CN114524716A - β-榄香烯乙烯基化偶联衍生物及其制备和在制备抗肿瘤药物中的应用 - Google Patents

β-榄香烯乙烯基化偶联衍生物及其制备和在制备抗肿瘤药物中的应用 Download PDF

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CN114524716A
CN114524716A CN202210185780.6A CN202210185780A CN114524716A CN 114524716 A CN114524716 A CN 114524716A CN 202210185780 A CN202210185780 A CN 202210185780A CN 114524716 A CN114524716 A CN 114524716A
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vinylation
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CN114524716B (zh
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谢恬
叶杨
徐冰
叶向阳
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Hangzhou Normal University
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Abstract

本发明公开β‑榄香烯乙烯基化偶联衍生物及其制备和在制备抗肿瘤药物中的应用。本发明提供了式(I)所示结构的一类结构新颖的β‑榄香烯乙烯基化偶联衍生物、含有式(I)化合物的药物组合物及水合物，以及这些化合物的同位素衍生物、手性异构体、变构体、不同的盐、前药和制剂等。本发明还提供了所述一类结构新颖的β‑榄香烯乙烯基化偶联衍生物的制备方法、用途，以及这些化合物对各种肿瘤细胞株增殖抑制的活性。本发明中的一类结构新颖的β‑榄香烯乙烯基化偶联衍生物有望成为抗肿瘤候选药物，治疗结肠癌、肺癌。

Description

β-榄香烯乙烯基化偶联衍生物及其制备和在制备抗肿瘤药物 中的应用
技术领域
本发明涉及β-榄香烯衍生物的制备技术领域，具体涉及β-榄香烯乙烯基化偶联衍生物及其制备和在制备抗肿瘤药物中的应用。
背景技术
榄香烯是一类小分子挥发油类化合物，主要从温郁金的块根中提取获得。目前文献中所报道的榄香烯主要包括α-榄香烯、(±)-β-榄香烯、γ-榄香烯和δ-榄香烯，其中(-)-β-榄香烯是其发挥抗肿瘤作用的主要活性成分，具有广谱抗肿瘤活性，对多种癌症均有一定的疗效，如肝癌、乳腺癌、肺癌等。目前，以榄香烯为主要成分的多种制剂在临床上均取得了一定的抗癌疗效。
β-榄香烯作为为数不多的拥有我国自主知识产权的抗肿瘤新药，其衍生物的研究近年来已经取得了很大的进展。从构效关系的研究结里看，β-槛香烯的双键及其骨架对活性有着重要的影响，凡是不破坏3个双键的化合物，其活件均没有受到太大影响。但是由于榄香烯极性小、水溶性差，生物口服利用度低，限制了其临床应用。因此，需要对榄香烯进行结构改造以获得水溶性好、生物口服利用度更高，生物活性优于榄香烯，且毒副作用小的榄香烯衍生物。
β-榄香烯的结构修饰工作从20世纪70年代开始，发展至今，已经合成的β-榄香烯衍生物数目已有150余种，涉及到还原氧化、含硫、含氮、酯类、酥类、醇类、糖苷等几个大类。目前关于β-榄香烯乙烯基化偶联的研究少之又少，故有望于以β-榄香烯为母体构建一系列β-榄香烯乙烯基化偶联的衍生物进而研究其抗肿瘤活性，有望开发出新的抗肿瘤药物。
发明内容
本发明的第一个目的是针对现有技术的不足，提供一种β-榄香烯乙烯基化偶联衍生物。
β-榄香烯乙烯基化偶联衍生物，或其光学异构体、消旋体、单一对映异构体、可能的非对映异构体，或其药学上可接受的盐、前药、氘代衍生物、水合物、溶剂化物，所述β-榄香烯乙烯基化偶联衍生物的结构如式(I)所示：
Figure BDA0003523340640000011
式(I)中：
Figure BDA0003523340640000012
分别独立选自以下结构片段：
Figure BDA0003523340640000021
进一步地，所述β-榄香烯乙烯基化偶联衍生物为如下结构所示的化合物1～22中的任一种：
Figure BDA0003523340640000031
本发明的第二个目的是提供了所述β-榄香烯乙烯基化偶联衍生物的制备方法。
对于式(I)结构的β-榄香烯乙烯基化偶联衍生物，可采用合成路线：
Figure BDA0003523340640000041
具体包括步骤：
(1)首先将β-榄香烯A-1进行烯丙位单溴取代反应得中间体A-2；
(2)然后将中间体A-2通过选择性亲核取代反应得中间体A-3；
(3)最后将中间体A-3与烯溴A-4进行乙烯基化偶联，得式(I)所示的β-榄香烯乙烯基化偶联衍生物；
本发明式(I)所示化合物可通过如上的方法制得，然而该方法的条件，如反应物、溶剂、所用化合物的量、反应温度、反应所需时间等不限于上面的解释。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得，这样的组合可由本发明所属领域的技术人员容易地进行。
本发明各合成路线的步骤(1)均可采用现有技术，如公开号为CN110683932A中公开的
本发明的第三个目的是提供了所述的β-榄香烯乙烯基化偶联衍生物，或其光学异构体、消旋体、单一对映异构体、可能的非对映异构体，或其药学上可接受的盐、前药、氘代衍生物、水合物、溶剂化物在制备抗肿瘤药物中的应用。
本发明的第四个目的是提供了一种抗肿瘤药物，含有安全有效量的所述的β-榄香烯乙烯基化偶联衍生物，或其光学异构体、消旋体、单一对映异构体、可能的非对映异构体，或其药学上可接受的盐、前药、氘代衍生物、水合物、溶剂化物。
作为优选，所述抗肿瘤药物还可以包括药学上可以接受的载体。
作为优选，所述应用和所述抗肿瘤药物中，所述肿瘤包括结肠癌、肺癌。
由于本发明化合物具有抑制各种肿瘤细胞株增殖的活性，因此，本发明化合物及其各种晶型、药学上可接受的无机或有机盐、水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解各种疾病，包括各种癌症。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有5-1000mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组分能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如
Figure BDA0003523340640000042
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增溶剂，如淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，如羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，如甘油；(d)崩解剂，如琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐和碳酸钠；(e)缓溶剂，如石蜡；(f)吸收加速剂，如季胺化合物；(g)润湿剂，如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，如高岭土；(i)润滑剂，如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型，如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部位中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型，包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，如乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂，包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要推进剂一起混合。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～5000mg，优选5～2000mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明与现有技术相比，主要优点包括：本发明提供了式(I)所示结构的β-榄香烯乙烯基化偶联衍生物、含有式(I)化合物的药物组合物及水合物，以及这些化合物的同位素衍生物、手性异构体、变构体、不同的盐、前药和制剂等。本发明还提供了所述β-榄香烯乙烯基化偶联衍生物的制备方法、用途，以及这些化合物对各种肿瘤细胞株的增殖的活性。本发明中的β-榄香烯C-C键偶联衍生物有望成为抗肿瘤候选药物，治疗各种癌症，如肺癌、肝癌、结直肠癌、胃癌、前列腺癌、卵巢癌、乳腺癌或脑胶质瘤等。
具体实施方式
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的操作方法，通常按照常规条件，或按照制造厂商所建议的条件。
实施例1：化合物1的制备
Figure BDA0003523340640000061
中间体1d
(1)在0℃条件下，向化合物1a(20mmol，100mol％)的二氯甲烷(DCM)(80mL)溶液中加入CBr4(30mmol，150mol％)，然后在氮气保护的条件下通过恒压滴液漏斗逐滴滴加PPh3(60mmol，300mol％)的DCM(70mL)溶液。TLC监测反应进程，反应完全后减压除去约一半体积的二氯甲烷，然后加入石油醚(PE)(100mL)沉淀三苯基氧磷(TPPO)。硅藻土过滤和蒸发后，将残渣溶解在PE(50mL)中，使TPPO进一步沉淀。重复多次得到粗二溴化物1b(～20mmol，100mol％)，直接用于下一步。
(2)在室温条件下，向粗二溴化物1b(～20mmol，100mol％)和NEt3(60mmol，300mol％)的无水N,N-二甲基甲酰胺(DMF)(20mL)溶液中加入亚磷酸二甲酯(60mmol，300mol％)，搅拌过夜。在减压条件下将DMF蒸除，加入水溶液(60mL)，用PE(2×100mL)萃取，合并的有机相用盐酸水溶液(1M，55mL)洗涤，然后用无水硫酸钠干燥。干燥剂经过滤除去，滤液在减压条件下浓缩，所得的粗品1c直接用于下一步。
(3)将上一步的粗产物1c(～20mmol，100mol％)溶解在异丙醇(i-PrOH)(30mL)中。加入固体氢氧化钠(17mmol，85mol％)加热回流>5小时。将反应混合物冷却至室温，用正己烷(100mL)萃取，合并的有机相依次用盐酸水溶液(1M，75mL)、水溶液(2×100mL)洗涤，然后用无水硫酸钠干燥。干燥剂经过滤除去，滤液在减压条件下浓缩，所得的粗品经硅胶柱层析(乙酸乙酯/石油醚(0.5％)体系洗脱)纯化，得白色固体1d(2.65g，收率62％)。1H NMR(500MHz,CDCl3)δ7.25–7.21(m,2H),7.04(d,J＝14.0Hz,1H),6.87–6.83(m,2H),6.61(d,J＝13.9Hz,1H),3.81(s,3H).
化合物1
向配备有磁力搅拌器的烘箱干燥过的Schlenk管中依次加入中间体1d(0.150mmol，1.0equiv)、中间体1e(0.300mmol，2.0equiv)、NiCl2(PPh3)2(9.8mg，0.015mmol，10mol％)、Zn(19.6mg,0.300mmol,2.0equiv)、4,4'-二叔丁基-2,2'-联吡啶(4.0mg，0.015mmol，10mol％)和MgCl2(28.6mg，0.300mmol，2.0equiv)。然后将Schlenk管使用双排管抽放气三次确保反应在氮气氛围下，最后用注射器加入N,N-二甲基乙酰胺(DMA)(1.0mL)溶液。在25℃下搅拌12小时。反应完全后，无需后处理，将反应混合物直接通过硅胶柱层析(乙酸乙酯/石油醚(2％)体系洗脱)纯化，得无色油状液体1(43.3mg，收率86％)。1HNMR(500MHz,CDCl3)δ7.31(d,J＝8.7Hz,2H),6.85(d,J＝8.7Hz,2H),6.37(d,J＝15.8Hz,1H),6.08(dt,J＝15.7,7.1Hz,1H),5.83(dd,J＝17.4,10.9Hz,1H),4.92(dd,J＝8.1,1.2Hz,1H),4.89(s,1H),4.87(s,1H),4.83(dd,J＝5.0,1.3Hz,2H),4.61(s,1H),3.81(s,3H),2.95(d,J＝7.0Hz,2H),2.02(dd,J＝11.8,4.3Hz,2H),1.72(s,3H),1.64–1.59(m,2H),1.54–1.42(m,4H),1.02(s,3H).13C NMR(126MHz,CDCl3)δ158.92,153.40,150.38,147.81,130.81,130.65,127.27,126.63,114.06,112.26,110.01,108.76,55.41,52.90,44.30,40.09,39.98,38.83,33.36,27.33,24.93,16.76.HRMS(ESI)m/z([M-H]-)calcd forC24H31O:335.2380.Found:335.2380.
实施例2：化合物2的制备
Figure BDA0003523340640000071
中间体2d
参照实施例1里面中间体1d的合成步骤，得无色油状液体2d(881mg，收率21％)。1HNMR(500MHz,CDCl3)δ8.07(d,J＝2.5Hz,1H),7.55(dd,J＝8.6,2.5Hz,1H),7.03(d,J＝14.0Hz,1H),6.71(d,J＝8.7Hz,1H),6.66(d,J＝14.0Hz,1H),3.94(s,3H).
化合物2
参照实施例1里面化合物1的合成步骤，得无色油状液体2(36.9mg，收率73％)。1HNMR(500MHz,CDCl3)δ8.08(t,J＝5.5Hz,1H),7.64(dd,J＝8.6,2.4Hz,1H),6.69(d,J＝8.6Hz,1H),6.34(d,J＝15.9Hz,1H),6.10(dt,J＝15.8,7.0Hz,1H),5.81(dd,J＝17.3,11.0Hz,1H),4.99–4.75(m,5H),4.59(s,1H),3.93(s,3H),2.95(d,J＝6.9Hz,2H),1.99(ddd,J＝15.9,11.2,5.0Hz,2H),1.71(s,3H),1.65–1.56(m,3H),1.50–1.41(m,3H),1.01(s,3H).13C NMR(126MHz,CDCl3)δ163.43,153.06,150.32,147.77,145.08,135.54,128.25,127.52,126.97,112.29,110.93,110.07,109.01,53.61,52.90,44.41,40.02(d,J＝11.8Hz),38.83,33.37,29.84,27.32,24.93,16.76.HRMS(ESI)m/z([M+H]+)calcd forC23H32NO:338.2478.Found:338.2475.
实施例3：化合物3的制备
Figure BDA0003523340640000072
化合物3
参照实施例1里面化合物1的合成步骤，得无色油状液体3(39.7mg，收率80％)。1HNMR(500MHz,CDCl3)δ7.75(d,J＝8.3Hz,2H),7.43(d,J＝8.3Hz,2H),6.36(ddd,J＝30.6,15.8,11.4Hz,2H),5.81(dd,J＝17.3,11.0Hz,1H),4.94–4.87(m,3H),4.82(d,J＝5.9Hz,2H),4.59(s,1H),2.99(d,J＝6.8Hz,2H),2.01(dt,J＝18.0,10.4Hz,2H),1.71(s,3H),1.64–1.56(m,3H),1.52–1.42(m,3H),1.01(s,3H).13C NMR(126MHz,CDCl3)δ169.12,152.70,150.29,147.77,141.53,131.61,130.50,127.86,126.29,112.31,110.10,109.32,100.12,52.89,44.48,40.01(d,J＝9.9Hz),38.82,33.36,29.84,27.30,24.93,16.77.HRMS(ESI)m/z([M+H]+)calcd for C24H30N:332.2373.Found:332.2378.
实施例4：化合物4的制备
Figure BDA0003523340640000081
化合物4
参照实施例1里面化合物1的合成步骤，得无色油状液体4(43.1mg，收率77％)。1HNMR(500MHz,CDCl3)δ8.54(s,1H),8.10(s,1H),7.61(d,J＝8.5Hz,2H),7.49(d,J＝8.6Hz,2H),6.44(d,J＝15.8Hz,1H),6.29(dt,J＝15.8,7.0Hz,1H),5.82(dd,J＝17.3,11.0Hz,1H),4.97–4.87(m,3H),4.83(d,J＝1.4Hz,2H),4.60(s,1H),2.99(d,J＝6.9Hz,2H),2.06–1.97(m,2H),1.71(s,3H),1.64–1.58(m,3H),1.52–1.42(m,3H),1.01(s,3H).13C NMR(126MHz,CDCl3)152.81,152.68,150.29,147.77,140.84,137.95,135.73,130.55,130.06,127.38,120.29,112.32,110.11,109.26,52.90,44.49,40.06,39.98,38.78,33.37,27.32,24.94,16.77.HRMS(ESI)m/z([M+H]+)calcd for C25H32N3:374.2591.Found:374.2590.
实施例5：化合物5的制备
Figure BDA0003523340640000082
中间体5g
参照实施例1里面中间体1d的合成步骤，得白色固体5d，然后在冰浴条件下，向化合物5d(358mg，1.58mmol)和化合物5f(288.4mg，1.5mmol)的无水DCM(10mL)溶液中，依次加入DMAP(37mg，0.3mmol)、DCC(464mg，2.25mmol)，搅拌过夜。在减压条件下将DCM蒸除，向残余物中加入水溶液(40mL)，然后用乙酸乙酯(3×20mL)萃取。合并的有机相用饱和食盐水(2×20mL)洗涤，然后用无水硫酸钠干燥。干燥剂经过滤除去，滤液在减压条件下浓缩，所得的粗品经硅胶柱层析(乙酸乙酯/石油醚(0.5％)体系洗脱)纯化，得白色固体5g(581mg，收率97％)。1H NMR(500MHz,CDCl3)δ7.93(d,J＝8.4Hz,2H),7.32(d,J＝8.3Hz,2H),7.18(d,J＝8.0Hz,2H),7.15–7.07(m,3H),6.90(d,J＝14.0Hz,1H),4.42–4.33(m,2H),3.26–3.18(m,1H),2.45(d,J＝7.2Hz,2H),1.84(dt,J＝13.5,6.8Hz,1H),1.38(d,J＝7.0Hz,3H),0.89(d,J＝6.6Hz,6H).
化合物5
参照实施例1里面化合物1的合成步骤，得无色油状液体5(67.6mg，收率86％)。1HNMR(500MHz,CDCl3)δ7.91(d,J＝7.9Hz,2H),7.38(d,J＝8.0Hz,2H),7.19(d,J＝7.7Hz,2H),7.10(d,J＝7.7Hz,2H),6.49–6.30(m,2H),5.82(d,J＝6.4Hz,1H),5.01(s,1H),4.93–4.92(m,1H),4.89(s,1H),4.83(s,2H),4.58–4.57(m,1H),4.42–4.31(m,2H),3.21(dd,J＝13.9,7.0Hz,1H),2.99(d,J＝6.7Hz,2H),2.45(d,J＝7.1Hz,2H),2.09(s,3H),2.01(d,J＝6.8Hz,2H),1.85(dt,J＝13.3,6.7Hz,1H),1.60(s,2H),1.47(s,4H),1.38(d,J＝6.8Hz,3H),0.99(s,3H),0.90(d,J＝6.6Hz,6H).13C NMR(126MHz,CDCl3)δ194.56,170.79,166.38,152.57,150.20,150.07,148.49,147.40,142.14,140.45,140.09,131.70,130.66,129.96,129.30,127.11,125.95,112.38,111.02,110.13,109.28,70.02,66.20,52.77,45.13,44.42,41.93,39.90,38.79,33.13,30.29,27.13,24.90,22.48(d,J＝3.1Hz),21.08,18.13,16.69.HRMS(ESI)m/z([M+H]+)calcd for C37H49O2:525.3727.Found:525.3722.
实施例6：化合物6的制备
Figure BDA0003523340640000091
中间体6g
参照实施例5里面中间体5g的合成步骤，得无色油状液体6g(267mg，收率82％)。1HNMR(500MHz,CDCl3)δ7.98(d,J＝8.3Hz,2H),7.34(d,J＝8.3Hz,2H),7.13(d,J＝14.0Hz,1H),6.91(d,J＝14.0Hz,1H),5.09(t,J＝7.1Hz,1H),4.40–4.29(m,2H),1.99(dd,J＝22.5,7.6Hz,2H),1.80(dt,J＝12.5,6.3Hz,1H),1.66(s,3H),1.59(s,3H),1.34–1.28(m,2H),1.24(dd,J＝15.0,7.7Hz,2H),0.96(d,J＝6.6Hz,3H).
化合物6
参照实施例1里面化合物1的合成步骤，得无色油状液体6(63.7mg，收率87％)。1HNMR(500MHz,CDCl3)δ7.97(d,J＝7.9Hz,2H),7.41(d,J＝8.0Hz,2H),6.50–6.29(m,2H),5.82(dd,J＝17.4,10.8Hz,1H),5.10(dd,J＝6.9,5.9Hz,1H),4.92(s,1H),4.91(s,1H),4.89(d,J＝2.6Hz,1H),4.82(d,J＝5.1Hz,2H),4.60(s,1H),4.46–4.27(m,2H),2.99(d,J＝6.8Hz,2H),2.07–1.97(m,4H),1.92(d,J＝10.1Hz,1H),1.86–1.79(m,1H),1.75(d,J＝9.2Hz,1H),1.71(s,3H),1.68(s,3H),1.61(s,3H),1.56(d,J＝8.1Hz,1H),1.51–1.44(m,3H),1.31(dd,J＝17.7,7.5Hz,4H),1.01(s,3H),0.97(d,J＝6.5Hz,3H).13C NMR(126MHz,CDCl3)δ166.64,152.66,150.27,147.72,142.14,131.72,131.48,130.72,130.00,129.01125.99,124.71,112.30,110.08,109.31,63.53,52.87,44.47,40.00(d,J＝10.8Hz),38.84,37.13,35.66,35.06,33.35,29.72,27.30,25.84,25.54,24.93,19.65,17.80,16.75.HRMS(ESI)m/z([M+H]+)calcdfor C34H49O2:489.3727.Found:489.3730.
实施例7：化合物7的制备
Figure BDA0003523340640000101
中间体7g
参照实施例5里面中间体5g的合成步骤，得无色油状液体7g(281mg，收率89％)。1HNMR(500MHz,CDCl3)δ8.00(d,J＝8.2Hz,2H),7.35(d,J＝8.3Hz,2H),7.13(d,J＝14.0Hz,1H),6.91(d,J＝14.0Hz,1H),5.84(s,1H),4.73–4.70(m,3H),2.17(d,J＝3.6Hz,1H),1.93–1.89(m,2H),1.74(s,3H),1.58–1.49(m,2H),1.30(d,J＝9.8Hz,2H).
化合物7
参照实施例1里面化合物1的合成步骤，得无色油状液体7(59.5mg，收率82％)。1HNMR(500MHz,CDCl3)δ7.97(d,J＝8.3Hz,2H),7.40(d,J＝8.3Hz,2H),6.38(dt,J＝15.8,12.4Hz,2H),5.82–5.80(m,2H),5.00(s,1H),4.91(s,1H),4.88(d,J＝2.1Hz,1H),4.81(s,2H),4.71(dd,J＝8.9,5.0Hz,4H),4.57(s,1H),2.98(d,J＝6.7Hz,2H),2.17(d,J＝5.1Hz,3H),2.08(s,3H),2.01(s,2H),1.90(d,J＝10.0Hz,3H),1.70–1.69(m,3H),1.59(s,2H),1.46(d,J＝3.4Hz,4H),1.29(s,1H),1.00–0.99(m,3H).13C NMR(126MHz,CDCl3)δ194.56,170.79,154.90,152.57,150.06,148.48,147.40,132.89,131.73,130.66,130.02,125.96,125.59,112.36,111.01,110.12,108.90,68.78,66.20,55.80,52.76,48.46,45.71,44.42,41.92,40.95,39.89,38.79,36.51,35.00,33.12,30.56.HRMS(ESI)m/z([M+H]+)calcd forC34H45O2:485.3414.Found:485.3409.
实施例8：化合物8的制备
Figure BDA0003523340640000111
化合物8
参照实施例1里面化合物1的合成步骤，得无色油状液体8(50.1mg，收率75％)。1HNMR(500MHz,CDCl3)δ8.01(d,J＝7.7Hz,1H),7.59(d,J＝3.6Hz,1H),7.32(d,J＝7.5Hz,1H),7.24(t,J＝3.9Hz,1H),6.72(d,J＝3.3Hz,2H),6.32(dt,J＝15.7,7.1Hz,1H),5.80(dd,J＝17.4,10.9Hz,1H),4.93–4.77(m,5H),4.58(s,1H),3.02(d,J＝7.0Hz,2H),2.00(dd,J＝12.0,3.9Hz,2H),1.70(s,3H),1.65(s,12H),1.46(ddd,J＝9.0,7.8,2.6Hz,3H),1.00(s,3H).13C NMR(126MHz,CDCl3)δ153.17,150.37,147.82,135.65,134.23,130.42(d,J＝8.5Hz),128.63,125.92,124.48,119.37,115.42,114.66,113.93,112.29,110.04,109.06,105.62,83.83,52.92,44.45,40.05(d,J＝12.6Hz),39.20,33.41,29.85,28.34,27.36,24.94,16.78.HRMS(ESI)m/z([M-H]-)calcdfor C30H38NO2:444.2908.Found:444.2908.
实施例9：化合物9的制备
Figure BDA0003523340640000121
中间体9g
参照实施例5里面中间体5g的合成步骤，得无色油状液体9g(416mg，收率69％)。1HNMR(500MHz,CDCl3)δ7.99(d,J＝8.4Hz,2H),7.34(d,J＝8.3Hz,2H),7.13(d,J＝14.1Hz,1H),6.90(d,J＝14.0Hz,1H),5.45(t,J＝7.0Hz,1H),4.83(d,J＝7.0Hz,2H),2.04(d,J＝5.1Hz,2H),1.75(s,3H),1.51(dd,J＝13.3,6.7Hz,1H),1.39–1.11(m,20H),0.88–0.81(m,12H).
化合物9
参照实施例1里面化合物1的合成步骤，得无色油状液体9(73.6mg，收率78％)。1HNMR(500MHz,CDCl3)δ7.98(d,J＝8.4Hz,2H),7.40(d,J＝8.4Hz,2H),6.54–6.26(m,2H),5.82(dd,J＝17.3,11.0Hz,1H),5.46(dd,J＝7.0,6.0Hz,1H),4.93–4.89(m,2H),4.83(dd,J＝5.9,4.0Hz,3H),4.60(s,1H),3.20(dt,J＝13.3,5.0Hz,1H),2.99(d,J＝6.8Hz,2H),2.07–1.98(m,5H),1.95–1.89(m,2H),1.75(s,3H),1.71(s,3H),1.63–1.57(m,5H),1.48(ddd,J＝13.1,9.9,5.1Hz,8H),1.16–1.12(m,5H),1.09–1.05(m,5H),1.01(s,3H),0.86(d,J＝5.5Hz,12H).13C NMR(126MHz,CDCl3)δ166.66,152.68,150.29,147.74,142.87,142.13,131.69,130.74,130.07,129.03,125.98,118.37,112.31,110.08,109.32,61.98,55.89,52.88,44.47,40.05,39.79,39.52,38.85,37.57,37.51,37.44,36.77,35.07,33.36,32.87(d,J＝15.3Hz),29.85,28.12,27.30,25.60,25.19,24.94,24.61,22.82(d,J＝11.7Hz),19.88(d,J＝3.7Hz),16.69(d,J＝18.4Hz),14.27.HRMS(ESI)m/z([M+H]+)calcd forC44H69O2:629.5292.Found:629.5291.
实施例10：化合物10的制备
Figure BDA0003523340640000131
中间体10g
参照实施例5里面中间体5g的合成步骤，得白色固体10g(1.07g，收率91％)。1HNMR(500MHz,CDCl3)δ7.97(dd,J＝8.5,1.6Hz,2H),7.39–7.34(m,2H),7.34–7.30(m,2H),7.30–7.27(m,2H),7.20(dd,J＝8.1,6.8Hz,2H),7.16–7.10(m,4H),6.91(d,J＝14.1Hz,1H),6.82–6.76(m,2H),6.62–6.56(m,2H),4.57(dd,J＝5.5,3.9Hz,2H),4.16(dd,J＝5.6,3.9Hz,2H),3.41(t,J＝7.4Hz,2H),2.92(t,J＝7.5Hz,2H).
化合物10
参照实施例1里面化合物1的合成步骤，得无色油状液体10(86.4mg，收率81％)。1HNMR(500MHz,CDCl3)δ7.96(d,J＝8.2Hz,2H),7.42–7.36(m,4H),7.31(d,J＝6.2Hz,3H),7.23–7.19(m,2H),7.16(d,J＝7.2Hz,3H),6.82(d,J＝8.7Hz,2H),6.61(d,J＝8.7Hz,2H),6.51–6.31(m,2H),5.86–5.80(m,1H),5.11(d,J＝13.8Hz,1H),4.92(s,1H),4.91(s,1H),4.84(d,J＝6.9Hz,2H),4.61(s,1H),4.59–4.56(m,2H),4.20–4.14(m,2H),3.43(t,J＝7.4Hz,2H),3.00(d,J＝8.7Hz,2H),2.95–2.91(m,2H),2.05–2.00(m,2H),1.73(s,3H),1.62(dd,J＝7.5,3.3Hz,2H),1.51–1.45(m,4H),1.03(s,3H).13C NMR(126MHz,CDCl3)δ166.44,156.86,152.58,150.24,148.88,147.68,142.94,142.41,141.75,141.03,135.41(d,J＝5.3Hz),131.93,131.86,130.62,130.16,129.63,129.49,128.46,128.34,127.07,126.73,125.98,113.72,113.13,112.29,110.07,109.33,79.52,65.88,63.33,52.83,44.43,42.93,41.65,39.96(d,J＝9.6Hz),38.75(d,J＝14.8Hz),33.31,29.81,27.26,24.92.HRMS(ESI)m/z([M+Na]+)calcdfor C48H51ClNaO3:733.3419.Found:733.3482.
实施例11：肿瘤细胞增殖抑制实验
体外抗肿瘤活性评价
1.实验设备与试剂
1.1仪器
生物安全柜(上海百基生物科技有限公司)、恒温二氧化碳培养箱(THERMO)、酶联免疫分析仪(Spark)、倒置显微镜(Nikon)、移液枪一套(eppendorf)和离心机(beckmancoulter)。
1.2试剂
McCoy’S 5A(浙江森瑞生物科技有限公司)、RPMI 1640(浙江森瑞生物科技有限公司)、Fatal Bovine Serum(BI)、PBS(浙江森瑞生物科技有限公司)、Trypsin(浙江森瑞生物科技有限公司)、DMSO(Coolaber)和CCK-8(Coolaber)。
1.3细胞株
人结肠癌细胞(HCT116)、人肺癌细胞(A549)。
2.实验方法
1)取对数生长期的受试细胞，经胰酶消化、计数后，以5×104/mL的浓度接种于96孔培养板中，每孔100μL(每孔5×103个细胞)，于37℃，5％CO2培养箱中培养24h；
2)用McCoy’S 5A或RPMI 1640完全培养基稀释待测药物至不同浓度。实验组更换含不同浓度被测样品的培养液，对照组更换含等体积溶剂(DMSO)的培养液，每组设立3个平行孔，于37℃，5％CO2培养箱中继续培养48h；
其中，HCT116细胞使用McCoy’S 5A完全培养基，A549细胞使用RPMI 1640完全培养基。
3)每孔加入CCK-8溶液10μL，于37℃继续培养1-4h，酶标仪在490nm处测定每个孔的吸光度值(OD值)；
4)用以下公式计算存活率和抑制率
细胞存活率＝[(As-Ab)/(Ac-Ab)]×100％
抑制率＝[(Ac-As)/(Ac-Ab)]×100％
应用GraphPadPrism 7.0软件,使用非线性回归模型绘制S型剂量-存活率曲线并计算IC50值。
As：实验孔(含有细胞的培养基、CCK-8、待测药物)的吸光度
Ac：对照孔(含有细胞的培养基、CCK-8、溶媒(DMSO)的吸光度
Ab：空白孔(不含细胞和待测药物的培养基、CCK-8)的吸光度
3.实验结果
按上述实验方法测定了目标化合物以及阳性对照药β-榄香烯对两种肿瘤细胞的增殖抑制作用，结果如表1所示。
表1目标化合物对肿瘤细胞抑制率的影响
Figure BDA0003523340640000141
100μM化合物作用于肿瘤细胞48h。
结果显示，化合物4的抗肿瘤细胞增殖作用明显强于阳性对照β-榄香烯。
选取化合物4按上述实验方法测定IC50值，结果如表2所示。
表2目标化合物对肿瘤细胞的半数抑制浓度
Figure BDA0003523340640000151
不同浓度的化合物作用于肿瘤细胞48h。
结果显示，化合物4表现出明显强于阳性对照β-榄香烯的抑制细胞增殖的活性。
此外应理解，在阅读了本发明的上述描述内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (8)

1.β-榄香烯乙烯基化偶联衍生物，或其光学异构体、消旋体、单一对映异构体、可能的非对映异构体，或其药学上可接受的盐、前药、氘代衍生物、水合物、溶剂化物，其特征在于，所述β-榄香烯衍生物的结构如式如下(I)所示：
Figure FDA0003523340630000011
结构式(I)中：
Figure FDA0003523340630000012
分别独立选自以下结构片段：
Figure FDA0003523340630000013
2.根据权利要求1所述的β-榄香烯乙烯基化偶联衍生物，或其光学异构体、消旋体、单一对映异构体、可能的非对映异构体，或其药学上可接受的盐、前药、氘代衍生物、水合物、溶剂化物，其特征在于，所述β-榄香烯乙烯基化偶联衍生物为如下结构所示的化合物1～22中的任一种：
Figure FDA0003523340630000021
3.权利要求1-2任一项所述的β-榄香烯乙烯基化偶联衍生物的制备方法，其特征在于，采用合成路线：
Figure FDA0003523340630000031
具体包括步骤：
(1)首先将β-榄香烯A-1进行烯丙位单溴取代反应得中间体A-2；
(2)然后将中间体A-2通过选择性亲核取代反应得中间体A-3；
(3)最后将中间体A-3与烯溴A-4进行乙烯基化偶联，得式(I)所示的β-榄香烯乙烯基化偶联衍生物；
其中
Figure FDA0003523340630000032
分别独立选自以下结构片段：
Figure FDA0003523340630000033
4.根据权利要求1或2所述的β-榄香烯乙烯基化偶联衍生物，或其光学异构体、消旋体、单一对映异构体、可能的非对映异构体，或其药学上可接受的盐、前药、氘代衍生物、水合物、溶剂化物在制备抗肿瘤药物中的应用。
5.根据权利要求4所述的应用，其特征在于，所述肿瘤包括结肠癌、肺癌。
6.一种抗肿瘤药物，其特征在于，含有安全有效量的权利要求1或2所述的β-榄香烯乙烯基化偶联衍生物，或其光学异构体、消旋体、单一对映异构体、可能的非对映异构体，或其药学上可接受的盐、前药、氘代衍生物、水合物、溶剂化物。
7.根据权利要求6所述的一种抗肿瘤药物，其特征在于，所述抗肿瘤药物还包括药学上可以接受的载体。
8.根据权利要求6或7所述的一种抗肿瘤药物，其特征在于，所述肿瘤包括结肠癌、肺癌。
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