CN102603761B - 含有异羟肟酸结构的表鬼臼毒化合物及制备方法和用途 - Google Patents
含有异羟肟酸结构的表鬼臼毒化合物及制备方法和用途 Download PDFInfo
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- CN102603761B CN102603761B CN 201210023070 CN201210023070A CN102603761B CN 102603761 B CN102603761 B CN 102603761B CN 201210023070 CN201210023070 CN 201210023070 CN 201210023070 A CN201210023070 A CN 201210023070A CN 102603761 B CN102603761 B CN 102603761B
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- epipodophyllotoxin
- hydroxamic acid
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Abstract
本发明提供了一种通式I所示的含有异羟肟酸结构的新型表鬼臼毒素衍生物及其药学上可接受的盐及其制备方法和用途；在通式I中，X为-NH-、-O-、-S-、-NH-CH2-、-O-CH2-或-S-CH2-；Y为芳香环、取代的芳香环、芳杂环或取代的芳杂环；Z为-O-、-NHCO-或-CONH-；B为C1-C8的烷基、C2-C8的链烯基、炔基或环烷基。该化合物具有良好的抗肿瘤活性，在临床上可以进行口服、静脉注射或肌肉注射方式应用。
Description
技术领域
本发明涉及一类作用于拓扑异构酶II及组蛋白去乙酰化酶的多靶点抑制剂，以及制备这些化合物的方法和用途。更具体地说，涉及具有以下结构的新型表鬼臼毒素衍生物(I)以及它们的制备方法和这些化合物在抗肿瘤领域中的应用。
背景技术
DNA拓扑异构酶是一类重要的抗肿瘤靶点，鬼臼毒素(1)是代表性的作用于拓扑异构酶II的抗肿瘤化合物，最早从盾叶鬼臼中分离获得之后又从八角莲、西藏鬼臼和山荷叶等近缘植物中得到，其具有显著的抗肿瘤和抗病毒活性，但因毒性强、副作用大而使其应用受到限制。
由鬼臼毒素结构改造所得的衍生物依托泊苷(etoposide,VP-16) (2)及其磷酸盐(etoposide phosphate, 或称etopophos) 和替尼泊苷(teniposide, VM-26) (3)已成为应用于临床的抗癌代表药物。它们对小细胞肺癌、睾丸癌、急性白血病以及恶性淋巴肿瘤等多种癌症均有良好的疗效。该类化合物能作用于拓扑异构酶II，形成一种药物-酶-DNA三者之间稳定的可裂性复合物，干扰DNA拓扑异构酶II，致使受损的DNA不能修复，从而诱导细胞凋亡。
抗肿瘤药物研究的一个新趋势是发展能够同时作用于多个靶点的单一药物。由于阻断了肿瘤细胞生存的多条途径，这种小分子药物能够克服传统的药物容易产生耐药性的缺点。例如，第一代酪氨酸激酶抑制剂伊马替尼作用靶点较为单一，主要抑制酪氨酸激酶Bcr-Abl。病人服用一段时间的伊马替尼后容易产生耐药性。第二代酪氨酸激酶抑制剂尼罗替尼和达沙替尼具有abl和src双重激酶抑制的能力，能够治疗对伊马替尼产生耐药的患者，从而显示出比第一代药物更好的治疗效果。
哺乳动物的蛋白去乙酰化酶(HDAC)是一类含有锌离子的酰胺水解酶，可以分为第一类(HDAC-1、HDAC-2、HDAC-3和HDAC-8)、第二类(HDAC-4、HDAC-5、HDAC-7、HDAC-9、HDAC-10)和第四类(HDAC-11)。组蛋白去乙酰化酶抑制剂(HDACi)可以抑制白血病和实体肿瘤细胞增殖，并诱导细胞分化。另外，HDAC抑制剂可以使正常细胞产生一个G2期关卡，使得正常细胞能够以一种安全的方式退出细胞周期，这是HDAC抑制剂对正常细胞的毒副作用非常小的原因之一。
本发明将HDAC抑制剂和鬼臼毒素类化合物相结合，发展了新型杂化分子，具有双重的抗肿瘤活性。
发明内容
本发明的目的是寻找一类新型的含有异羟肟酸片段的表鬼臼毒素衍生物及其药学上可接受的盐，这种化合物具备拓扑异构酶II及组蛋白去乙酰化酶双重抑制作用。
本发明的另一目的是提供一种制备所述新型表鬼臼毒素类化合物及其药学上可接受的盐的方法。
本发明的另一目的是提供一种用于治疗癌症的组合物，该组合物包含治疗有效量的一种或多种所述表鬼臼毒素类化合物及其药学上可接受的盐以及药学上可接受的载体。所述药学上可接受的盐包括但不限于该化合物与盐酸、硫酸、磷酸、甲磺酸、琥珀酸、马来酸、富马酸、酒石酸、柠檬酸等的加成盐。
本发明的再一目的是提供一种所述表鬼臼毒素类化合物及其药学上可接受的盐在制备抗肿瘤药物中的应用。这类多靶点抗肿瘤药物比原有药物具有更广的抗肿瘤谱，克服某些肿瘤株对这两种药物的耐药性。
本发明是关于表鬼臼毒素新型衍生物，这些化合物是在表鬼臼毒素的C4位引入异羟肟酸片段，并通过合理的片段进行连接。它们具有良好的抗肿瘤活性。
本发明所述的含有异羟肟酸片段的表鬼臼毒素类化合物及其药学上的盐具体结构如通式(I)所示：
其中，
X为-NH-、-O-、-S-、-NH-CH2-、-O-CH2-或-S-CH2-；
Y为芳香环、取代的芳香环、芳杂环或取代的芳杂环；优选为苯环或1,2,3-三氮唑；
Z为-O-、-NHCO-或-CONH-；优选为-O-；
B为C1-C8的烷基、C2-C8的链烯基、炔基或环烷基，优选为C3-C7的烷基。
本发明提供了一种所述的含有异羟肟酸片段的表鬼臼毒素类化合物及其药学上可接受盐的制备方法，该方法包括如下步骤：
其中，n=3-7；
a）化合物II在甲醇中与氯化亚砜反应，得化合物III；本步反应温度为0-40 ℃；
b）在碱作用条件下，化合物III与硝基苯酚反应得到化合物IV；碱为叔丁醇钾、叔丁醇钠、碳酸钠、碳酸铯、碳酸钾等，优选为碳酸钾，反应溶剂为四氢呋喃、N,N-二甲基甲酰胺、二甲亚砜等，优选为二甲基甲酰胺；
c）在碱作用条件下，化合物IV水解得化合物V；碱为氢氧化钠、氢氧化钾、氢氧化锂、碳酸钾等，优选为氢氧化钠；反应溶剂为乙醇-水、甲醇-水、四氢呋喃-水，优选为乙醇-水；
d）在无水条件下，化合物V与氯化亚砜反应，得化合物VI；反应溶剂为二氯甲烷、甲苯；反应温度为0-80℃，优选为40-60℃；
e）在碱和催化剂共同作用下，化合物VI与N-boc-O-TBS羟胺反应得化合物VII；碱为三乙胺、吡啶、二乙基苯胺等，优选为三乙胺；催化剂为二甲氨基吡啶；反应温度为-20-20℃，优选为-20-0℃；
f）在催化加氢体系作用下，化合物VII的硝基被还原，得化合物VIII，本步骤所述催化体系为：采用Pd/C加氢反应还原硝基；溶剂为甲醇或者乙醇；
g）碱性条件下，化合物VIII与4-碘-4-脱氧-4’-去甲基表鬼臼毒素反应，得化合物IX；碱为三乙胺和碳酸钡；溶剂为二氯甲烷、甲苯、四氢呋喃、乙腈、N，N-二甲基甲酰胺、二甲亚砜等，优选为乙腈；本步反应温度为0-40℃，优选为20-30℃；
h）化合物IX在酸性条件下脱除保护基，得化合物I-1；所述酸为盐酸、硫酸、三氟醋酸等，优选为三氟醋酸；溶剂为二氯甲烷、二氯乙烷、乙腈、四氢呋喃等，优选为二氯甲烷。
本发明所涉及的化合物具有良好的抗肿瘤活性，在临床上可以进行口服、静脉注射及肌肉注射等方式应用。
具体实施方式
本发明的新型表鬼臼毒衍生物和制备方法在如下实施例中更详细地叙述，但实施例不构成对本发明的限制。
实施例 1
1.1 化合物2的制备
将5g 4-溴丁酸溶于100 mL甲醇中，室温滴加氯化亚砜3.3 mL，滴完后继续反应 1小时，减压除去溶剂及过量的氯化亚砜后得无色液体5.4 g。产率99.6%。
实施例 2
1.2 化合物3的制备
室温下，将4.52 g碳酸钾加入含对硝基苯酚3.79 g的N,N-二甲基甲酰胺溶液中，搅拌半小时后加入4-溴丁酸甲酯5.4 g，100℃反应12小时。冷却至室温后，加入100 mL水，以100 mL乙酸乙酯萃取，有机相用水洗，饱和食盐水洗，无水硫酸钠干燥，过滤，减压蒸馏得黄色油状物。将乙醚加入此油状物中，析出大量固体，过滤后用少量乙醚洗涤，干燥后得浅黄色固体3.3 g，产率46.0%。
实施例 3
1.3 化合物4的制备
室温下，将4-(4-硝基苯氧基)丁酸甲酯2.1 g溶于10 mL四氢呋喃中，加入3M氢氧化钠水溶液5 mL，回流2小时后冷却至室温。加入1M盐酸20 mL，用乙酸乙酯萃取，有机相用水洗，饱和食盐水洗，无水硫酸钠干燥，过滤，减压蒸馏得黄色固体1.9 g，产率96.0%。
实施例 4
1.4 化合物5的制备
将4-(4-硝基苯氧基)丁酸450 mg溶于5 mL甲苯，室温下滴加氯化亚砜440 μl, 升温至60℃反应2小时，冷却至室温后旋蒸除去溶剂。
实施例 5
1.5 化合物6的制备
将988 mg TBDMSO-NH-boc，1.67 mL三乙胺，24 mg N,N-二甲胺基吡啶溶于10 mL乙腈并冷却至-10 ℃，滴加溶有化合物5的乙腈溶液，反应10分钟后加入适量硅胶拌样，以乙酸乙酯石油醚为淋洗剂柱层析，得白色固体434 mg，产率46%。
1H NMR (CDCl3, 500 MHz): 0.15 (s, 6H), 1.01 (s, 9H), 1.58 (s, 9H), 2.18-2.22 (m, 2H), 3.03 (t, J = 7.0 Hz, 2H), 4.14 (t, J = 6.2 Hz, 2H), 6.95 (d, J = 9.2 Hz, 2H), 8.20 (d, J = 9.1Hz, 2H)。
实施例 6
1.6 化合物7的制备
将化合物6 400 mg溶于20 mL乙醇中，加入40 mg钯碳(10%)，室温下加氢反应。2小时候终止反应，过滤除去催化剂，滤液旋干得产物360 mg, 产率98%。
1H NMR (CDCl3, 500 MHz): 0.14 (s, 6H), 0.99 (s, 9H), 1.54 (s, 9H), 2.05-2.15 (m, 2H), 2.97 (t, J = 10 Hz, 2H), 3.25-3.50 (br, 2H), 3.93 (t, J = 5 Hz, 2H), 6.61 (d, J = 10 Hz, 2H), 6.71 (d, J = 10Hz, 2H)。
实施例7
1.7 化合物8的制备
将9-(4,6-O-亚乙基-β-D-吡喃葡萄糖苷)-4'-去甲基表鬼臼毒素 322 mg，TMS-Cl 239 mg， NaI 330 mg在15 mL乙腈中反应2h后，加入TEA 195 mg，BaCO3 325 mg,搅拌10分钟后加入化合物7 300 mg，室温搅拌过夜。反应液经过滤浓缩后，经柱层析分离得所述产物。
1H NMR (CDCl3, 500 MHz): 0.17 (s, 6H), 1.02 (s, 9H), 1.69 (s, 9H), 2.10-2.20 (m, 2H), 2.95-3.20 (m, 4H), 3.60 (s, 1H), 3.81 (s, 6H), 3.95-4.70 (m, 6H), 5.47 (s, 1H), 5.97 (d, J = 9.5 Hz, 2H), 6.35 (s, 2H), 6.48-6.82 (m, 6H)。
实施例8
1.8 化合物9的制备
将化合物8 50 mg溶于2 mL二氯甲烷中,加入1 mL三副醋酸,室温反应16小时。减压旋干溶剂后柱层析分离，得化合物9 20 mg。 1H NMR (CDCl3, 500 MHz):1.95-2.10 (m, 2H), 2.27-2.31 (m, 2H), 3.05-3.30 (m, 2H), 3.61-3.62 (m, 1H), 3.64 (s, 6H), 3.90-4.00 (m, 3H), 4.30-4.95 (m, 4H), 5.97 (d, J = 5.6 Hz, 2H), 6.40 (s, 2H), 6.52 (s, 1H), 6.68-6.80 (m, 5H); HRMS (ESI): m/z calcd for C31H32N2NaO10 [M+Na]+ 626.1949, found 615.1934。
实施例9 HDAC抑制活性测试：
以Ac-Lys-Tyr-Lys(Ac)-AMC 为底物，采用荧光检测法，在96孔或384孔平底微孔板中检测酶活性。底物Ac-Lys-Tyr-Lys(Ac)-AMC分别经HDAC1，HDAC3去乙酰化后，利用胰酶水解得到的产物AMC在荧光检测仪的355nm激发460nm发射光下可被检测到荧光信号。通过检测随时间荧光信号的变化，计算得到反应初速度。
以Boc-lys(Ac)-AMC为底物，采用荧光检测法，在96孔或384孔平底微孔板中检测酶活性。底物Boc-lys(Ac)-AMC经HDAC6去乙酰化后，利用胰酶水解得到的产物AMC在荧光检测仪的355 nm激发460 nm发射光下可被检测到荧光信号。通过检测随时间荧光信号的变化，计算得到反应初速度。
表1. 对HDAC的抑制活性
表1显示了本发明所述的化合物对HDAC具有与SAHA相当的活性，其中化合物ZX-010，ZX-011显示出比SAHA更好的HDAC抑制活性。
实施例 10 所有化合物的细胞毒活性测试都在相应的肿瘤细胞株上进行，每100μL的培养液中有6000～10000个肿瘤细胞，置于96 孔板中(Falcon，CA)。肿瘤细胞分成三份，用梯度浓度的药物处理，在37℃下培养72h，采用SRB法测试。50％的肿瘤细胞生长抑制时药物的浓度即IC50 使用量效曲线来计算的。
表2. 对HCT116细胞的生长抑制活性
表2显示了本发明所述的化合物对HCT116具有良好的抑制活性。
Claims (5)
1.一种通式I所示的含有异羟肟酸结构的表鬼臼毒素衍生物及其药学上可接受的盐：
其中，
X为-NH-；
Y为未经取代的苯环；
Z为-O-；
B为C1-C8的烷基。
2.一种通式I-1所示的含有异羟肟酸结构的表鬼臼毒素衍生物及其药学上可接受的盐的制备方法，该方法包括如下步骤：
其中，n=3-7；
a）化合物II在甲醇中与氯化亚砜反应，得化合物III，反应温度为0-40 ℃；
b）在碱作用条件下，化合物III与硝基苯酚反应得到化合物IV；所述碱为叔丁醇钾、叔丁醇钠、碳酸钠、碳酸铯或碳酸钾；
c）在碱作用条件下，化合物IV水解得化合物V；所述碱为氢氧化钠、氢氧化钾、氢氧化锂或碳酸钾；
d）在无水条件下，化合物V与氯化亚砜反应，得化合物VI，反应温度为0-80 ℃；
e）在碱和催化剂共同作用下，化合物VI与N-boc-O-TBS羟胺反应得化合物VII，反应温度为-20-20 ℃；所述碱为三乙胺、吡啶或二乙基苯胺；催化剂为二甲氨基吡啶；
f）在催化加氢体系作用下，化合物VII的硝基被还原，得化合物VIII；所述催化体系为：采用Pd/C加氢反应还原硝基；
g）碱性条件下，化合物VIII与4-碘-4-脱氧-4’-去甲基表鬼臼毒素反应，得化合物IX，反应温度为0-40 ℃；所述碱为三乙胺和碳酸钡；
h）化合物IX在酸性条件下脱除保护基，得化合物I-1；所述酸为盐酸、硫酸或三氟醋酸。
3.一种用于治疗癌症的组合物，该组合物包含治疗有效量的一种或多种权利要求1所述的含有异羟肟酸结构的表鬼臼毒素衍生物及其药学上可接受的盐以及药学上可接受的载体。
4.一种权利要求1所述的含有异羟肟酸结构的表鬼臼毒素衍生物及其药学上可接受的盐在制备抗肿瘤药物中的应用。
5.一种权利要求1所述的含有异羟肟酸结构的表鬼臼毒素衍生物及其药学上可接受的盐在制备治疗结肠癌或肺癌的药物中的应用。
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004033423A2 (en) * | 2002-10-11 | 2004-04-22 | Plantaceutica Inc. | Anticancer compounds |
| WO2005023817A1 (fr) * | 2003-09-02 | 2005-03-17 | Les Laboratoires Servier | Derives de 9-amino-podophyllotoxine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
| CN101817829A (zh) * | 2010-04-02 | 2010-09-01 | 浙江大学 | 4-取代苯胺基表鬼臼毒素衍生物及用途 |
| CN102131814A (zh) * | 2008-08-19 | 2011-07-20 | 皮埃尔法布雷医药公司 | 新型表鬼臼毒素的(多)氨基烷基氨基烷基酰胺、烷基-脲或烷基-磺酰胺衍生物、其制备方法及其作为抗癌剂在治疗中的用途 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004033423A2 (en) * | 2002-10-11 | 2004-04-22 | Plantaceutica Inc. | Anticancer compounds |
| WO2005023817A1 (fr) * | 2003-09-02 | 2005-03-17 | Les Laboratoires Servier | Derives de 9-amino-podophyllotoxine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
| CN102131814A (zh) * | 2008-08-19 | 2011-07-20 | 皮埃尔法布雷医药公司 | 新型表鬼臼毒素的(多)氨基烷基氨基烷基酰胺、烷基-脲或烷基-磺酰胺衍生物、其制备方法及其作为抗癌剂在治疗中的用途 |
| CN101817829A (zh) * | 2010-04-02 | 2010-09-01 | 浙江大学 | 4-取代苯胺基表鬼臼毒素衍生物及用途 |
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| N-(氨基吡啶)苯甲酰胺类组蛋白去乙酰化酶抑制剂的合成及其抗肿瘤活性研究;张庆伟，等;《中国药物化学杂志》;20111031;第21卷(第5期);第362-369页，参见全文 * |
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