell lines with ICs50 valus of 1.38±0.12?M,1.47±0.03?M,1.52±0.07?M,53.44±0.15?M,respectively,which was close to the positive control(colchicine).The results of cell apoptosis and cell cycle arrest bioassays showed that compound D08 cuold induce the apoptosis of MCF-7 cells in a time-and dose-dependent manner and could cause cell cycle block in the G2/M phase.In addition,molecular docking simulation showed that D08 was interacted with tubulin through a hydrogen bond and other forces.Therefore,CA-4 analogues bearing 1,5-benzothiazepine skeleton are the potential tubulin inhibitors which could be further modified to enhance biological activity.In summary,based on the rhodamine and 1,5-benzothiazepine heterocycles,this study provides a design basis for exploiting sensors for clinical diagnosis of HSA and a new design idea for the development of novel CA-4 analogues.There are broad prospects on application and development.