二氢卟吩p<sub>6</sub>醚类光敏剂的合成及光动力抗癌活性研究

马福家; 孟志; 张星杰; 王媛; 马志强; 姚建忠

doi:10.3969/j.issn.1006-0111.201907017

二氢卟吩p₆醚类光敏剂的合成及光动力抗癌活性研究

doi: 10.3969/j.issn.1006-0111.201907017

1.
海军军医大学海军特色医学中心药剂科, 上海 200052
2.
海军军医大学药学院, 上海 200433
3.
宁夏医科大学药学院, 宁夏银川 750004
4.
海军军医大学药学院, 上海 200433;宁夏医科大学药学院, 宁夏银川 750004

基金项目: 国家自然科学基金（81172950），上海市科委重点科技攻关项目（11431920401）

Design, synthesis and antitumor activities of chlorin p₆ ether derivatives as photosensitizer for photodynamic therapy

1.
Department of Pharmacy, Naval Characteristic Medical Center of PLA, Shanghai 200052, China
2.
School of Pharmacy, Naval Medical University, Shanghai 200433, China
3.
School of Pharmacy, Ningxia Medical University, Yinchuan 750004, China
4.
School of Pharmacy, Naval Medical University, Shanghai 200433, China;School of Pharmacy, Ningxia Medical University, Yinchuan 750004, China

摘要: 目的基于前期研究表明二氢卟吩f的3-乙烯基成醚修饰具有更强的光敏抗肿瘤活性而设计合成二氢卟吩p₆醚类光敏剂（ 1 ），研究其初步体外光动力抗癌活性。方法以蚕沙叶绿素a粗提物酸水解产物脱镁叶绿酸a（ 5 ）经碱及空气氧化降解制得的紫红素-18（ 4 ）为先导物，通过碱水解和CH₂N₂甲基化制得二氢卟吩p₆三甲酯（ 2 ）， 2 与33% HBr加成后再和烷氧醇发生亲核取代反应生成目标化合物（ 1 ），并评价其对黑色素瘤B16-F10细胞的光动力杀伤效应。结果 6个目标化合物 1a - 1f 对黑色素瘤B16-F10细胞的体外光动力抗癌活性均优于同类阳性对照药他拉泊芬和维替泊芬，其结构经电喷雾质谱（ESI-MS）、氢谱（¹H NMR）、碳谱（¹³C NMR）及电喷雾高分辨质谱（ESI-HRMS）确证。结论二氢卟吩p₆醚类光敏剂具有光动力抗癌活性强、治疗指数（暗毒/光毒比）高等优点，值得进一步开发研究。
- 光动力治疗 /
- 光敏剂 /
- 二氢卟吩p₆ /
- 醚衍生物 /
- 抗肿瘤
Abstract: Objective To designe, synthesize a series of chlorin p₆ ether photosensitizers and preliminarily investigate their photodynamic antitumor activity based on previous research results that alkoxyl ether derivatives of 3-vinyl on chlorin f exhibited stronger photosensitive antitumor activity than parent compound. Methods Purpurin-18 ( 4 ) was obtained by oxidative degradation with air and alkali on pheophorbide a ( 5 ) which was prepared through acid hydrolysis of chlorophyll a from crude chlorophyll extracts in Chinese traditional herb named Silkworm excrement. Then, chlorin p₆ trimethylester ( 2 ) were formed via basic hydrolysis of internal anhydride ring for lead compound 3 and following immediately methylation with CH₂N₂. The intermediate 2 reacted with 33% HBr, following nucleophilic substitution with various alkoxyl alcohol to get six title compounds ( 1 ). All title compounds were subjected to photodynamic antitumor activity screening for melanoma B16-F10 cell in vitro. Results All title compounds showed much higher phototoxicity against melanoma B16-F10 cells than talaporfin and verteporfin. Their structures were confirmed by ¹H-NMR, ¹³C-NMR, ESI-MS and ESI-HRMS spectra. Conclusion Chlorin p₆ ether compounds were promising candidate photosensitizers for PDT applications due to theirs high dark toxicity/phototoxicity ratio and excellent phototoxicity, which were worthy of further research and development.
- photodynamic therapy (PDT) /
- photosensitizer /
- chlorine p₆ /
- ether derivatives /
- antitumor

[1]	AGOSTINIS P, BERG K, CENGEL K A, et al. Photodynamic therapy of cancer: an update[J]. CA Cancer J Clin,2011,61(4):250-281
[2]	ABRAHAMSE H, HAMBLIN M R. New photosensitizers for photodynamic therapy[J]. Biochem J,2016,473(4):347-364
[3]	DOUGHERTY T J. An update on photodynamic therapy applications[J]. J Clin Laser Med Surg,2002,20(1):3-7
[4]	DROGAT N, GADY C, GRANET R, et al. Design and synthesis of water-soluble polyaminated chlorins and bacteriochlorins - With near-infrared absorption[J]. Dye Pigment,2013,98(3):609-614
[5]	OLIVEIRA K, MOMO P, ASSIS F, et al. Chlorins: natural sources, synthetic developments and main applications[J]. Curr Org Synth,2014,11(1):42-58
[6]	MENG Z, YU B, HAN G Y, et al. Chlorin p6-based water-soluble amino acid derivatives as potent photosensitizers for photodynamic therapy[J]. J Med Chem,2016,59(10):4999-5010
[7]	ZHANG X J, MENG Z, MA Z Q, et al. Design and synthesis of novel water-soluble amino acid derivatives of chlorin p6 ethers as photosensitizer[J]. Chin Chem Lett,2019,30(1):247-249
[8]	GAO Y H, LOVREKOVIĆ V, KUSSAYEVA A, et al. The photodynamic activities of dimethyl 13¹-[2-(guanidinyl)ethylamino] chlorin e₆ photosensitizers in A549 tumor[J]. Eur J Med Chem,2019,177:144-152
[9]	张丹萍, 陈志龙, 杨晓霞, 等. 光动力药物的研究与开发[J]. 药学进展, 2007, 31(12):529-535
[10]	闵祥燕, 曹宁, 严懿嘉, 等. 光动力新药帕利泊芬研究进展[J]. 药学进展, 2019, 43(3):231-237
[11]	沈卫镝, 姚建忠, 方勇, 等. 叶绿素a降解产物紫红素-18的光动力效应[J]. 中国医药工业杂志, 2001, 32(5):217-219
[12]	姚建忠, 陈文晖, 贺祥, 等. 二氢卟吩F甲醚的合成及其光敏化力和肿瘤光生物活性[J]. 药学学报, 2000, 35(1):63-66
[13]	姚建忠, 刘建飞, 张万年, 等. 2-(1-羟基)乙基二氢卟吩f及其醚衍生物的合成和肿瘤光生物活性[J]. 中国药物化学杂志, 2001, 11(1):1-4
[14]	姚建忠, 许德余, 陈文晖, 等. 蚕沙叶绿素的降解及二氢卟吩P6酰胺衍生物的合成[J]. 中国医药工业杂志, 1999, 30(9):403-406

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二氢卟吩p₆醚类光敏剂的合成及光动力抗癌活性研究

doi: 10.3969/j.issn.1006-0111.201907017

Design, synthesis and antitumor activities of chlorin p₆ ether derivatives as photosensitizer for photodynamic therapy

计量

二氢卟吩p₆醚类光敏剂的合成及光动力抗癌活性研究

doi: 10.3969/j.issn.1006-0111.201907017

1. 海军军医大学海军特色医学中心药剂科, 上海 200052

2. 海军军医大学药学院, 上海 200433

3. 宁夏医科大学药学院, 宁夏银川 750004

4. 海军军医大学药学院, 上海 200433;宁夏医科大学药学院, 宁夏银川 750004

English Abstract

Design, synthesis and antitumor activities of chlorin p₆ ether derivatives as photosensitizer for photodynamic therapy

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二氢卟吩p6醚类光敏剂的合成及光动力抗癌活性研究

doi: 10.3969/j.issn.1006-0111.201907017

Design, synthesis and antitumor activities of chlorin p6 ether derivatives as photosensitizer for photodynamic therapy

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出版历程

二氢卟吩p6醚类光敏剂的合成及光动力抗癌活性研究

doi: 10.3969/j.issn.1006-0111.201907017

1. 海军军医大学海军特色医学中心药剂科, 上海 200052 2. 海军军医大学药学院, 上海 200433 3. 宁夏医科大学药学院, 宁夏 银川 750004 4. 海军军医大学药学院, 上海 200433;宁夏医科大学药学院, 宁夏 银川 750004

English Abstract

Design, synthesis and antitumor activities of chlorin p6 ether derivatives as photosensitizer for photodynamic therapy

全文HTML

目录

二氢卟吩p₆醚类光敏剂的合成及光动力抗癌活性研究

Design, synthesis and antitumor activities of chlorin p₆ ether derivatives as photosensitizer for photodynamic therapy

二氢卟吩p₆醚类光敏剂的合成及光动力抗癌活性研究

1. 海军军医大学海军特色医学中心药剂科, 上海 200052

2. 海军军医大学药学院, 上海 200433

3. 宁夏医科大学药学院, 宁夏银川 750004

4. 海军军医大学药学院, 上海 200433;宁夏医科大学药学院, 宁夏银川 750004

Design, synthesis and antitumor activities of chlorin p₆ ether derivatives as photosensitizer for photodynamic therapy