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《山东大学学报(理学版)》 ›› 2019, Vol. 54 ›› Issue (7): 35-41.doi: 10.6040/j.issn.1671-9352.0.2018.264

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一种新型的紫杉烷生物素共轭物的制备

景云荣1(),王昌伟2   

  1. 1. 牡丹江师范学院制药工程系, 黑龙江 牡丹江 157011
    2. 中国科学院广州生物医药与健康研究院, 广东 广州 510530
  • 收稿日期:2018-05-15 出版日期:2019-07-20 发布日期:2019-06-27
  • 作者简介:景云荣(1985—),女,博士,讲师,研究方向为天然抗肿瘤药物. E-mail: swxjyr@126.com
  • 基金资助:
    黑龙江省教育厅资助项目(1353MSYQN011);黑龙江省自然科学基金资助项目(QC2015014);牡丹江市科学技术计划研究项目(Z2016s0026);牡丹江师范学院博士科研启动基金(MNUB201405)

Synthesis of novel taxoid-biotin conjugate

Yun-rong JING1(),Chang-wei WANG2   

  1. 1. Mudanjiang Normal University, Department of Pharmaceutical Engineering, Mudanjiang 157011, Heilongjiang, China
    2. Guangzhou Institute of Biomedicine and Health, Chinese Academy of Science, Guangzhou 510530, Guangdong, China
  • Received:2018-05-15 Online:2019-07-20 Published:2019-06-27
  • Supported by:
    黑龙江省教育厅资助项目(1353MSYQN011);黑龙江省自然科学基金资助项目(QC2015014);牡丹江市科学技术计划研究项目(Z2016s0026);牡丹江师范学院博士科研启动基金(MNUB201405)

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摘要：

生物素与肿瘤细胞表面的生物素受体结合,通过受体介导的内吞作用将共轭物摄入细胞内,二硫键在肿瘤细胞中能够开链,释放出活性物质,实现靶向性给药,从而大大降低传统化疗药物因缺乏对肿瘤细胞的选择性而引起的毒副作用。用巯基置换的方式,合成含有二硫键的连接链;用将羧酸基团转化为酰肼基团的方法,将生物素转化为生物素酰肼;选用具有抗多药耐药性的含氟紫杉烷SB-T-12854作为细胞毒分子;通过含有二硫键的连接链将含氟紫杉烷化合物SB-T-12854与生物素酰肼进行偶连,形成一种新型的紫杉烷生物素共轭物。

关键词: 靶向型给药系统, 紫杉烷, 生物素, 共轭物

Abstract:

The conjugate is designed to be specific to the biotin receptors overexpressed on tumor cell surface and internalized efficiently through receptor-mediated endocytosis, followed by smooth drug release via glutathione-triggered self-immolation of the linker. An efficient mechanism-based tumor-targeting drug delivery system, based on tumor-specific biotin-receptor mediated endocytosis, has reduced the undesirable side effects associated with the traditional cytotoxic chemotherapeutic agents which lack of selectivity to tumor cells and normal cells. The disulfide linker is prepared by subsititution of sulfhydryl group. The tumor-targeting molecule biotin moiety is prepared by conversion of carboxylic acid group to acyl hydrazide group. Fluorotaxane SB-T-12854 with anti multidrug resistance is choosed as th cytotoxic agent. The tumor-targeting drug delivery system is a novel conjugate of a cytotoxic agent (SB-T-12854), a disulfide linker and a tumor-targeting molecule (biotin).

Key words: tumor-specific drug delivery system, taxoid, biotin, conjugate

中图分类号: 

  • R965.1

图1

二硫键自动开链的机制"

图2

SB-T-12854和SB-T-12854-生物素共轭物"

图3

SB-T-12854生物素共轭物的合成 反应条件:(a)高锰酸钾,二氯甲烷,室温; (b)硫脲,氢溴酸, 70 ℃; (c)氢氧化钠溶液,室温; (d)乙醇,回流; (e)三异丙基氯硅烷,三乙胺,二氯甲烷,室温; (f)30%双氧水溶液,乙醇,室温; (g)氢氧化锂,水/四氢呋喃, 60 ℃; (h)乙醇,室温; (i)氯化亚砜,甲醇,回流; (j)水合肼,甲醇,回流; (k)N, N’-二异丙基碳二亚胺, 4-二甲氨基吡啶,二氯甲烷,室温; (l)70%氢氟酸吡啶溶液,乙腈/吡啶, 0 ℃; (m)N-羟基琥珀酰亚胺, N, N’-二异丙基碳二亚胺, 4-二甲氨基吡啶,二氯甲烷,室温; (n)二甲基亚砜,室温。"

图4

荧光标记的分子探针"

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