CN111253339A - 一类新型姜黄素衍生物的合成制备方法以及在癌症治疗的应用 - Google Patents

一类新型姜黄素衍生物的合成制备方法以及在癌症治疗的应用 Download PDF

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CN111253339A
CN111253339A CN201911333226.2A CN201911333226A CN111253339A CN 111253339 A CN111253339 A CN 111253339A CN 201911333226 A CN201911333226 A CN 201911333226A CN 111253339 A CN111253339 A CN 111253339A
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curcumin
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徐学军
杨玉坡
杨争艳
朱艳霞
段超群
曹艳艳
张韶华
刘瑞
徐春萍
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Henan Radio Medical Technology Co ltd
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Abstract

本发明提供一类新型姜黄素衍生物的制备方法和该类化合物在化学、生物学以及医学领域的应用，实验结果显示本发明所提供的姜黄素衍生物较姜黄素原药的溶解性和体内生物利用度得到提高，其抗肿瘤活性亦显著增强；其与人体内癌症相关的生物靶点STAT3蛋白有较强的结合活性；此外，细胞增殖实验(CCK‑8)的结果显示本发明所涉及的化合物能显著抑制非小细胞肺癌细胞株PC9和HCC827的增殖，特别是对分别具有吉非替尼(Gefitinib)、阿法替尼(Afatinib)或厄洛替尼(Erlotinib)抗性的PC9GR，PC9AR，HCC827AR和HCC827ER细胞具有更强的增殖抑制作用。该项研究将对此类化合物在肿瘤临床治疗以及其他生物学方面的应用具有重要的意义。

Description

一类新型姜黄素衍生物的合成制备方法以及在癌症治疗的 应用
技术领域
本发明属于肿瘤原药研发技术领域，具体涉及一种姜黄素类化合物及其生物学可接受的 盐，其制备方法和应用。
背景技术
2017年国家癌症中心发布的中国最新癌症数据显示，在中国，每年新发癌症病例达429 万，占全球新发病例的20％，死亡281万例(中国肿瘤临床与康复，2017(5)：574-574)。2017 年中国CFDA批复上市的5个抗癌新药没有一个创新靶点，中国原创的靶向新药寥寥无几，总 体反映了国内靶向原创药物的研发水平落后于欧美。如何在药物研发方面做到“双创”(疾 病相关的首次用于临床治疗的新靶点和全新化合物)是考验我们中国医药研发实力的试金石。 寻求新的靶点和有潜力的药物先导化合物，在特定的肿瘤治疗领域有所突破，是医药研发科 研人员的当务之急。STAT3-JAK信号传导通路对肿瘤细胞的生长有正向调控的作用，近十年 来，STAT3蛋白作为治疗癌症的生物学靶点备受青睐，截止2017年，美国FDA批准在临床测 试的STAT3信号传导通路抑制类抗癌药物先导化合物有30余种(Johnson D E，et al.，Nature Reviews Clinical Oncology，2018，15(4)：234)。基于STAT3信号传导的抗癌靶向药物有 靶点新和抗癌谱宽等特点，近期的临床测试结果显示了此类药物在未来肿瘤临床治疗方面具 有巨大的开发潜力和广阔的市场空间。姜黄素(Curcumin)是从姜科植物姜黄中提取的一种 色素，属于天然酚类化合物，研究证明其具有抗炎、抗氧化和抗增殖等多种作用。也有研究 表明Curcumin是p300组蛋白乙酰转移酶(HATs)的抑制剂，并且对NF-κB和 MAPKs具有抑制作用。由于水溶性差、体内药物存留的半衰期较短、导致化合物体内生物利 用度较低，使Curcumin应用和研究明显受限。本发明通过优化结构设计，改善Curcumin衍 生物的溶解性，增强该类化合物的体内生物利用度，筛选了能够靶向STAT3信号的新型抗肿 瘤化合物。
发明内容
本发明提供一类姜黄素衍生物的制备方法以及在肿瘤生物学领域的应用，实验结果显示 本发明所提供的姜黄素类化合物较姜黄素原药的溶解性明显提高，其与人体内癌症相关的靶 点STAT3的SH2结构域有较强的结合活性，肿瘤细胞增殖实验(CCK-8)显示本发明所涉及的 化合物能显著抑制非小细胞肺癌PC9细胞及其耐药株、HCC827细胞及其耐药株的增殖，进一 步深入研究将对此类化合物在肿瘤临床治疗以及其他生物学方面的应用具有重要的意义。
本发明采用如下技术方案
一种姜黄素类化合物，其特征在于，结构式如通式I和II所示：
Figure BSA0000198289670000021
其中，
X为-CH2-或-CO-；
p＝0、1、2、3、4、...10；
Y为-CH2-；
m＝1、2、3、4、...10；
L＝C或N；
Z＝C或N；
E＝C或N；
D＝C或N；
A选自：
Figure BSA0000198289670000022
等，其中n＝0，1、2、3、4；
Figure BSA0000198289670000023
其中，
X为-CH2-或-CO-；
p＝0、1、2、3、4、...10；
Y为-CH2-；
m＝1、2、3、4、...10；
Z＝C、O或N；
D＝C、O或N；
E＝C、O或N；
A选自：
Figure BSA0000198289670000031
等，其中n＝0、1、2、3、4；
所述的姜黄素类化合物，其特征在于，具体为如下结构的化合物：
Figure BSA0000198289670000032
所述的姜黄素类化合物与乙酸、二氢乙酸、苯甲酸、柠檬酸、山梨酸、丙酸、草酸、富马酸、马来酸、盐酸、苹果酸、磷酸、亚硫酸、硫酸、香草酸、酒石酸、抗坏血酸、硼酸、 乳酸和乙二胺四乙酸中的至少一种形成的生物学可接受的盐。
所述的姜黄素类化合物的制备方法，其特征在于，包括以下步骤：
(1)将摩尔比为1∶1.1的
Figure BSA0000198289670000033
与
Figure BSA0000198289670000034
溶 解于有机溶剂中，并加入碳酸钾，TLC检测反应结束后，后处理得到
Figure BSA0000198289670000041
(2)将摩尔比为1∶6的
Figure BSA0000198289670000042
与
Figure BSA0000198289670000043
溶解 于有机溶剂中，并加入吡啶，TLC检测反应结束后，后处理得到
Figure BSA0000198289670000044
所述的姜黄素类化合物的制备方法，其特征在于，所述
Figure BSA0000198289670000045
通过以下方法制备得到：将摩尔比为1∶1.1 的
Figure BSA0000198289670000046
与
Figure BSA0000198289670000047
溶解于有机溶剂中，并加入碳酸 钾，TLC检测反应结束后，后处理得到
Figure BSA0000198289670000048
所述的姜黄素类化合物的制备方法，其特征在于，所述
Figure BSA0000198289670000051
通过以下方法制备得到：将摩尔比为1∶1.5的
Figure BSA0000198289670000052
与
Figure BSA0000198289670000053
溶解于有机溶剂中，并加入醋酸铜，三乙胺， TLC检测反应结束后，后处理得到
Figure BSA0000198289670000054
本发明所用的术语“卤素”是指氟、氯、溴或碘，优选的卤素基团为氟、氯或溴。
根据上述式I姜黄素类化合物的结构差异，本发明同时提供了两种制备方法，如下：
结构式如1a至1f所示的姜黄素类化合物可以由流程1所示路线合成，原料一步两步亲 核取代反应即可得到目标化合物。
流程1
Figure BSA0000198289670000055
Ia：X＝-CH2-，Y＝-(CH2)2-，
Figure BSA0000198289670000056
L＝C，E＝C，Z＝C，D＝C
1b：X＝-CH2-，Y＝-(CH2)2-，
Figure BSA0000198289670000057
L＝C，E＝C，Z＝C，D＝C
1c：X＝-CH2-，Y＝-(CH2)2-，
Figure BSA0000198289670000061
L＝C，E＝C，Z＝C，D＝C
1d：X＝-CH2-，Y＝-(CH2)2-，
Figure BSA0000198289670000062
L＝N，E＝C，Z＝C，D＝C
1e：X＝-CH2-，Y＝-CH2-，
Figure BSA0000198289670000063
L＝N，E＝C，Z＝N，D＝C
1f：X＝-CH2-，Y＝-(CH2)2-，
Figure BSA0000198289670000064
L＝N，E＝N，Z＝C，D＝C
对于X，Y，A，L，E，Z和D的具体基团包括上述1a，1b，1c，1d，1e，1f对应的基团 但不限于这些基团/化合物，还可以是其他的本领域技术人员容易理解想到采用该流程1进行合成的化合物。对于权利要求书中的限定的合成工艺/流程的情况应作同样的理解，不应被视 为限定，更不能限定为具体的化合物。
结构式如1g至1i所示的姜黄素类化合物可以由流程2所示路线合成，原料一步两步亲 核取代反应即可得到目标化合物。
流程2
Figure BSA0000198289670000065
1g：X＝-CH2-，Y＝-(CH2)2-，
Figure BSA0000198289670000066
Z＝O，D＝C，E＝C
1h：X＝-CH2-，Y＝-(CH2)2-，
Figure BSA0000198289670000067
Z＝O，D＝N，E＝C
1i：X＝-CH2-，Y＝-(CH2)2-，
Figure BSA0000198289670000068
Z＝N，D＝C，E＝C
对于X，Y，A，E，Z和D的具体基团包括上述1g，1h，1i对应的基团但不限于这些基团/化合物，还可以是其他的本领域技术人员容易理解想到采用该流程2进行合成的化合物。包 对于权利要求书中的限定的合成工艺/流程的情况应作同样的理解，不应被视为限定，更不能 限定为具体的化合物。
结构式如2a至2f所示的姜黄素类化合物可以由流程3所示路线合成，原料经过一步酯 化反应即可得到目标化合物。
流程3
Figure BSA0000198289670000071
2a：X＝-CO-，Y＝-(CH2)2-，
Figure BSA0000198289670000072
L＝C，E＝C，Z＝C，D＝C
2b：X＝-CO-，Y＝-(CH2)2-，
Figure BSA0000198289670000073
L＝C，E＝C，Z＝C，D＝C
2c：X＝-CO-，Y＝-(CH2)2-，
Figure BSA0000198289670000074
L＝C，E＝C，Z＝C，D＝C
2d：X＝-CO-，Y＝-(CH2)2-，
Figure BSA0000198289670000075
L＝N，E＝C，Z＝C，D＝C
2e：X＝-CO-，Y＝-CH2-，
Figure BSA0000198289670000076
L＝N，E＝C，Z＝N，D＝C
2f：X＝-CO-，Y＝-(CH2)2-，
Figure BSA0000198289670000077
L＝N，E＝N，Z＝C，D＝C
对于X，Y，A，L，E，Z和D的具体基团包括上述2a～2f对应的基团但不限于这些基团/化合物，还可以是其他的本领域技术人员容易理解想到采用该流程3进行合成的化合物。包对于权利要求书中的限定的合成工艺/流程的情况应作同样的理解，不应被视为限定，更不能 限定为具体的化合物。
结构式如3a至3c所示的姜黄素类化合物可以由流程5所示路线合成，原料经过一步酯 化反应即可得到目标化合物。
流程4
Figure BSA0000198289670000078
3a：Y＝-(CH2)2-，
Figure BSA0000198289670000079
3b：Y＝-(CH2)2-，
Figure BSA00001982896700000710
3c：Y＝-(CH2)2-，
Figure BSA0000198289670000081
对于Y，m和A的具体基团包括上述3a～3c对应的基团但不限于这些基团/化合物，还可 以是其他的本领域技术人员容易理解想到采用该流程4进行合成的化合物。包对于权利要求 书中的限定的合成工艺/流程的情况应作同样的理解，不应被视为限定，更不能限定为具体的 化合物。
本发明的目的是寻找具有高STAT3抑制作用且具有较低毒性的新化合物。
本发明还涉及所述姜黄素类化合物、其药学上可接受的盐、所述衍生物的溶剂化合物、 或者所述盐的溶剂化合物在制备用于治疗或辅助治疗和/或预防哺乳动物的肿瘤的药物中的 用途，主要是由STAT3介导的肿瘤或由STAT3驱动的肿瘤细胞增殖和迁移药物中的用途，也 可以是与STAT3细胞信号传导相关疾病的药物，具体地，所述哺乳动物为人类。
本发明一个方面涉及上述的具有式I结构的新型姜黄素类化合物、其药学上可接受的盐、 所述衍生物的溶剂合物、或者所述盐的溶剂合物制备用于治疗和/或预防哺乳动物中与STAT3 细胞信号传导相关疾病的药物中的用途。具体地，所述哺乳动物为人类。
根据本发明，完全可以预期本发明化合物可用于治疗STAT3信号传导异常活跃或蛋白高 表达而引起的肿瘤。STAT3相关的肿瘤包括肺癌、乳腺癌、结直肠癌、白血病、头颈癌以及 前列腺癌等其他所有癌症。
本发明的有益效果如下：
本发明公开了一类全新姜黄素类化合物的合成和成盐制备方法，以及将此类化合物及其 成盐形态作为活性成分在细胞生长调控机制和癌症治疗方面的应用。此姜黄素类化合物及其 盐因其独特的结构特征，可以通过结构中的功能基团与生物体内与肿瘤疾病相关的蛋白位点 相结合，并与受体发生氢键和疏水相互作用，从而达到抑制肿瘤细胞增殖的目的。例如 curcuminA001，curcuminB001和curcuminD001等此类姜黄素化合物属于STAT3抑制剂，对 非小细胞肺癌细胞的增殖有明显的拮抗效果。由此表明，此类化合物对肿瘤机制研究及癌症 的临床治疗有潜在的重要意义和开阔的应用前景。
附图说明
图1是化合物curcumin，curcuminA001，curcuminB001和curcuminD001分别抑制肺癌 PC9细胞增殖的实验，Gefitinib为阳性对照，图中CKK-8法检测的结果以IC50(μmol/L)值 进行表征。
图2是化合物curcumin，curcuminA001，curcuminB001和curcuminD001分别抑制肺癌 PC9AR细胞增殖的实验，Gefitinib为阳性对照，图中CKK-8法检测的结果以IC50(μmol/L) 值进行表征。
图3是化合物curcumin，curcuminA001，curcuminB001和curcuminD001分别抑制肺癌 PC9GR细胞增殖的实验，Gefitinib为阳性对照，图中CKK-8法检测的结果以IC50(μmol/L) 值进行表征。
图4是化合物curcumin，curcuminA001，curcuminB001和curcuminD001分别抑制肺癌 HCC827细胞增殖的实验，Gefitinib为阳性对照，图中CKK-8法检测的结果以IC50(μmol/L) 值进行表征。
图5是化合物curcumin，curcuminA001，curcuminB001和curcuminD001分别抑制诱导 人非小细肺癌HCC827AR细胞增殖的实验，Gefitinib为阳性对照，图中CKK-8法检测的结果 以IC50(μmol/L)值进行表征.
图6是化合物curcumin，curcuminA001，curcuminB001和curcuminD001分别抑制肺癌 HCC827ER细胞增殖的实验，Gefitinib为阳性对照，图中CKK-8法检测的结果以IC50(μmol/L) 值进行表征。
图7是curcuminA001docking实验结果。
图8是curcuminD001docking实验结果。
具体实施方式
为了使本发明的技术目的、技术方案和有益效果更加清楚，下面结合附图和具体实施例 对本发明的技术方案作出进一步的说明。
在本发明合成式I和式II化合物的方法中，反应所用的各种原材料是本领域技术人员根 据已有知识可以制备得到的，或者是可以通过文献公知的方法制得的，或者是可以通过商业 购得的。以上反应方案中所用的中间体、原材料、试剂、反应条件等均可以根据本领域技术 人员已有知识做适当改变的。
在本发明中，除非另外说明，其中：(i)温度以摄氏度(℃)表示，操作在室温环境下进行；更具体地，所述室温是指20-30℃；(ii)有机溶剂用常用干燥方法干燥，溶剂的蒸 发使用旋转蒸发仪减压蒸发，浴温不高于50℃；展开剂和洗脱剂均为体积比；(iii)反应 过程用薄层色谱(TLC)跟踪；(iv)终产物具有满意的质子核磁共振(1H-NMR)。
实施例1：化合物1a-1f的合成
参照流程1
Figure BSA0000198289670000101
1a：X＝-CH2-，Y＝-(CH2)2-，
Figure BSA0000198289670000102
L＝C，E＝C，Z＝C，D＝C
1b：X＝-CH2-，Y＝-(CH2)2-，
Figure BSA0000198289670000103
L＝C，E＝C，Z＝C，D＝C
1c：X＝-CH2-，Y＝-(CH2)2-，
Figure BSA0000198289670000104
L＝C，E＝C，Z＝C，D＝C
1d：X＝-CH2-，Y＝-(CH2)2-，
Figure BSA0000198289670000105
L＝N，E＝C，Z＝C，D＝C
1e：X＝-CH2-，Y＝-CH2-，
Figure BSA0000198289670000106
L＝N，E＝C，Z＝N，D＝C
1f：X＝-CH2-，Y＝-(CH2)2-，
Figure BSA0000198289670000107
L＝N，E＝N，Z＝C，D＝C
具体合成方法，以化合物1a为例，结构式如下：
Figure BSA0000198289670000108
化合物1a名称为(1E，6E)-1-(4-羟基-3-甲氧基苯基)-7-(3-甲氧基-4-(4-(2-(哌啶-1- 基)乙氧基)苄氧基)苯基)-1，6-庚二烯-3，5-二酮，其合成路线如下所示：
Figure BSA0000198289670000109
步骤1.(1E，6E)-1-(4-羟基-3-甲氧基苯基)-7-(3-甲氧基-4-(4-(2-(哌啶-1-基)乙氧基) 苄氧基)苯基)-1，6-庚二烯-3，5-二酮(1a)
将姜黄素(1)(300mg，0.814mmol，1.0eq)，1-(2-(4-(氯甲基)苯氧基)乙基)哌啶(227 mg，0.896mmol，1.1eq)和碳酸钾(225mg，1.63mmol，2.0eq)溶于N，N-二甲基甲酰 胺(10mL)，25℃反应36小时。TLC(二氯甲烷∶甲醇＝10∶1，Rf/化合物1＝0.85，Rf/化合 物1a＝0.30)显示原料反应完毕。将反应液用50毫升乙酸乙酯稀释，并依次用水(50mL)， 食盐水(50mL*3)洗涤，有机相用无水硫酸钠干燥，然后旋干得到粗品。粗产物用柱层析纯 化(二氯甲烷∶甲醇＝80∶1～20∶1)得到52mg(1E，6E)-1-(4-羟基-3-甲氧基苯基)-7-(3- 甲氧基-4-(4-(2-(哌啶-1-基)乙氧基)苄氧基)苯基)-1，6-庚二烯-3，5-二酮(1a)，棕红色固 体，产率10.9％。
1H NMR(DMSO-d6，400MHz)δ：9.68(brs，1H)，7.59，7.55(dd，J＝4.0Hz，J＝4.0 Hz，2H)，7.39-7.33(m，4H)，7.26-7.24(m，1H)，6.97(d，J＝12Hz，2H)，6.85-6.75 (m，3H)，5.76(s，1H)，5.07(s，2H)，4.13(m，2H)，3.84(s，3H)，3.83(s，3H)，3.40 (m，4H)，2.70(m，2H)，1.55(m，4H)，1.40(m，2H)
化合物1b～1f的合成方法参照实施例1，区别之处在于：化合物1b～1f的合成过程中， 在步骤1中，分别用1-(2-(4-(氯甲基)苯氧基)乙基)吗啡啉，2-(4-(氯甲基)苯氧基)-N，N- 二乙基胺，1-(2-((6-(氯甲基)吡啶-3-基)氧代)乙基)环己亚胺，2-(氯甲基)-5-(1-四氢吡咯 甲氧基)嘧啶，2-(6-(氯甲基)哒嗪-3-氧代)-N，N-二甲基乙基胺代替1-(2-(4-(氯甲基)苯氧 基)乙基)哌啶。此处对于其详细的制备过程不再赘述。
实施例2：化合物1g-1i的合成
参照流程2
Figure BSA0000198289670000111
1g：X＝-CH2-，Y＝-(CH2)2-，
Figure BSA0000198289670000112
Z＝O，D＝C，E＝C
1h：X＝-CH2-，Y＝-(CH2)2-，
Figure BSA0000198289670000113
Z＝O，D＝N，E＝C
1i：X＝-CH2-，Y＝-(CH2)2-，
Figure BSA0000198289670000114
Z＝N，D＝C，E＝C
具体合成方法，以化合物1g为例，结构式如下：
Figure BSA0000198289670000121
化合物1g名称为(1E，6E)-1-(4-(5-(2--环己亚胺基)呋喃)-3-甲氧基苯基)-7-(4-羟基 -3-甲氧基苯基)-1，6-庚二烯-3，5-二酮，其合成路线如下所示：
Figure BSA0000198289670000122
步骤1.(1E，6E)-1-(4-(5-(2--环己亚胺基)呋喃)-3-甲氧基苯基)-7-(4-羟基-3-甲氧基 苯基)-1，6-庚二烯-3，5-二酮(1g)
将姜黄素(1)(300mg，0.814mmol，1.0eq)，1-(2-(5-(氯甲基)呋喃氧基)乙基)环己亚胺(231mg，0.896mmol，1.1eq)和碳酸钾(225mg，1.63mmol，2.0eq)溶于N，N- 二甲基甲酰胺(10mL)，25℃反应36小时。TLC(二氯甲烷∶甲醇＝10∶1，Rf/化合物1＝0.85， Rf/化合物1a＝0.30)显示原料反应完毕。将反应液用50毫升乙酸乙酯稀释，并依次用水(50 mL)，食盐水(50mL*3)洗涤，有机相用无水硫酸钠干燥，然后旋干得到粗品。粗产物用柱 层析纯化(二氯甲烷∶甲醇＝80∶1～20∶1)得到60mg(1E，6E)-1-(4-(5-(2--环己亚胺基) 呋喃)-3-甲氧基苯基)-7-(4-羟基-3-甲氧基苯基)-1，6-庚二烯-3，5-二酮(1g)，棕红色固体， 产率12.5％。
1H NMR(DMSO-d6，400MHz)δ：9.68(brs，1H)，7.59，7.55(dd，J＝4.0Hz，J＝4.0 Hz，2H)，7.39-7.33(m，3H)，6.97(d，J＝12Hz，2H)，6.85-6.75(m，3H)，5.76(s，1H)， 5.07(s，2H)，4.13(m，2H)，3.84(s，3H)，3.83(s，3H)，3.40(m，4H)，2.70(m，2H)， 1.55(m，4H)，1.40(m，4H)
化合物1h～1i的合成方法参照实施例2，区别之处在于：化合物1h～1i的合成过程中， 在步骤1中，分别用2-(氯甲基)-5-(2-哌啶乙氧基)噁唑，1-(2-(5-(氯甲基)吡咯氧基)乙基) 哌啶。此处对于其详细的制备过程不再赘述。
实施例3：化合物2a-2f的合成
参照流程3
Figure BSA0000198289670000131
2a：X＝-CO-，Y＝-(CH2)2-，
Figure BSA0000198289670000132
L＝C，E＝C，Z＝C，D＝C
2b：X＝-CO-，Y＝-(CH2)2-，
Figure BSA0000198289670000133
L＝C，E＝C，Z＝C，D＝C
2c：X＝-CO-，Y＝-(CH2)2-，
Figure BSA0000198289670000134
L＝C，E＝C，Z＝C，D＝C
2d：X＝-CO-，Y＝-(CH2)2-，
Figure BSA0000198289670000135
L＝N，E＝C，Z＝C，D＝C
2e：X＝-CO-，Y＝-CH2-，
Figure BSA0000198289670000136
L＝N，E＝C，Z＝N，D＝C
2f：X＝-CO-，Y＝-(CH2)2-，
Figure BSA0000198289670000137
L＝N，E＝N，Z＝C，D＝C
具体合成方法，以化合物2a为例，结构式如下：
Figure BSA0000198289670000138
化合物2a的名称为4-((1E，6E)-7-(4-羟基-3-甲氧基苯基)-3，5-二氧代-1，6-庚二烯-1- 基)-2-甲氧基苯基-4-(2-(哌啶-1-基)乙氧基)苯酯，其合成路线如下：
Figure BSA0000198289670000139
步骤1. 4-((1E，6E)-7-(4-羟基-3-甲氧基苯基)-3，5-二氧代-1，6-庚二烯-1-基)-2-甲氧 基苯基-4-(2-(哌啶-1-基)乙氧基)苯酯(2a)
将姜黄素(1)(300mg，0.814mmol，1.0eq)，4-(2-哌啶乙氧基)苯甲酰氯(4)(1.31g，4.89mmol，6.0eq)和吡啶(386mg，4.89mmol，6.0eq)溶于50mL无水二氯甲烷，0℃反应5小时。TLC(二氯甲烷∶甲醇＝10∶1，Rf/化合物3＝0.85，Rf/化合物2a＝0.30)显示原 料反应完毕，并有新点产生。将反应液缓慢倒入100mL水中，用二氯甲烷萃取(100mL*3)， 合并有机相，用无水硫酸钠干燥，然后减压浓缩旋干得到粗品。粗产品用柱层析纯化(二氯甲 烷∶甲醇＝80∶1～20∶1)得到48mg 4-((1E，6E)-7-(4-羟基-3-甲氧基苯基)-3，5-二氧代-1，6- 庚二烯-1-基)-2-甲氧基苯基-4-(2-(哌啶-1-基)乙氧基)苯酯(2a)，黄色固体，产率10.1％。
1H NMR(DMSO-d6，400MHz)δ：9.90(brs，1H)，9.72(brs，1H)，8.11(d，J＝8.0Hz，2H)，7.62-7.56(m，3H)，7.35-7.18(m，5H)，7.01(d，J＝12Hz，1H)，6.85-6.82(m， 2H)，6.15(s，1H)，4.49(m，2H)，4.02(s，3H)，4.01(s，3H)，3.51(m，4H)，3.01(m， 2H)，1.96-1.91(m，4H)，1.75(m，2H)
化合物2b～2f的合成方法参照实施例2，区别之处在于：化合物2b～2f的合成过程中， 在步骤1中，分别用4-(2-吗啉乙氧基)苯甲酰氯，4-(2-二乙胺基乙氧基)苯甲酰氯，5-(2-(环 己亚胺基)乙氧基)吡啶甲酰氯，5-(1-四氢吡咯甲氧基)嘧啶-2-甲酰氯，6-(2-(二甲胺基)乙 氧基)哒嗪-3-甲酰氯代替4-(2-哌啶乙氧基)苯甲酰氯。此处对于其详细的制备过程不再赘述。
实施例4：化合物3a-3c的合成
参照流程4
Figure BSA0000198289670000141
3a：Y＝-(CH2)2-，
Figure BSA0000198289670000142
3b：Y＝-(CH2)2-，
Figure BSA0000198289670000143
3c：Y＝-(CH2)2-，
Figure BSA0000198289670000144
具体合成方法，以化合物3a为例，结构式如下：
Figure BSA0000198289670000145
化合物3a名称为(1E，6E)-1-(4-(5-(2--环己亚胺基)呋喃)-3-甲氧基苯基)-7-(4-羟基-3-甲氧基苯基)-1，6-庚二烯-3，5-二酮，其合成路线如下所示：
Figure BSA0000198289670000151
步骤1.(1E，6E)-1-(4-羟基-3-甲氧基苯基)-7-(3-甲氧基-4-(4-(2-哌啶乙氧基)苯氧基) 苯基)-1，6-庚二烯-3，5-二酮(3a)
将姜黄素(1)(300mg，0.814mmol，1.0eq)，4-(2-哌啶乙氧基)苯硼酸(304mg，1.22mmol，1.5eq)，醋酸铜(148mg，0.814mmol，1.0eq)和三乙胺(412mg，4.07mmol，5.0 eq)溶于二氯甲烷(10mL)，25℃反应18小时。TLC(二氯甲烷：甲醇＝10∶1，Rf/化合物1＝ 0.85，Rf/化合物1a＝0.30)显示原料反应完毕。将反应液旋干得到粗品。粗产物用柱层析 纯化(二氯甲烷∶甲醇＝80∶1～20∶1)得到55mg(1E，6E)-1-(4-羟基-3-甲氧基苯基)-7-(3- 甲氧基-4-(4-(2-哌啶乙氧基)苯氧基)苯基)-1，6-庚二烯-3，5-二酮(3a)，棕红色固体，产率 11.8％。
1H NMR(DMSO-d6，400MHz)δ：9.68(brs，1H)，7.59，7.55(dd，J＝4.0Hz，J＝4.0Hz，2H)， 7.39-7.33(m，4H)，7.26-7.24(m，1H)，6.97(d，J＝12Hz，2H)，6.85-6.75(m，3H)，5.76(s，1H)，4.13 (m，2H)，3.84(s，3H)，3.83(s，3H)，3.40(m，4H)，2.70(m，2H)，1.55(m，4H)，1.40(m，2H)
化合物4b～4c的合成方法参照实施例5，区别之处在于：化合物3b～3c的合成过程中，在 步骤1中，分别用4-(2-吗啡啉乙氧基)苯硼酸，4-(2-环己亚胺乙氧基)苯硼酸。此处对于其 详细的制备过程不再赘述。+
非小细胞肺癌细胞的增殖抑制实验
方法：分别收集对数生长期的PC9、PC9AR、PC9GR、HCC827、HCC827AR和HCC827ER细胞， 计数，调整细胞悬液浓度为50000个/mL，铺96孔板，每孔加入100μL细胞悬液，即每孔5000个细胞，过夜培养；次日对上述瘤细胞分别加curcumin，curcuminA001，curcuminB001，curcuminD001和Gefitinib处理，各组化合物的工作浓度均设9个梯度，分别为0.09765，0.1953、0.3906、1.5625、3.125、6.25、12.5、25和50μmol。每个浓度设3个平行复孔， 并设加等体积DMSO的溶剂对照组。继续培养48h后，每孔加入10μl Cell Counting Kit-8(CCK-8)试剂，37℃，5％CO2孵育4h后，利用酶标仪检测，测定吸收波长为450nm的 OD值，记录结果。抑制率计算公式：(1-OD实验组/OD对照组)×100％。利用GraphPad Prism 6软件拟合各化合物剂量浓度-抑制率曲线，计算得出IC50值(结果对应图1)。其统计结果 如下表所示：
Figure BSA0000198289670000161
表中显示：curcuminA001，curcuminB001，curcuminD001在低浓度下，对肺癌细胞株(PC9、 PC9AR、PC9GR)均有抑制作用，以curcuminA001最为显著；对非小细胞肺癌细胞株(HCC827、 HCC827AR、HCC827ER)的抑制作用，以curcuminD001最为显著。依据分子模拟图7(图7为 curcuminA001与STAT3蛋白SH2功能域相互作用的界面注释，上图为对接结果立体图，下图 为对接结果二维图，其中下图中紫色表示配体暴露位置。)的结论，curcuminA001与STAT3-SH2 功能域的磷酸化络氨酸激酶作用区域有显著的相互作用，curcuminA001酚羟基和苄基醚氧原 子(作为I式姜黄素化合物的公共基团)分别参与了与关键氨基酸-赖氨酸591的相互作用， 苄氧基邻位甲氧基的氧原子与ARG609残基胺基氢原子形成氢键，并且酮羰基氧原子与GLU638 主链胺基氢原子形成氢键。所以，curcuminA001的酚羟基、苄氧基邻位的甲氧基氧原子、苄 基醚氧原子以及酮羰基氧原子是I式姜黄素化合物的公共基团，也是参与蛋白分子相互作用 的关键基团，由此推断，作为I式姜黄素化合物的氨基与STAT3蛋白SH2功能域的磷酸化络 氨酸相互作用区域有强相互作用，I式姜黄素化合物均为STAT3作用于赖氨酸591、精氨酸 609和谷氨酸638位点的抑制剂，所以，I式姜黄素化合物均能抑制STAT3蛋白与信号传导中 上下游蛋白的结合，抑制STAT3蛋白的磷酸化、阻断STAT3信号传导下游基因的表达、诱导 相关肿瘤细胞的凋亡，并达到控制肿瘤生长的作用。
分子对接(docking)实验
对接方法：所有的计算机配位模拟(docking)的实验均在sybyl X2.1.1的操作平台上 完成，所用的计算机配位模拟(docking)的工具为SUEFLEX DOCK。依据所选的位点(主要 包括磷酸化酪氨酸作用位点LYS591、ARG595、ARG609以及疏水相互作用位点GLU638)进行 计算，确定势能面(potential gradient)并作计算机配位模拟(docking)的实验。依据模 拟(docking)的分数(Score)和构象及相互作用进行分析。
对接结果分析：curcuminA001与STAT3-SH2结构域关键氨基酸LYS591、ARG609、GLU638 有显著的极性相互作用。虚拟对接结果显示：酚羟基邻位的甲氧基氧原子与LYS591残基氨基 氢原子形成氢键，苄氧基邻位的氧原子与ARG609支链氨基氢原子形成氢键，酮羰基氧原子与 GLU638主链氨基氢原子形成氢键，苄基醚氧原子与LYS591支链氨基氢原子形成氢键(图7)。 curcuminD001与STAT3-SH2结构域关键氨基酸LYS591、GLU638有显著的极性相互作用。其 中，苯甲酸酯基中的两个氧原子与LYS591支链氨基氢原子形成双氢键盐桥，酮羰基氧原子与 GLU638主链上的氨基氢原子形成氢键，酚羟基氢原子与GLU638支链羧基氧原子形成氢键(图 8)(图8为curcuminD001与STAT3蛋白SH2功能域相互作用的界面注释，上图为对接结果 立体图，下图为对接结果二维图，其中下图中紫色表示配体暴露位置。)。
依据分子模拟(图7、图8)的结论，I式姜黄素化合物的酚羟基邻位的甲氧基氧原子、 酚羟基氧原子以及氢原子、苄氧基苄基醚氧原子和邻位的氧原子以及酮羰基氧原子与STAT3 蛋白SH2功能域的磷酸化络氨酸相互作用区域有强相互作用，I式姜黄素化合物均为STAT3 作用于赖氨酸591、谷氨酸638位点的抑制剂。所以，I式姜黄素化合物均能与STAT3蛋白的 SH2结构域结合。SH2结构域对于STAT3的二聚体的形成具有关键作用，对该结构域的竞争性 结合，将进一步影响STAT3的核转位和下游抗凋亡、促增殖或转移等相关靶基因的表达，从 而达到控制肿瘤生长和演进的作用。
因此，按照药物开发的一般途径(先进行常规的抗肿瘤体外筛选，然后进行针对性的研 究)，本发明的化合物可以应用到与STAT3细胞信号传导异常相关的癌症(如肺癌、乳腺癌、 结直肠癌、白血病、头颈癌以及前列腺癌等)治疗药物中，可通过与人体可接受的酸成盐或 与药用载体混合制备抗肿瘤药物。
最后所应说明的是：上述实施例仅用于说明而非限制本发明的技术方案，任何对本发明 进行的等同替换及不脱离本发明精神和范围的修改或局部替换，其均应涵盖在本发明权利要 求保护的范围之内。

Claims (9)

1.一种姜黄素类化合物，其特征在于，结构式如通式I和II所示：
Figure FSA0000198289660000011
其中，
X为-CH2-或-CO-；
p＝0、1、2、3、4、...10；
Y为-CH2-；
m＝1、2、3、4、...10；
L＝C或N；
Z＝C或N；
E＝C或N；
D＝C或N；
A选自：
Figure FSA0000198289660000012
等，其中n＝0，1、2、3、4；
Figure FSA0000198289660000013
其中，
X为-CH2-或-CO-；
p＝0、1、2、3、4、...10；
Y为-CH2-；
m＝1、2、3、4、...10；
Z＝C、O或N；
D＝C、O或N；
E＝C、O或N；
A选自：
Figure FSA0000198289660000021
等，其中n＝0、1、2、3、4。
2.根据权利要求1所述的姜黄素类化合物，其特征在于，具体为如下结构的化合物：
Figure FSA0000198289660000022
。
3.权利要求1或2所述的姜黄素类化合物与乙酸、二氢乙酸、苯甲酸、柠檬酸、山梨酸、丙酸、草酸、富马酸、马来酸、盐酸、苹果酸、磷酸、亚硫酸、硫酸、香草酸、酒石酸、抗坏血酸、硼酸、乳酸和乙二胺四乙酸中的至少一种形成的生物学可接受的盐。
4.权利要求1或2所述的姜黄素类化合物的制备方法，其特征在于，包括以下步骤：
(1)将摩尔比为1∶1.1的
Figure FSA0000198289660000023
与
Figure FSA0000198289660000024
溶解于有机溶剂中，并加入碳酸钾，TLC检测反应结束后，后处理得到
Figure FSA0000198289660000031
(2)将摩尔比为1∶6的
Figure FSA0000198289660000032
与
Figure FSA0000198289660000033
溶解于有机溶剂中，并加入吡啶，TLC检测反应结束后，后处理得到
Figure 1
。
5.根据权利要求4所述的姜黄素类化合物的制备方法，其特征在于，所述
Figure FSA0000198289660000035
通过以下方法制备得到：将摩尔比为1∶1.1的
Figure FSA0000198289660000036
与
Figure FSA0000198289660000037
溶解于有机溶剂中，并加入碳酸钾，TLC检测反应结束后，后处理得到
Figure FSA0000198289660000038
6.根据权利要求4所述的姜黄素类化合物的制备方法，其特征在于，所述
Figure FSA0000198289660000041
通过以下方法制备得到：将摩尔比为1∶1.5的
Figure FSA0000198289660000042
与
Figure FSA0000198289660000043
溶解于有机溶剂中，并加入醋酸铜，三乙胺，TLC检测反应结束后，后处理得到
Figure FSA0000198289660000044
7.权利要求3所述的姜黄素类化合物和生物学可接受的盐，其特征在于，通过以下方法制备：将所述姜黄素类化合物溶于4M的HCl/MeOH溶液中，室温下反应，TLC检测反应结束后，后处理即得。
8.权利要求1至3任一项所述的姜黄素类化合物以及生物学可接受的盐作为STAT3抑制剂在物理、化学、生物学和医学等方面的用途。
9.权利要求1至3任一项所述的姜黄素类化合物及其生物学可接受的盐在制备用于治疗与STAT3细胞信号传导相关疾病如肺癌、乳腺癌、结直肠癌、白血病、头颈癌以及前列腺癌等的药物中的用途。
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