CN112500278A - NQO1激活的Combretastatin类前药的设计和制备方法 - Google Patents

NQO1激活的Combretastatin类前药的设计和制备方法 Download PDF

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CN112500278A
CN112500278A CN202011556706.8A CN202011556706A CN112500278A CN 112500278 A CN112500278 A CN 112500278A CN 202011556706 A CN202011556706 A CN 202011556706A CN 112500278 A CN112500278 A CN 112500278A
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combretastatin
nqo1
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cancer
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唐寿初
吴志华
李嘉
董康
王晓磊
刘剑
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Lanzhou University
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Abstract

本发明提供了NQO1激活的Combretastatin类前药的设计和制备方法，由于肿瘤细胞中高表达的NQO1，引入NQO1激活的醌酸链实现了对肿瘤细胞的靶向作用，能够在肿瘤细胞中高效、快速的释放Combretastatin类原药，达到抑制肿瘤增殖的目的。本发明合成方法简单，原料廉价易得，能够实现工业化生产。

Description

NQO1激活的Combretastatin类前药的设计和制备方法
技术领域
本发明涉及NQO1激活的Combretastatin类前药的设计和制备方法。
背景技术
癌症已成为危害人类生命与健康的最大敌人之一，防控癌症已经上升为我国的国家战略。根据数据统计，我国2018年癌症新发病例为380.4万例，占全球癌症新发病例21.0％，癌症死亡病例为229.6万例，占全球癌症死亡23.9％。我国癌症发病率前5位癌种依次为肺癌、胃癌、结直肠癌、肝癌和乳腺癌。我国死亡率前5位癌种依次为肺癌、肝癌、胃癌、食管癌和结直肠癌。中国30岁以上人群癌症发病率快速上升，60岁以上人群发病人数最多。
NAD(P)H：醌氧化还原酶1(NQO1)能够专性催化醌两电子还原反应,具有化学保护和生物激活作用。值得注意的是，NQO1在多种肿瘤细胞特别是肺癌、结肠癌、乳腺癌细胞中的表达远超于正常组织。由于NQO1在肿瘤细胞的高表达的特性,它被认为是治疗多种肿瘤的潜在分子靶标。靶向NQO1药物有望实现高选择性、特异性杀灭肿瘤细胞。
南非矮生柳树Combretum caffrum的次级代谢产物CA-4等具有极强的抗肿瘤活性。CA-4作为强效的具有苯乙烯结构的β微管蛋白抑制剂，对众多肿瘤细胞都有很强的抑制作用。然而，其水溶性低和选择性差的特点限制了它在临床的用途，设计一类NQO1激活的Combretastatin类化合物前药可以很好地解决这类问题。
发明内容
本发明的所述方涉及新NQO1激活的Combretastatin类前药的设计和制备法。
所述Combretastatin类前药为以下结构：
Figure BDA0002858526040000011
本发明提供Combretastatin类前药的制备方法，包括以下步骤：
反应瓶中加入溶剂1，3-甲基-3-(2,4,5-三甲基-3,6-二氧代环己-1,4-二烯-1-基)丁酸和EDCI，搅拌10分钟，再加入DMAP和Combretastatin衍生物，室温反应，TLC检测直至原料消失，硅胶分离纯化得到目标化合物，反应方程式为：
Figure BDA0002858526040000021
上述的NQO1激活的Combretastatin类前药的设计和制备方法，其特征在于：所用的溶剂1为二氯甲烷，四氢呋喃中的一种。
根据权利要求1所述的NQO1激活的Combretastatin类前药的设计和制备方法，其特征在于：所用的缩合剂为EDCI，DCC中的一种。
上述的NQO1激活的Combretastatin类前药应用于抑制细胞增殖紊乱和各类抗癌细胞活性，癌症如淋巴癌、骨癌、肝癌、乳腺癌、胃癌、肺癌、白血病。
具体实施方式
下面的实施例可以使本专业技术人员更全面的理解本发明，但不以任何方式限制本发明。
实施例1：制备NQO1激活的Combretastatin类前药1的反应步骤：
反应瓶中加入4mL DCM，3-甲基-3-(2,4,5-三甲基-3,6-二氧代环己-1,4-二烯-1-基)丁酸5(25mg)和EDCI(22mg)，搅拌10分钟，再加入DMAP(12mg)和Combretastatin衍生物3(32mg)，室温反应，TLC检测直至原料消失，硅胶分离纯化得到目标化合物1(50mg，91％)。
实施例1所得产品1的结构、核磁数据如下：
Figure BDA0002858526040000031
1H NMR(400MHz,Chloroform-d)δ7.07(dd,J＝8.5,2.1Hz,1H),6.90(d,J＝2.1Hz,1H),6.79(d,J＝8.5Hz,1H),6.46(s,2H),6.41(s,2H),3.82(s,3H),3.72(s,3H),3.66(s,6H),3.19(s,2H),2.14(s,3H),1.89(s,6H),1.48(s,6H).13C NMR(101MHz,Chloroform-d)δ170.60,152.95,152.22,150.08,143.00,139.10,138.85,138.28,132.42,130.00,129.49,128.49,127.72,123.06,111.90,60.91,55.88,55.76,47.14,38.47,28.78,14.26,12.61,12.12.
实施例2：制备NQO1激活的Combretastatin类前药2的反应步骤：
反应瓶中加入4mL THF，3-甲基-3-(2,4,5-三甲基-3,6-二氧代环己-1,4-二烯-1-基)丁酸5(30mg)和DCC(25mg)，搅拌10分钟，再加入Combretastatin衍生物3(38mg)和DMAP(15mg)，室温反应，TLC检测直至原料消失，硅胶分离纯化得到目标化合物1(54mg，83％)。
实施例2所得产品2的结构、核磁数据如下：
Figure BDA0002858526040000032
1H NMR(400MHz,Chloroform-d)δ8.47(d,J＝1.9Hz,1H),7.74(s,1H),7.17(dd,J＝8.5,2.0Hz,1H),6.93(d,J＝4.6Hz,2H),6.83(d,J＝8.5Hz,1H),6.72(s,2H),3.91(s,6H),3.87(s,3H),3.86(s,3H),3.12(s,2H),2.17(s,3H),1.96(d,J＝3.4Hz,6H),1.52(s,6H).13C NMR(101MHz,CDCl3)δ191.44,187.54,170.36,153.34,153.01,147.22,143.36,138.43,138.35,137.52,133.35,130.38,127.91,127.77,127.01,121.58,117.39,109.99,103.21,60.97,56.10,55.81,50.82,38.26,29.08,14.25,12.71,12.20.
实施例3
抗增殖活性实验
收集对数期CT26、HuH-7、LoVo、PLC/PRF/5、MG-63、SW480、GES-1细胞，调整细胞悬液浓度，每孔加入100ul,铺板使待测细胞调密度至3000孔，(边缘孔用无菌PBS填充)。5％CO2，37℃孵育，至细胞单层铺满孔底(96孔平底板),加入浓度梯度的药物1,细胞贴壁后即可加药，设置9个浓度梯度,每孔100ul,设3个复孔.5％CO2，37℃孵育72小时，倒置显微镜下观察。每孔加入20ulMTT溶液(5mg/ml，即0.5％MTT)，继续培养4h。终止培养，小心吸去孔内培养液。每孔加入150ul二甲基亚砜，置摇床上低速振荡10min，使结晶物充分溶解。在酶联免疫检测仪OD490nm处测量各孔的吸光值。
实施例3的体外抗增殖活性实验结果如下：
Figure BDA0002858526040000041

Claims (4)

1.NQO1激活的Combretastatin类前药的设计和制备方法，其中化合物结构为：
Figure FDA0002858526030000011
NQO1激活的Combretastatin类前药的制备方法：反应瓶中加入溶剂1，3-甲基-3-(2,4,5-三甲基-3,6-二氧代环己-1,4-二烯-1-基)丁酸和缩合剂，搅拌10分钟，再加入DMAP和Combretastatin衍生物，室温反应，TLC检测直至原料消失，硅胶分离纯化得到目标化合物，反应方程式为：
Figure FDA0002858526030000012
2.根据权利要求1所述的NQO1激活的Combretastatin类前药的设计和制备方法，其特征在于：所用的溶剂1为二氯甲烷，四氢呋喃中的一种。
3.根据权利要求1所述的NQO1激活的Combretastatin类前药的设计和制备方法，其特征在于：所用的缩合剂为EDCI，DCC中的一种。
4.权利要求1所述的NQO1激活的Combretastatin类前药应用于抑制细胞增殖紊乱和各类抗癌细胞活性，癌症如淋巴癌、骨癌、肝癌、乳腺癌、胃癌、肺癌、白血病。
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Publication number Priority date Publication date Assignee Title
US20040152629A1 (en) * 2000-12-21 2004-08-05 Hadfield John Anthony Substituted stilbenes and their reactions
CN111362837A (zh) * 2020-03-23 2020-07-03 新乡医学院 一种NQO1激活型Combretastatin A4前药及其合成方法和应用

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Application publication date: 20210316