CN110437281A - 一种吡啶盐改性的含有不同硝基芳杂环的前药小分子 - Google Patents
一种吡啶盐改性的含有不同硝基芳杂环的前药小分子 Download PDFInfo
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- CN110437281A CN110437281A CN201910650638.2A CN201910650638A CN110437281A CN 110437281 A CN110437281 A CN 110437281A CN 201910650638 A CN201910650638 A CN 201910650638A CN 110437281 A CN110437281 A CN 110437281A
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/58—Pyridine rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一种吡啶盐改性的含有不同硝基芳杂环的前药小分子,其结构式为式(I)、式(II)或式(III):本发明通过设计合成了一系列新型的小分子低氧激活前药,通过对已合成的前药筛选发现,不同芳杂环改性的低氧激活前药对氧气的敏感程度不同,其中含有呋喃环改性的前药分子在细胞水平对3LL,PC‑3,HepG2以及B16表现出最好的低氧毒性;通过构建小鼠肺癌3LL细胞模型,研究其抗肿瘤活性发现,发现呋喃环改性的前药分子Q1能够更有效地抑制肿瘤细胞的增殖。
Description
技术领域
本发明涉及化学医药领域;具体涉及一种吡啶盐改性的含有不同硝基芳杂环的前药小分子及其制备方法及应用。
背景技术
肿瘤是机体在各种致瘤因子作用下,局部组织细胞增生形成的,在临床上有实体瘤和非实体瘤之分。实体肿瘤的微脉管系统承担了血液与组织液之间氧、代谢产物和能量信息交换的功能。微脉管结构的异常以及肿瘤细胞过度生长和增殖消耗大量营养和氧气,共同构成了实体肿瘤微环境的低氧特点。低氧对肿瘤的发生和发展起着重要的作用,临床上,肿瘤低氧会促进肿瘤对放、化疗耐受性的产生。研究发现,肿瘤低氧可促进血管新生,促进肿瘤侵袭和转移,帮助肿瘤逃避体内免疫监视,抑制DNA修复途径、增加基因组的不稳定性,降低肿瘤细胞对药物敏感性等众多生物学意义。基于此,低氧也是一个良好的肿瘤治疗靶点。利用低氧的特点设计低氧诱导的药物可以特异性地使药物活性分子在肿瘤低氧区发挥药效,从而避免对正常组织产生毒性。
目前已经发展了许多肿瘤化疗的药物,如氮芥类、嘧啶类、铂类、卟啉类等。在各种抗肿瘤化疗药物中,氮芥类化合物是使用较早而又重要的一类抗肿瘤药,该类药物是一种强的烷化试剂,对肿瘤的杀伤能力较大,抗肿瘤范围广,合成简便,成本低廉,但其选择性较差,毒性较大,水溶性比较有限,使其不容易给药。而针对低氧肿瘤的治疗主要有两种策略:低氧激活前药和靶向于低氧相关信号通路的小分子抑制剂。对于小分子抑制剂来讲,目前的热点旨在寻求低氧诱导因子1(HIF1)的抑制剂,由于这类抑制剂在杀灭肿瘤低氧细胞时的重大缺陷还未被探明,所以这类分子水平的靶向药物大多数应用于其他领域或者作为低选择性的低氧细胞毒药物。低氧激活前药是一类对本身无毒或毒性较低、进入肿瘤低氧微环境后即可被激活从而释放出细胞毒性药物,从而发挥抗肿瘤治疗效果;而在正常组织中影响较小,即使可以被还原也可以通过氧气氧化重新变回到无毒性原型药物。与化疗药物相比,低氧前药靶向性更强,毒性更小。因此,本发明通过将烷基化的氮芥引入硝基化合物类前药分子中,在降低化疗药物毒性的同时可以有效地增加前药分子的低氧肿瘤靶向性,而通过前药分子的吡啶化可以增加药物分子的水溶性,有效地实现药物分子的静脉给药,有效地调节前药整体分子的脂水分配。即本发明拟以含硝基的不同氧化还原电势芳杂环作为还原酶低氧响应物,首先通过化学键(醚键或酯键)连接不同的烷化剂氮芥药物释放分子,后通过功能化吡啶盐改性来构建一系列新型的小分子肿瘤低氧前药分子库,通过筛选,达到对低氧肿瘤组织治疗的目的。
发明内容
本发明要解决的技术问题是:克服现有技术的不足,即低氧对肿瘤的发生和发展起着重要的作用,临床上,肿瘤低氧会促进肿瘤对放、化疗耐受性的产生。常规的化疗药物由于选择性较差,毒性较大,水溶性比较有限,使其给药存在一定的困难。低氧激活前药分子的构建,理论上可以增加药物分子的靶向性从而降低对正常组织的毒性,本发明通过引入一系列含硝基的芳杂环作为还原酶低氧响应物,通过化学键或修饰基团连接不同的烷化剂氮芥药物释放分子,构建一系列吡啶盐改性的含有不同硝基芳杂环的前药小分子药物库,并给出其合成方法,进而实现对低氧肿瘤组织治疗的目的。
本发明采用的技术方案为:
本发明涉及一种吡啶盐改性的含有不同硝基芳杂环的前药小分子,其结构式为式(Ⅰ)、式(II)、式(Ⅲ):
其中R为如下取代基中的一种;
R’为如下取代基中的一种:
Linker为醚键-O-、酯键
更优选地,R为如下取代基中的一种
更优选地,所述的Linker为酯键
本发明还提供了上述前药小分子的制备方法,结构式中linker为酯键;该制备方法,包括如下步骤:
a、含羟基的芳杂环的合成
首先将原料式(a)-式(k)溶于无水甲醇中,冰浴条件下向其中加入硼氢化钠,室温反应,点板确定反应终点,后向其中加入水停止反应,旋蒸除去溶剂甲醇,后用二氯甲烷萃取得油相,无水硫酸钠干燥两个小时,过滤旋蒸除去溶剂,得粗品,用石油醚:乙酸乙酯过柱得产物;(核磁确定其结构)。
原料的结构为:
b、吡啶盐前体的合成
-80℃,氩气保护下,将步骤a产物溶于干燥的THF溶液中,向其中加入1.0M二(三甲基硅基)氨基锂的THF溶液,反应十分钟,后滴加三氟醋酸钠的THF溶液,继续低温反应两个小时,向混合溶液中加入正丙胺、正丁胺、正戊胺或正已胺的THF溶液,继续低温-80℃反应,点板确定反应终点,后恢复室温,用水终止反应,旋蒸除去THF溶液,萃取干燥,过滤旋蒸,用石油醚:乙酸乙酯:甲醇过柱,得产物;(核磁确定其结构。)
c、吡啶盐改性前药的合成
将步骤b合成的吡啶盐前体溶于吡啶溶液中,氩气保护下,80℃-90℃搅拌反应24h以上,点板确定反应终点,用油泵旋蒸除去吡啶溶剂,得吡啶盐粗品,用二氯甲烷乙酸乙酯多次超声冲洗除去油溶性原料,将粗品溶于水中过滤得水溶液,用冻干机冻干得吡啶盐改性的前药产物,核磁确定其结构。
优选地,所述的步骤a中原料式(a)-式(k)的用量为10mmol;硼氢化钠用量为15-40mmol;所述的步骤b中,步骤a产物的用量是2mmol;二(三甲基硅基)氨基锂用量是2-3mmol;三氟醋酸钠的用量是2-3mmol;正丙胺、正丁胺、正戊胺或正已胺用量是2-3mmol;所述的步骤c中,步骤b合成的吡啶盐前体的用量为1mmol;吡啶溶液的用量为10ml。
本发明还提供了上述吡啶盐改性的含有不同硝基芳杂环的前药小分子在制备抗肿瘤药物中的用途。所述的肿瘤如肺癌、前列腺癌、肝癌、黑色素瘤等。本发明所具有的有益效果:
本发明通过设计合成了一系列新型的小分子低氧激活前药,通过对已合成的前药筛选发现,不同芳杂环改性的低氧激活前药对氧气的敏感程度不同,其中含有呋喃环改性的前药分子在细胞水平对3LL,PC-3,HepG2以及B16表现出最好的低氧毒性;通过构建小鼠肺癌3LL细胞模型,研究其抗肿瘤活性发现,发现呋喃环改性的前药分子Q1能够更有效地抑制肿瘤细胞的增殖。
附图说明
图1为低氧(0.5%)下,临床前药TH-302和合成前药Q1-Q5对HepG2,3LL细胞抑制效果图;
图2为在正常氧(21%)和低氧(0.5%)下,临床前药与我们合成前药(TH-302,Q1,Q4)对HepG2、B16和PC-3细胞的抑制效果图;
图3为在不同氧气浓度下(21%,10%,5%,2%,0.5%),小分子前药Q1对HepG2细胞的抑制效果图;
图4为动物实验,不同实验组与对照组小鼠体重随时间变化图;
图5为不同实验组与对照组小鼠肿瘤随时间变化情况图;
图6为不同实验组与对照组小鼠处死后取出肿瘤组织照片图。
具体实施方式
下面结合具体实施例对本发明作进一步说明,但不限定本发明的保护范围。
以中间连接基团为酯键,连接的脂肪胺为正丙胺,其中一种烷基化试剂为例进行阐述具体实施方案,其他的类似。
合成步骤
1.1. 5-硝基糠基乙醇2a
将5-硝基糠醛(10mmol,1.41g)溶于甲醇(100ml)中,冰浴条件下向其中加入硼氢化钠(15mmol,0.6g),室温反应3h,点板确定反应终点,后向其中加入水(10ml)停止反应,旋蒸除去溶剂甲醇,后用二氯甲烷(25ml*3)萃取三次得油相,无水硫酸钠干燥两个小时,过滤旋蒸除去溶剂,得粗品,用石油醚:乙酸乙酯(4:1)过柱得产物2a(0.91g,62.9%)。1H NMR(400MHz,CDCl3)δ(ppm)5.01(d,2H,J=8.0Hz,-CH2),6.94(d,1H,J=8.0Hz,furyl-H),7.54(d,1H,J=8.0Hz,furyl-H)。
1.2. 2-(羟甲基)-5-硝基噻吩2b
将上述步骤1.1中的5-硝基糠醛换成5-硝基噻吩-2-甲醛(10mmol,1.57g),其他步骤类似,得产物2b(1.39g,88.6%)。1H NMR(400MHz,CDCl3)δ(ppm)4.88(d,2H,J=8.0Hz,-CH2),6.94(d,1H,J=8.0Hz,thienyl-H),7.82(d,1H,J=8.0Hz,thienyl-H)。
1.3. 4-硝基苯甲醇2c
将上述步骤1中的5-硝基糠醛换成4-硝基苯甲醛(10mmol,1.51g),其他步骤类似,得产物2c(1.38g,90%)。1H NMR(400MHz,CDCl3)δ(ppm)4.86(d,2H,J=8.0Hz,-CH2),7.55(d,1H,J=8.0Hz,phenyl-H),8.24(d,1H,J=8.0Hz,phenyl-H)。
2.1 5-硝基苯并呋喃-2-甲醇2d
将5-硝基苯并呋喃-2-羧酸乙酯(10mmol,2.35g)溶于四氢呋喃与甲醇(60ml:5ml)的溶液中,冰浴条件下,向其中加入硼氢化钠粉末(30mmol,1.2g),冰浴下继续反应1h,后恢复室温反应,点板确定反应终点,然后将上述溶液倒入冷水(200ml)中终止反应,调节溶液PH为7,旋蒸除去THF和CH3OH,萃取干燥,旋蒸,用石油醚:乙酸乙酯(4:1)过柱,得产物2d(1.23g,63.5%)。1H NMR(400MHz,CDCl3)δ(ppm)4.85(d,2H,J=8.0Hz,-CH2),6.83(s,1H,benzofuryl-H),7.56(d,1H,J=8.0Hz,benzofuryl-H),8.24(d,1H,J=8.0Hz,benzofuryl-H),8.51(s,1H,benzofuryl-H)。
2.2. 2-硝基噻唑-5-甲醇2e
将上述步骤2.1中的5-硝基苯并呋喃-2-羧酸乙酯换成2-硝基噻唑-5-羧酸乙酯(10mmol,2g),其他步骤类似,得产物2e(1.12g,70%)。1H NMR(400MHz,CDCl3)δ(ppm)4.42(d,2H,J=8.0Hz,-CH2),8.52(s,1H,thiazolyl-H)。
3.吡啶盐前体合成
-80℃,氩气保护下,将2a-2e等(2mmol)溶于干燥的THF(50ml)溶液中,向其中加入1.0M二(三甲基硅基)氨基锂的THF溶液(2.2mmol,2.2ml),反应十分钟,后滴加三氟醋酸钠(2.2mmol,0.56g)的THF(3ml)溶液,继续低温反应1-2小时,向混合溶液中加入正丙胺(3mmol,2.5ml)的THF(2ml)溶液,继续反应点板确定反应终点,后恢复室温后,用水终止反应,旋蒸除去THF溶液,萃取干燥,过滤旋蒸,用石油醚:乙酸乙酯:甲醇过柱,得产物3a-3e。
3a(0.33g,42.1%):1H NMR(400MHz,CDCl3)δ(ppm)0.91-0.94(m,3H,-CH3),1.50-1.56(m,2H,-CH2),2.86-2.92(m,4H,-CH2),3.41-3.48(m,2H,-CH2),3.62-3.67(m,4H,-CH2),5.03(d,2H,J=8.0Hz,-CH2),6.65(d,1H,J=4.0Hz,furyl-H),7.27(d,1H,J=4.0Hz,furyl-H).
3b(0.27g,33.5%):1H NMR(400MHz,CDCl3)δ(ppm)0.91-0.95(m,3H,-CH3),1.51-1.55(m,2H,-CH2),2.87-2.90(m,2H,-CH2),3.42-3.48(m,4H,-CH2),3.63-3.66(m,4H,-CH2),5.16(d,2H,J=8.0Hz,-CH2),7.02(d,1H,J=8.0Hz,thienyl-H),7.82(d,1H,J=8.0Hz,thienyl-H).
3c(0.23g,28.7%):1H NMR(400MHz,CDCl3)δ(ppm)0.91-0.95(m,3H,-CH3),1.51-1.54(m,2H,-CH2),2.87-2.92(m,2H,-CH2),3.40-3.46(m,4H,-CH2),3.64-3.67(m,4H,-CH2),5.12(d,2H,J=8.0Hz,-CH2),7.55(d,2H,J=8.0Hz,phenyl-H),8.24(d,2H,J=8.0Hz,phenyl-H).
3d(0.39g,44.6%):1H NMR(400MHz,CDCl3)δ(ppm)0.82-0.86(m,3H,-CH3),1.37-1.43(m,2H,-CH2),2.65-2.69(m,2H,-CH2),3.20-3.26(m,4H,-CH2),3.62-3.68(m,4H,-CH2),5.07(d,2H,J=8.0Hz,-CH2),7.21(s,1H,benzofuryl-H),7.84(d,1H,J=8.0Hz,benzofuryl-H),8.24(d,1H,J=8.0Hz,benzofuryl-H),8.66(s,1H,benzofuryl-H).
3e(0.21g,26.1%):1H NMR(400MHz,CDCl3)δ(ppm)0.92-0.95(m,3H,-CH3),1.38-1.41(m,2H,-CH2),1.56-1.62(m,2H,-CH2),3.60-3.64(m,4H,-CH2),4.37-4.42(m,4H,-CH2),5.01(d,2H,J=8.0Hz,-CH2),8.52(s,1H,thiazolyl-H).
4.吡啶盐的合成
将吡啶盐前体3a-3e(1mmol)溶于吡啶溶液(10ml)中,氩气保护下,80℃-90℃搅拌反应24h以上,点板确定反应终点,用油泵旋蒸除去吡啶溶剂,得吡啶盐粗品,用二氯甲烷乙酸乙酯多次超声冲洗除去油溶性的副产物,将产物溶于水中过滤得水溶液,用冻干机冻干得产物Q1-Q5,核磁确定产物结构。
Q1(0.20g,37.2%):1H NMR(400MHz,D2O)δ(ppm)1.02-1.06(m,3H,-CH3),1.69-1.73(m,2H,-CH2),2.86-2.93(m,4H,-CH2),3.33-3.34(m,2H,-CH2),3.65-3.69(m,4H,-CH2),5.03(d,2H,J=8.0Hz,-CH2),6.82(d,1H,J=4.0Hz,furyl-H),7.45(d,1H,J=4.0Hz,furyl-H),8.06-8.17(m,4H,pyridyl-H),8.58-8.66(m,2H,pyridyl-H),9.00-9.03(m,4H,pyridyl-H).
Q2(0.25g,43.8%):1H NMR(400MHz,D2O)δ(ppm)1.02-1.06(m,3H,-CH3),1.70-1.72(m,2H,-CH2),2.89-2.93(m,2H,-CH2),3.15-3.24(m,4H,-CH2),4.72-4.75(m,4H,-CH2),5.04(d,2H,J=8.0 Hz,-CH2),7.82(d,1H,J=8.0 Hz,thienyl-H),8.03-8.10(m,4H,pyridyl-H),8.24(d,1H,J=8.0 Hz,thienyl-H),8.56-8.60(m,2H,pyridyl-H),8.85-8.94(m,4H,pyridyl-H).
Q3(0.17g,31%):1H NMR(400MHz,D2O)δ(ppm)0.91-0.95(m,3H,-CH3),1.51-1.56(m,2H,-CH2),2.87-2.93(m,2H,-CH2),3.40-3.46(m,4H,-CH2),4.64-4.67(m,4H,-CH2),5.05(d,2H,J=8.0Hz,-CH2),7.55(d,2H,J=8.0Hz,phenyl-H),8.10-8.14(m,4H,pyridyl-H),7.24(d,2H,J=8.0Hz,phenyl-H),8.59-8.63(m,2H,pyridyl-H),9.12-9.16(m,4H,pyridyl-H).
Q4(0.25g,42.1%):1H NMR(400MHz,D2O)δ(ppm)1.02-1.06(m,3H,-CH3),1.68-1.73(m,2H,-CH2),2.89-2.93(m,2H,-CH2),3.21-3.24(m,4H,-CH2),4.69-4.72(m,4H,-CH2),5.03(d,2H,J=8.0Hz,-CH2),7.47(s,1H,benzofuryl-H),7.72(d,1H,J=8.0 Hz,benzofuryl-H),8.02(d,1H,J=8.0Hz,benzofuryl-H),8.08-8.16(m,4H,pyridyl-H),8.59-8.67(m,2H,pyridyl-H),8.68(s,1H,benzofuryl-H),9.12-9.22(m,4H,pyridyl-H).
Q5(0.20g,35.6%):1H NMR(400MHz,D2O)δ(ppm)0.96-1.02(m,3H,-CH3),1.26-1.29(m,2H,-CH2),1.38-1.40(m,2H,-CH2),4.10-4.15(m,4H,-CH2),4.38-4.41(m,4H,-CH2),5.01(d,2H,J=8.0Hz,-CH2),8.03-8.10(m,4H,pyridyl-H),8.51(s,1H,thiazolyl-H),8.57-8.65(m,2H,pyridyl-H),8.96-9.13(m,4H,pyridyl-H).
细胞实验
为了评价不同氧气浓度下前药的细胞毒性,选用小鼠肺癌3LL肿瘤细胞,PC-3人源前列腺癌、HepG2人源肝癌细胞、B16小鼠黑色素瘤细胞为肿瘤细胞模型进行实验,分别将三种细胞在DMEM完全培养基中培养(90%DMEM+10%FBS+1%PS),待细胞传2-3代,细胞状态良好之后,将细胞(5×103细胞/孔)种植在96孔板中,将96孔板置于CO2恒温培养箱中培养待细胞贴壁后,每个孔中加入不同浓度的前药(2μM~20μM~50μM~100μM~200μM),并设立未加入前药的细胞作为空白对照组,每组设5个平行,在不同的氧气浓度下(21%~10%~5%~2%~0.5%)培养24h,然后向每个孔中加入10μL的MTT溶液,放入恒温培养箱中孵育4h(37℃),将96孔板取出并移除培养基,每孔中加入100μL的DMSO,震荡15min使甲臜结晶溶解,利用酶标仪检测吸光度(578nm),并利用吸光度值公式计算细胞的存活率。细胞的相对存活率(%)=实验组吸收/对照组吸收×100%。
通过测试前药分子Q1-Q5对于HepG2,3LL肿瘤细胞的低氧响应性发现(图1),Q1-Q5对三种不同的肿瘤细胞都表现出了一定的氧气响应性,低氧浓度下(0.5%)对细胞的毒性远远大于常氧(21%)毒性(图2),这与实验设计的目的相吻合,肿瘤细胞中由于还原酶的存在,使得在低氧浓度下,前药分子断裂释放出化疗药物分子,从而杀灭肿瘤细胞;此外Q1对于HepG2细胞表现出与临床用的前药TH-302相比拟的肿瘤细胞抑制效果;而相比TH-302,我们合成的前药Q1-Q5对三种细胞都表现出了更小的常氧(21%)毒性,表明对正常组织具有更小的毒副作用,为我们后期前药分子的合成评估提供了有力的支撑。此外,通过研究前药分子在不同氧气浓度下作用于HepG2细胞的响应性我们发现如图3所示,随着氧气浓度降低(21%~10%~5%~2%~0.5%),Q1对于HepG2细胞的毒性逐渐增强。这些结果都表明本发明制备的新型的小分子前药具有良好的肿瘤低氧响应特性。
动物实验
小鼠模型建立
所有的动物都是符合实验动物使用伦理的相关规定。购买自斯贝福(北京)生物技术有限公司的雌性C57小鼠(6-8周,17-18g),为了构建小鼠皮下异位种植的小鼠肺癌3LL肿瘤模型,取雌性C57小鼠,通过在小鼠背部注射100μL含有1*106 3LL细胞的无血清DMEM培养液。注射细胞六天后,开始测量肿瘤体积(长*宽2/2)并且开始给药。体内毒性测试
小鼠被随机分成4组,每组6只(化疗组5只),分别作为空白对照组,紫杉醇PTX化疗组(5mg/kg,200μL),呋喃环改性前药Q1为基础的实验组(40mg/kg,200μL),前药与化疗药协同治疗PTX+Q1组(40mg/kg+5mg/kg,400μL),每天注射一次,连续注射5天,第一天注射药物记为治疗第一天,每天记录小鼠的体重和肿瘤体积变化,实验结果如图3-5所示。
图4所示实验组与对照组小鼠体重随时间变化曲线,由图中可以看出注射药物之后小鼠的体重基本没有变化,说明药物对小鼠基本没有潜在的毒副作用。而如图5所示,小鼠的体积随时间变化曲线我们可以看出,呋喃环改性的前药分子Q1表现出了明显的肿瘤抑制效果,相比之下前药Q1与化疗药物紫杉醇共同用药组肿瘤抑制效果略优,这与体外细胞实验结果中呋喃环改性的前药分子Q1在不同氧气浓度下对3LL细胞具有一定的杀伤效果相吻合。
Claims (8)
1.一种吡啶盐改性的含有不同硝基芳杂环的前药小分子,其特征在于:其结构式为式(Ⅰ)、式(II)或式(Ⅲ):
其中R为如下取代基中的一种;
R’为如下取代基中的一种:
Linker为醚键-O-、酯键
2.根据权利要求1所述的一种吡啶盐改性的含有不同硝基芳杂环的前药小分子,其特征在于:R为如下取代基中的一种:
3.根据权利要求1所述的一种吡啶盐改性的含有不同硝基芳杂环的前药小分子,其特征在于:Linker为酯键
4.权利要求1所述前药小分子的制备方法,结构式中linker为酯键;该制备方法,包括如下步骤:
a、含羟基的芳杂环的合成
首先将原料式(a)-式(k)溶于无水甲醇中,冰浴条件下向其中加入硼氢化钠,室温反应,点板确定反应终点,后向其中加入水停止反应,旋蒸除去溶剂甲醇,后用二氯甲烷萃取得油相,无水硫酸钠干燥两个小时,过滤旋蒸除去溶剂,得粗品,用石油醚:乙酸乙酯过柱得产物;
原料的结构为:
b、吡啶盐前体的合成
-80℃,氩气保护下,将步骤a产物溶于干燥的THF溶液中,向其中加入1.0M二(三甲基硅基)氨基锂的THF溶液,反应十分钟,后滴加三氟醋酸钠的THF溶液,继续低温反应两个小时,向混合溶液中加入正丙胺、正丁胺、正戊胺或正已胺的THF溶液,继续低温-80℃反应,点板确定反应终点,后恢复室温,用水终止反应,旋蒸除去THF溶液,萃取干燥,过滤旋蒸,用石油醚:乙酸乙酯:甲醇过柱,得产物;
c、吡啶盐改性前药的合成
将步骤b合成的吡啶盐前体溶于吡啶溶液中,氩气保护下,80℃-90℃搅拌反应24h以上,点板确定反应终点,用油泵旋蒸除去吡啶溶剂,得吡啶盐粗品,用二氯甲烷乙酸乙酯多次超声冲洗除去油溶性原料,将粗品溶于水中过滤得水溶液,用冻干机冻干得吡啶盐改性的前药产物,核磁确定其结构。
5.根据权利要求4所述前药小分子的制备方法,其特征在于:所述的步骤a中原料式(a)-式(k)的用量为10mmol;硼氢化钠用量为15-40mmol。
6.根据权利要求5所述前药小分子的制备方法,其特征在于:所述的步骤b中,步骤a产物的用量是2mmol;二(三甲基硅基)氨基锂用量是2-3mmol;三氟醋酸钠的用量是2-3mmol;正丙胺、正丁胺、正戊胺或正已胺用量是2-3mmol。
7.根据权利要求6所述前药小分子的制备方法,其特征在于:所述的步骤c中,步骤b合成的吡啶盐前体的用量为1mmol;吡啶溶液的用量为10ml。
8.权利要求1-3任一项所述的吡啶盐改性的含有不同硝基芳杂环的前药小分子在制备抗肿瘤药物中的用途。
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