肉桂酸类似物的合成和抗糖尿病活性研究  

Study on Synthesis of Cinnamic Acid Analogues and Their Anti-diabetic Activity

作　　者：关丽 夏焱鑫 李爱云 苏琬真 徐玥峰 王菁 李伟泽[1] GUAN Li;XIA Yanxin;LI Aiyun;SU Wanzhen;XU Yuefeng;WANG Jing;LI Weize(College of Pharmacy,Xi’an Medical University,Xi’an 710021 Shaanxi,China;Key Laboratory of Cellular Physiology,Ministry of Education,and Department of Physiology,Shanxi Medical University,Taiyuan 030001 Shanxi,China)

机构地区：[1]西安医学院药学院,陕西西安710021 [2]山西医科大学生理学系,细胞生理学教育部重点实验室,山西太原030001

出　　处：《中药新药与临床药理》2024年第12期1895-1901,共7页Traditional Chinese Drug Research and Clinical Pharmacology

基　　金：陕西省科技厅项目(2023-JC-QN-0827);西安市科协青年人才托举项目(959202413082);西安医学院科技创新团队配套项目(2021TDPT04);西安医学院大学生创新创业项目(121524024);山西省高等教育“百亿工程”科技引导专项(BYJL054);西安医学院2022年度科研能力提升计划项目(2022NLTS075)。

摘　　要：目的合成肉桂酸类似物,考察其抗糖尿病活性及作用机制。方法以不同取代的苯甲醛为原料,以乙酸钾为催化剂,通过Perkin反应与乙酸酐反应,合成肉桂酸类似物,并测试其在棕榈酸(PA)诱导下对胰岛β细胞的保护作用,同时探究优势化合物抗糖尿病的作用机制。结果10个目标化合物对胰岛β细胞有不同程度的保护作用,化合物RG-1和RG-4的细胞保护作用较强,细胞存活率分别为97.19%和89.68%。药理研究显示,化合物RG-1和RG-4可以减少细胞内活性氧的生成,抑制硫氧还蛋白互作蛋白(TXNIP)的表达,同时可以使丙二醛(MDA)含量下降,超氧化物歧化酶(SOD)活性升高,半胱天冬酶3(caspase 3)活性下降。此外,RG-1和RG-4表现出良好的药代动力学性质。结论该研究合成了10个肉桂酸类似物(RG-1~RG-10),其中RG-1和RG-4对胰岛β细胞的保护作用较强,其可通过抑制氧化应激发挥对胰岛β细胞的保护作用,是潜在的抗糖尿病小分子化合物。Objective To synthesize cinnamic acid analogues and investigate their anti-diabetic activity and mechanism.Methods With different substituted benzaldehyde and acetic anhydride as raw material,potassium acetate as catalyst,cinnamic acid analogues were synthesized through Perkin reaction.Then,their protective effects on isletβcells were tested under the stimulation of palmitic acid(PA).Furthermore,the anti-diabetic mechanism of the dominant compounds was explored.Results Ten target compounds showed varying degrees of protection against isletβcells,and compounds RG-1 and RG-4 exhibited strong cytoprotection.The cell survival rate was 97.19%and 89.68%,respectively.Molecular mechanism studies showed that compounds RG-1 and RG-4 could reduce the generation of intracellular reactive oxygen species,inhibit the expression of thioredoxin-interacting protein(TXNIP)protein,decrease malondialdehyde(MDA)content and cysteine aspartase 3(caspase 3)activity,as well as increase superoxide dismutase(SOD)activity.Furthermore,RG-1 and RG-4 exhibited favorable pharmacokinetic properties.Conclusion A total of 10 cinnamic acid analogues(RG1~RG10)were synthesized in this study.RG-1 and RG-4 exerted strong protective effects on isletβcells by inhibiting oxidative stress.RG-1 and RG-4 are potential anti-diabetic molecules.

关 键 词：肉桂酸类似物 糖尿病 胰岛Β细胞 抗氧化 作用机制 类药性 药代动力学 

分 类 号：R914.5[医药卫生—药物化学] R285.5[医药卫生—药学]