福建医科大学
硕士学位论文
姓名：康建军
申请学位级别：硕士
专业：药物化学
指导教师：林友文
2011-03
丹皮酚衍生物的合成及其抗肿瘤活性研究
中文摘要
重大疾病如恶性肿瘤、感染性疾病、心血管疾病、创伤和消化系统疾病等的防治及提高人类健康水平一
直是医学界追求的最主要目标。肿瘤的发生与发展不仅与癌细胞的分化异常及增殖过度密切相关，而且也与肿瘤细胞凋亡的减少相关。因而开发诱导肿瘤细胞凋亡的新药成为抗肿瘤药物研发的新思路。近年来的文献报道显示丹皮酚在体内、外实验中均具有抗肿瘤作用，并且诱导肿瘤细胞凋亡、影响凋亡相关基因表达可能是其作用机制之一。 本文以间苯二酚为原料，经乙酰化、甲基化两步合成丹皮酚。然后以丹皮酚为先导，以丹皮酚的酮羰基与胺类化合物的胺基缩合，合成一系列丹皮酚席夫碱衍生物，并以席夫碱为配体合成了丹皮酚及其衍生物金属配合物。目标化合物采用MTT法进行体外抗肿瘤活性筛选。 本论文的主要工作：
1、丹皮酚合成：以间苯二酚为原料，通过乙酰化得到2,4-二羟基苯乙酮，应用四丁基溴化铵（TBAB）为相转移催化剂与甲基化，直接用水蒸气蒸馏得到丹皮酚，总收率68.32%，目标化合物通过UV、IR等表征。该方法操作简便，稳定可靠，适合工业化生产。
2、合成12个丹皮酚类衍生物：其中8个席夫碱衍生物分别是N’-[1-（2,4-二羟基苯基）亚乙基]苯甲酰肼（B1）、双（2’.4’-二羟基-α-甲基苄基）-二亚胺（B2）、双（2’,4’-二羟基-α-甲基苄基）-乙二亚胺（B3）、双（2’,4’-二羟基-α-甲基苄基）-1,3-丙二亚胺（B4）、5-甲氧基-2-[1-（丙亚胺基）乙基]苯酚（P1）、双（2’-羟基-4’-甲氧基-α-甲基苄基）-二亚胺（P2）、双（2’-羟基-4’-甲氧基-α-甲基苄基）-
乙二亚胺（P3）、双（2’-羟基-4’-甲氧基-α-甲基苄基）-1,3-丙二亚胺（P4）；以及4个金属配合物：CuB1、CuPae、RuP
3、RuP4。化合物通过IR、1H-NMR、MS、元素分析进行结构表征，其中CuB1、RuP3、RuP4三个化合物未见文献报道。
3、体外抗肿瘤活性测试：利用MTT法对上述合成得到的其中8个丹皮酚
类衍生物进行体外抗肿瘤的活性测试。活性研究表明，CuB1对K562细胞抑制能力最强，其 IC50值为 6.94μg/mL，其次为CuPae（8.58μg/mL）、RuP4（10.65μg/mL）、RuP3（17.72μg/mL），CuPae对HL60细胞抑制能力最强，其IC50值为1.96μg/mL，其次为CuB1（2.03 μg/mL）、RuP4（9.31 μg/mL）、RuP3（9.55μg/mL）。其中CuB1与CuPae对K562、HL60的抑制活性最高，且呈现出明显的浓度效应关系，可作为进一步开发该类化合物的研究重点。
关键词：丹皮酚衍生物；席夫碱；合成；抗肿瘤活性
Study on synthesis and antitumor activities
of paeonol derivatives
Abstract
To prevent and cure serious diseases such as cancer, infectious disease, cardiovascular disease, trauma and digestive diseases and to improve human health has been the main goal pursued by the medical profession. Tumor occurrence and development were not only related to abnormal differentiation and proliferation of cancer cells but also to apoptosis decrease. Thus to research and develop the new drugs of inducing apoptosis of tumor cells would be a new way for curing cancer. Recent reports indicated paeonol have anti-tumor activities both in vivo and in vitro and induce tumor cell apoptosis. The expression of apoptosis-related genes may be one of the mechanisms.
In this paper, paeonol was synthesized by two-step of acetylation, methylation of resorcinol. Then paeonol as a precursor condensation of the ketone carbonyl of paeonol weith various amine compounds, to synthesize a series of Schiff base derivatives of paeonol, and Schiff base derivatives as ligand to synthesize metal complexes. The Anti-tumor activities of the target compounds were determined by MTT assay.载体构建
The main work of this paper:
1. Synthesis of paeonol by phase-transfer Catalysis: paeonol was synthesized from resorcin through two steps of acetylating and methylate with methyl iodide, using TBAB as the phase transfer catalyst,
moreover paeonol was purified by steam distillation. The total yield was 68.32%, the structure of paeonol was confirmed by UV, IR. The method was simple, stabilize and could be applied in the industrial production.
2. Synthesis of paeonol derivatives:
Schiff base derivatives:
N'-[1-(2,4-dihydroxyphenyl)ethylid-ene]benzohydrazide (B1)消息推送服务
无毒的Bi(2’,4’-dihydroxy-α- methylbenzylidene)-diimine (B2)
电子数据系统
Bi(2’,4’-dihydroxy-α-methylbenzyl-idene)-ethylenediimine （B3）
Bi(2’,4’-dihydroxy-α-methylbenzyl-idene)-1,3-trimethylenediimine （B4）
5-methoxy-2-[-1-(propylimino)ethyl]phenol（P1）
Bi(2’-hydroxy-4’-methoxy-α-methyl-benzylidene)-diimine （P2）
Bi(2’-hydroxy-4’-methoxy-α-methyl-benzylidene)-ethylenediimine（P3）
rta 飞
Bi(2’-hydroxy-4’-methoxy-α-methyl-benzylidene)-1,3-trimethylenediim-ine（P4）Metal complexes: CuB1、CuPae、RuP3、RuP4, and CuB1、RuP3、RuP4 three compounds have not been reported.
3. The anti-tumor activities of eight of the paeonol derivatives were determined by MTT assay. The results showed that paeonol derivatives suppress proliferation of K562、HL60 cells in a dose-dependent manner. The inhibiting rate of CuB1 on K562 cells was the highest with IC50 6.94 μg/mL, then IC50 of CuPae, RuP4, RuP3 were 8.58μg/mL ,10.65μg/mL,17.72μg/mL respectively. The inhibiting rate of CuPae on HL60 cells was the highest with IC50 1.96μg/mL, then IC50 of CuB1, RuP4, RuP3 were 2.03μg/mL, 9.31μg/mL, 9.55μg/mL respectively. Which showed CuB1 and CuPae display higher inhibitory activities on proliferation of K562、HL60 cells in a dose-dependent manner, they could be used as research emphasis to further development of this kind compounds.
营养米
Key words: Paeonol derivatives; Schiff base; Synthesis; Anti-tumor activity
豫公网安备41160202000603
站长QQ:729038198
关于我们
投诉建议