二氢卟吩类光敏剂设计、合成、作用机制研究和生物活性评价

发布时间：2018-03-06 21:03

本文选题：光动力治疗　切入点：光敏剂　出处：《第二军医大学》2016年硕士论文　论文类型：学位论文

【摘要】：光动力治疗已发展成为主流的肿瘤治疗手段,其中光敏剂是核心。第二代光敏剂二氢卟吩具有摩尔吸光系数强、毒性小以及皮肤光毒性持续时间短等优势,成为目前研究的热点。本课题组前期以蚕粪为最初原料,设计合成得到多个二氢卟吩类化合物。本论文主要内容是以紫红素-18为先导物,设计合成紫红素-18醚、二氢卟吩P6二甲酯以及苯并叶绿卟啉P6二甲酯三大类26个化合物,发现多个化合物具有较优的体外光动力抗肿瘤活性。一、基于二氢卟吩P6的水溶性光敏剂合成、机制研究和生物活性评价本课题组前期通过降解蚕粪得到多个二氢卟吩类先导物,进行结构修饰得到多个化合物。在此基础上采用上市药物维替泊芬和他拉泊芬的设计策略,设计合成出二氢卟吩P6二甲酯和苯并叶绿卟啉P6二甲酯以及相应氨基酸衍生物,两类共6个化合物。体外光动力抗肿瘤研究结果表明,光敏剂用氨基酸残基结构修饰后,细胞光毒性有一定程度降低,但暗毒性大大降低。其中化合物7b水溶性好、最大吸收波长处摩尔吸光系数强、单线态氧量子产率较高、暗毒性低以及体内外光动力抗肿瘤活性优于阳性药维替泊芬,有望成为候选药物。构效关系研究表明,氨基酸结构对活性有影响,天冬氨酸结构优于谷氨酸结构。二、二氢卟吩类光敏剂的设计、合成及光动力抗肿瘤活性研究大量研究资料以及本课题组前期研究结果表明,在二氢卟吩类光敏剂结构中引入醚类基团可有效改善光敏剂光动力抗肿瘤活性。以紫红素-18和化合物7b为基础,在其分子中引入不同醚类结构进行更深入的结构修饰,合成得到20个化合物。体外抗肿瘤活性测试表明大部分化合物具有较优的光毒性,其中化合物14d、15d和17h具有相对较高的暗毒性光毒性比,明显优于阳性药维替泊芬。综上所述,本研究通过对紫红素-18进行结构改造修饰,合成得到26个新化合物。本文创新点为:(1)以蚕粪为最初原料,实现了废物利用;(2)在光敏剂结构中引入氨基酸结构,大大改善了光敏剂水溶性,显著降低暗毒性;(3)发现一个水溶性、细胞暗毒性以及体内外抗肿瘤活性均优于上市药物维替泊芬的高活性、低毒性化合物7b。上述研究结果为研发新型光敏剂类药物奠定了一定基础。
[Abstract]:Photodynamic therapy (PDT) has developed into the mainstream of tumor therapy, in which Guang Min is the core. The second generation Guang Min has the advantages of strong molar absorptivity, low toxicity and short duration of skin phototoxicity. In the early stage of this study, several porphins were designed and synthesized from silkworm dung. The main content of this thesis is to design and synthesize porphyrin-18 ethers with purplatin-18 as the lead material, and the main content of this paper is to design and synthesize porphin-18 ethers with silkworm dung as the initial raw material. Porphine P6 dimethyl ester and benzoben porphyrin P6 dimethyl ester have been found to have excellent photodynamic antitumor activity in vitro. First, the synthesis of water-soluble Guang Min based on porphyrin P6. Mechanism study and Bioactivity Evaluation in the early stage of this study, we obtained several precursor compounds of porphine by degradation of silkworm dung, and modified several compounds by structural modification. On this basis, we adopted the design strategy of vitipofen and talapifen, which are listed on the market. Porphyrin P6 dimethyl ester and benzoben porphyrin P6 dimethyl ester and their corresponding amino acid derivatives were designed and synthesized. In vitro photodynamic antitumor studies showed that Guang Min was modified with amino acid residues. The phototoxicity of the cell was decreased to some extent, but the dark toxicity was greatly decreased. The compound 7b was water-soluble, the molar absorptivity was strong at the maximum absorption wavelength, and the yield of singlet oxygen was higher. Low dark toxicity and in vivo and in vitro photodynamic antitumor activity is superior to the positive drug vitipofen, which is expected to be a candidate drug. Studies on the structure-activity relationship show that the structure of amino acid has an effect on the activity, and the structure of aspartic acid is superior to the structure of glutamic acid. The design, synthesis and photodynamic antitumor activity of chlorin Guang Min were studied. The introduction of ether groups into the structure of chlorin Guang Min can effectively improve the photodynamic antitumor activity of Guang Min. On the basis of fuchsin 18 and compound 7b, different ether structures are introduced into its molecules for further structural modification. Twenty compounds were synthesized. The antitumor activity test in vitro showed that most of the compounds had better phototoxicity, and the compounds had a relatively high dark toxicity ratio of 15 days and 17 hours, which was obviously better than that of the positive drug vitipofen. In this study, 26 new compounds were synthesized by modifying the structure of purplatin -18. The innovation point of this paper is: (1) using silkworm dung as the initial raw material, the waste utilization is realized, and the amino acid structure is introduced into the structure of Guang Min. A water-soluble, cytotoxic and anti-tumor activity in vitro and in vivo was better than that of vitipofen. These results laid a foundation for the development of new Guang Min drugs.
【学位授予单位】：第二军医大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R91;R914

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