Study On The Asymmetric Michael Addition Reaction Of 3-substituted Oxyindoles And Nitroisoxazole Alkenes And Their Activity Evaluation

Cancer is the main health burden in both developed and underdeveloped countries.According to the World Health Organization(WHO),8.8 million people worldwide died of cancer in 2015.Although great progress has been made in the identification and treatment of tumors,factors such as poor patient compliance,drug resistance,and drug-induced toxicity.Therefore,it is urgent to find a new generation of anti-tumor drugs with small side effects,and the research on anti-tumor drugs such as vinblastine and vincristine based on natural products is also widely used.For clinical use.Cerium oxide,an important alkaloid skeleton compound,is also recognized as a probe for studying biological processes and is widely found in natural products and biologically active non-natural products.Many drug discovery systems are caused by terpenoids.For example,3-hydroxyindole has important significance due to its presence in natural products,and its structure has useful biological and pharmacological activities in medicinal chemistry.In addition,compounds having a chromone backbone have antibacterial,anti-inflammatory biological and pharmacological activities,and have attracted widespread attention from organic synthetic chemists.Therefore,the spirocyclic ruthenium oxide has a complicated structure and has the potential to be developed as a drug candidate.In recent years,its synthesis has attracted widespread interest from organic synthesis chemists.Therefore,the modification and transformation of the skeleton structure of natural products is an important way to find the skeleton of a lead compound with certain biological activity.The first part of this thesis is based on the research methodology of new drug research and the principle of splicing with the core skeleton of bioactive drugs.A series of 3,3-pyrrolidin spiro oxiranes having a chromone skeleton were obtained by a cycloaddition reaction.For the first time,the highly reactive group nitroisoxazole olefin with nitro group was introduced into asymmetric organic catalysis.The nitroisoxazole olefin and 3-substituted catalyzed by quinine thiourea as a chiral catalyst were designed.Asymmetric double Michael addition of ruthenium oxides in series and yields very high yields(up to 80% yield),diastereoselectivity(>20:1 dr)and enantioselectivity(up To 90% ee),a total of 24 compounds were synthesized,and the absolute configuration of the product was determined by single crystal diffraction or the like.Subsequently,we used the MTT method to evaluate the antitumor activity of K562(human leukemia tumor cell line)in 24 compounds.The second part of the thesis is the study of Michael addition reaction of pyrazolone compounds containing chromone skeleton with nitroisoxazole olefin compounds.5-pyrazolone compounds are important organic intermediates,mainly used in the synthesis of medicines,pesticides,dyes,etc.,broad-spectrum,high-efficiency,not easy to produce insect resistance,and have broad application prospects.Isooxazolyl and its derivatives are a class of five-membered heterocyclic compounds containing N,O.They are easy to form hydrogen bonds with compounds and coordinate with metal ions.They are important organic synthons and bioactive molecules and natural products.Important structural unit.In medicine,the main pharmacological activities include analgesic,anti-inflammatory,anti-caries,anticonvulsant,antibacterial,and excitatory nerves;in the field of pesticides,it mainly has biological activities such as insecticide,sterilization,and weeding.A total of 22 target products were synthesized,and a very high yield(up to 70% yield)was obtained,and the relative configurations of the products were determined by mass spectrometry,1H and 13 C NMR,and single crystal diffraction.Subsequently,we used the MTT method to evaluate the antitumor activity of K562(human leukemia tumor cell line)in 22 compounds.