Synthesis And Bioactivity Evaluation Of Polysubstituted Biphenyl Compounds

Cancer is a global problem,and anti-cancer is also a key research topic at home and abroad.Nowadays,most of the drugs used to treat cancer tumor cells are prone to drug resistance and have very large toxic side effects on tumor cells,and they require combination drugs.Therefore,it is imperative to find new anti-tumor drugs with low side effects.Natural compounds in nature with many types and structures provide us with many lead compounds with biologically active molecules.For example,o-hydroxyacetophenone is a common skeleton in many biologically active compounds and natural products,which has obvious pharmacological and biological activity in anti-tumor and other aspects;2-hydroxybenzophenone compounds have very high reactivity,so it is of great significance in drug synthesis and organic synthesis;compounds with biphenyl structure extracted from natural products have inhibitory effects on the central nervous system,anti-hepatitis,anti-cancer,anti-HIV virus and anti-oxidation and other biological activities.Biseno,its chemical name is 6-methoxycarbonyl-6’-hydroxymethyl-2,3,2’,3’-secondary dimethyldioxy-4,4’-dimethox ybiphenyl,The drug is my country’s first national first-class anti-hepatitis drug with independent intellectual property rights.According to the principle of drug splicing and the principle of active skeleton transition,the research of this thesis combines two or more skeletons into a skeleton molecule with potential biological activity,so as to optimize the original skeleton molecule to increase its activity or reduce toxic and side effects.Through the Michael/Aldol cyclized chromone-3-formaldehyde andγ-nitroaldehyde cascade benzoxation reaction,and through in vitro anti-tumor activity to study,hoping to screen high-efficiency and low-toxic anti-tumor active compound skeleton,for Lay the foundation for follow-up research.This paper is mainly divided into two parts:（1）Synthesis of 2-hydroxybenzophenone compounds based on biphenyl skeleton.First,at room temperature,under the catalysis of 1,8-diazabicycloundec-7-ene（DBU）,after 1a and 2a were reacted for 2 days,the target compound based on the biphenyl skeleton was obtained with a yield of 56%.2-Hydroxybenzophenone compound 3a.It is verified by observation and experiments that the reaction process is caused by the instability of 3a’,which may be due to the large group of the quaternaryα-carbonyl stereo center,which leads to decarboxylation and ring opening to obtain 3a.The reaction conditions were optimized,and 27 2-hydroxybenzophenone compounds based on the biphenyl skeleton were synthesized.The structures of all compounds were confirmed by ¹H NMR,¹³C NMR,and HRMS-ESI.（2）Evaluation of the anti-tumor activity of the synthesized compound in vitro.Considering all aspects of the laboratory conditions,this topic uses the MTT colorimetric analysis method（the positive control drug used:cisplatin）to perform in vitro anti-tumor activity on the synthesized 27 2-hydroxybenzophenone compounds based on the biphenyl skeleton To study its inhibitory effect on human chronic myeloid leukemia cell line K562.To study the in vitro anti-proliferative activity of compounds3e,3h,3r,3s and 3u on human chronic myeloid leukemia cell line K562.The research results show that the target compounds 3h,3r and 3u have a certain inhibitory activity on the proliferation of K562 cell lines,indicating that 2-hydroxybenzophenone compounds based on the biphenyl skeleton can be used as lead compounds for further research.