和厚朴酚衍生物的合成及防治结肠癌作用机制的预测

Synthesis of Magnolol Derivatives and Prediction of Its Mechanism of Action Against Colon Cancer

和厚朴酚具有广泛的药理活性,尤其是在结肠癌的治疗上有潜在的生物活性,但是由于自身的理化性质,导致其在开发利用中存在许多缺点。为了改善和厚朴酚稳定性差、水溶性低等缺点,通过糖基化改造进行结构修饰,再通过分子对接和网络药理学初步探究和厚朴酚衍生物防治结肠癌的作用机制。分别以D-半乳糖、D-葡萄糖、α-乳糖等为起始原料,通过对糖羟基保护与去保护,得到一系列单糖、二糖、三糖片段,将得到的糖片段对1的4′-OH进行修饰,合成了4种和厚朴酚糖苷化衍生物2~5,其结构经^(1)H NMR、^(13)C NMR鉴定。采用Swiss Target Prediction反向药效团匹配数据库预测和厚朴酚衍生物的作用靶点,运用GEO和Gene Cards数据库预测结肠癌相关的疾病靶点,构建PPI网络和“成分-靶点-疾病”网络,通过网络拓扑参数筛选核心靶基因,利用DAVID平台进行GO功能分析和KEGG信号通路富集分析。最后,利用AutoDock对核心靶基因进行分子对接,得到36个和厚朴酚衍生物防治结肠癌的核心靶基因,GO生物过程有323条,包括有丝分裂、染色体分离的调控、蛋白分解过程等;KEGG信号通路有13条,涉及人T细胞白血病病毒1感染、p53信号通路、FoxO信号通路等。通过AutoDock对核心靶基因进行分子对接,发现8个核心靶基因与和厚朴酚衍生物的亲和力在-10.1~-6.2 kcal/mol,亲和力相对较稳定。

Honokiol has a wide range of pharmacological activities,especially highlighting the potential biological activity in the treatment of colon cancer.However,because of its own physical and chemical properties,it has many shortcomings in development and utilization.In order to improve the shortcomings of honokiol’s poor stability and low water solubility,the purpose of improvement was achieved through glycosylation modification and structural modification,Through molecular docking and network pharmacology,the mechanism of prevention and treatment of colon cancer with magnolol derivatives was preliminarily explored.Using D-galactose,D-glucose andα-lactose as starting materials,a series of monosaccharide,disaccharide and trisaccharide fragments are obtained by protecting and deprotecting hydroxyl groups on sugar,they are combined with 4′-OH on 1,four magnolol glycoside derivatives 2~5 were synthesized,its structure was identified by ^(1)H NMR and ^(13)C NMR.The Swiss Target Prediction reverse pharmacophore matching database was used to predict and the target of magnolol derivatives;the GEO and Gene Cards databases were used to predict colon cancer-related disease targets,construct a PPI network and a“component-target-disease”network,the core target genes were screened by network topology parameters,go function analysis and KEGG signal path enrichment analysis were carried out by using David platform.Finally,AutoDock is used to do molecular docking to the core target genes.36 core target genes were obtained for the prevention and treatment of colon cancer with honokiol derivatives.There were 323 go biological processes,including mitosis,chromosome separation regulation,protein decomposition process,etc;There are 13 KEGG signaling pathways,including human T-cell leukemia virus 1 infection,p53 signaling pathway,FOXO signaling pathway,etc.The affinity between 8 core target genes and honokiol derivatives was-6.2~-10.1 kcal/mol,and the affinity was relatively stable.