本文選題：光動力治療　切入點(diǎn)：光敏劑　出處：《第二軍醫(yī)大學(xué)》2016年碩士論文　論文類型：學(xué)位論文

【摘要】：光動力治療已發(fā)展成為主流的腫瘤治療手段,其中光敏劑是核心。第二代光敏劑二氫卟吩具有摩爾吸光系數(shù)強(qiáng)、毒性小以及皮膚光毒性持續(xù)時(shí)間短等優(yōu)勢,成為目前研究的熱點(diǎn)。本課題組前期以蠶糞為最初原料,設(shè)計(jì)合成得到多個(gè)二氫卟吩類化合物。本論文主要內(nèi)容是以紫紅素-18為先導(dǎo)物,設(shè)計(jì)合成紫紅素-18醚、二氫卟吩P6二甲酯以及苯并葉綠卟啉P6二甲酯三大類26個(gè)化合物,發(fā)現(xiàn)多個(gè)化合物具有較優(yōu)的體外光動力抗腫瘤活性。一、基于二氫卟吩P6的水溶性光敏劑合成、機(jī)制研究和生物活性評價(jià)本課題組前期通過降解蠶糞得到多個(gè)二氫卟吩類先導(dǎo)物,進(jìn)行結(jié)構(gòu)修飾得到多個(gè)化合物。在此基礎(chǔ)上采用上市藥物維替泊芬和他拉泊芬的設(shè)計(jì)策略,設(shè)計(jì)合成出二氫卟吩P6二甲酯和苯并葉綠卟啉P6二甲酯以及相應(yīng)氨基酸衍生物,兩類共6個(gè)化合物。體外光動力抗腫瘤研究結(jié)果表明,光敏劑用氨基酸殘基結(jié)構(gòu)修飾后,細(xì)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、最大吸收波長處摩爾吸光系數(shù)強(qiáng)、單線態(tài)氧量子產(chǎn)率較高、暗毒性低以及體內(nèi)外光動力抗腫瘤活性優(yōu)于陽性藥維替泊芬,有望成為候選藥物。構(gòu)效關(guān)系研究表明,氨基酸結(jié)構(gòu)對活性有影響,天冬氨酸結(jié)構(gòu)優(yōu)于谷氨酸結(jié)構(gòu)。二、二氫卟吩類光敏劑的設(shè)計(jì)、合成及光動力抗腫瘤活性研究大量研究資料以及本課題組前期研究結(jié)果表明,在二氫卟吩類光敏劑結(jié)構(gòu)中引入醚類基團(tuán)可有效改善光敏劑光動力抗腫瘤活性。以紫紅素-18和化合物7b為基礎(chǔ),在其分子中引入不同醚類結(jié)構(gòu)進(jìn)行更深入的結(jié)構(gòu)修飾,合成得到20個(gè)化合物。體外抗腫瘤活性測試表明大部分化合物具有較優(yōu)的光毒性,其中化合物14d、15d和17h具有相對較高的暗毒性光毒性比,明顯優(yōu)于陽性藥維替泊芬。綜上所述,本研究通過對紫紅素-18進(jìn)行結(jié)構(gòu)改造修飾,合成得到26個(gè)新化合物。本文創(chuàng)新點(diǎn)為:(1)以蠶糞為最初原料,實(shí)現(xiàn)了廢物利用;(2)在光敏劑結(jié)構(gòu)中引入氨基酸結(jié)構(gòu),大大改善了光敏劑水溶性,顯著降低暗毒性;(3)發(fā)現(xiàn)一個(gè)水溶性、細(xì)胞暗毒性以及體內(nèi)外抗腫瘤活性均優(yōu)于上市藥物維替泊芬的高活性、低毒性化合物7b。上述研究結(jié)果為研發(fā)新型光敏劑類藥物奠定了一定基礎(chǔ)。
[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.
【學(xué)位授予單位】：第二軍醫(yī)大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2016
【分類號】：R91;R914

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