CN107216283A - 一种含有二氢吡啶结构的β-榄香烯衍生物及其制备方法和用途 - Google Patents
一种含有二氢吡啶结构的β-榄香烯衍生物及其制备方法和用途 Download PDFInfo
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Abstract
本发明涉及新药研发及肿瘤治疗领域,具体涉及一类新型的含有二氢吡啶结构的β‑榄香烯衍生物,特别涉及在β‑榄香烯13位直接或通过连接臂间接引入脑靶向二氢吡啶结构的衍生物。本发明还公开了这些具有脑靶向性功能的β‑榄香烯衍生物的制备方法和这些新型衍生物用于治疗胶质瘤的用途。
Description
技术领域
本发明涉及新药研发及医药技术领域,具体涉及一类新型的含有二氢吡啶结构的β-榄香烯衍生物,特别涉及通过脑靶向机制设计的含有二氢吡啶结构的β-榄香烯衍生物,这些β-榄香烯衍生物能较好地透过血脑屏障并在脑肿瘤部位释放出原药。本发明还公开了这些具有脑靶向功能的β-榄香烯衍生物的制备方法和这些新型衍生物用于治疗胶质瘤的用途。
技术背景
神经胶质瘤简称胶质瘤,也称为胶质细胞瘤,是最常见的原发性中枢神经系统肿瘤,约占所有颅内原发肿瘤的一半,广义是指所有神经上皮来源的肿瘤,狭义是指源于各类胶质细胞的肿瘤。胶质瘤大多发病缓慢,自出现症状至就诊时间一般为数周至数月,少数可达数年。近30年来,原发性恶性脑肿瘤发生率逐年递增,年增长率约为1.2%,中老年人群尤为明显。据文献报道,中国脑胶质瘤年发病率为3-6人/10万人,年死亡人数达3万人。胶质瘤系浸润性生长物,它和正常脑组织之间没有明显界限,难以完全切除,对放疗化疗不甚敏感,非常容易复发,生长在大脑等重要部位的良、恶性肿瘤,手术难以切除或根本不能手术。化学药物和一般抗肿瘤的中药,因血脑屏障等因素的影响,疗效也不理想,因此脑胶质瘤至今仍是全身肿瘤中预后最差的肿瘤之一。因此,开发易于透过血脑屏障的抗肿瘤药物,使其能集中在脑部选择性杀伤胶质瘤细胞具有重要的意义。
温莪术,又名温郁金、黑郁金,是一种具有抗肿瘤活性的多年生姜科植物。其根部含有非常丰富的挥发油,其中以倍半萜类烯烃及其衍生物为主。榄香烯(elemene),就是从温莪术挥发油中分离得到的一种倍半萜类化合物。目前,共分离鉴定出5种构型类型的榄香烯,包括α-榄香烯、β-榄香烯、δ-榄香烯和γ-榄香烯等成分,其中β-榄香烯(β-elemene)含量较多,也是最主要的抗肿瘤活性成分。
榄香烯作为我国自行研制的二类抗肿瘤新药,目前己用于临床多年,并取得了较好的治疗效果,其主要剂型包括脂质体口服液以及脂质体注射液。临床应用的榄香烯实为一种混合物,其中β-榄香烯为主要成分,在几种主要成分中抗肿瘤活性最强,发挥最主要的抗肿瘤作用。临床上单独使用榄香烯主要用于治疗癌性胸腹水及不能手术、不能耐受放化疗的中晚期肺癌、肝癌、食道癌、鼻咽癌、脑瘤、妇科肿瘤、骨转移癌、胃癌、白血病等癌症,可延长患者生存期、提高生活质量。
近年来,越来越多的研究表明榄香烯对胶质瘤具有较好的治疗效果,罗其中等人研究发现榄香烯对C6、U251和SHG-44胶质瘤细胞均具有明显的抑制增殖作用。相比之下,在相同药物浓度鼠源性胶质瘤细胞C6较人源性胶质瘤细胞U251及SHG-44敏感。榄香烯对胶质瘤细胞的增殖抑制效应呈剂量依赖性,随着药物浓度和药物作用时间的增加,抑制效应增强。榄香烯能显著抑制胶质瘤细胞集落形成,当浓度达到20mg/L~40mg/L以上时,几乎完全抑制了肿瘤细胞克隆集落的形成。冯海滨等人研究发现榄香烯及临床胶质瘤治疗药物替莫唑胺均具有抗胶质瘤增殖的作用,榄香烯对U87GSLC的生长抑制作用强于U87,提示相比于普通胶质瘤细胞,榄香烯可能对GSLC具有更高的敏感性,而替莫唑胺在体外细胞实验中表现为对U87敏感性高于U87GSLC,两者联合应用可提高替莫唑胺抑制胶质瘤细胞及胶质瘤干细胞样细胞增殖效果,作用效果表现为协同作用。综合前人研究发现,开发β-榄香烯为抗胶质瘤药物具有较好的前景。
但β-榄香烯的结构中只含有碳、氢两种元素,属挥发油类,脂溶性强,在水中几乎不溶。这些理化性质特点,导致榄香烯在临床应用中表现出一定的副作用。由于榄香烯亲脂性过强,亲水性过弱,也使其不易被人体吸收,导致生物利用度很低。而过强的亲脂性导致其不能很好地透过血脑屏障,也无法在脑部位聚集发挥应有的药效。
为了克服以上不足,使β-榄香烯能更好地透过血脑屏障,并使其能在脑中长时间驻留,发挥药效。本项目拟采用脑靶向设计策略,在β-榄香烯结构中引入二氢吡啶结构,从而达到靶向治疗胶质瘤的目的。二氢吡啶载体介导的脑靶向前药化学结构类似于烟酰胺腺嘌呤氢化二核苷,能被NADH-NAD+氧化还原辅酶所识别并快速氧化成相应的吡啶季胺盐,由于该辅酶催化氧化还原系统在全身分布不一致,其中脑组织较外周循环系统少,故脑中的生成时间较血浆组织中缓慢。吡啶季胺盐的强亲水性特点使其在外周组织中被迅速清除,而脑中缓慢生成的吡啶鎓盐则难以通过血脑屏障,被“封锁”于脑内,在水解酶的作用下缓慢水解释放出原药,同时裂解的小分子载体没有神经毒性,也可从脑内被清除。这种相对稳定的脑靶向递药系统可使原药缓慢释放并云集于脑内,从而发挥应有的药效。
发明内容
本发明的目的旨在寻找活性好,易于透过血脑屏障,靶向胶质瘤的β-榄香烯新药候选化合物,并进一步提供一种治疗胶质瘤的药物组合物。
本发明立足天然产物的结构改造,依据药物化学中的脑靶向设计原理,连接具有脑靶向性的二氢吡啶结构用以提高β-榄香烯对胶质瘤的靶向性,设计获得新型含有二氢吡啶结构的β-榄香烯衍生物,为解决上述技术问题,本发明提供如下技术方案:
具有如下结构的β-榄香烯化合物:
如上所述的脑靶向药物含有二氢吡啶结构,在到达脑肿瘤部位后能能被NADH-NAD+氧化还原辅酶所识别并快速氧化成相应的吡啶季胺盐,而被驻留在脑内,进而在水解酶的作用下缓慢水解释放出原药榄香烯,发挥抗胶质瘤作用。
上述具有脑靶向功能的β-榄香烯衍生物可用以上合成路线得到,其合成具体步骤概述如下:
首先以β-榄香烯为原料,将其与次氯酸钠发生氯代反应,生成13-氯-β-榄香烯、14-氯-β-榄香烯以及13,14-二氯-β-榄香烯混合物。将混合物用石油醚洗脱,通过硅胶柱层析,得到单氯代混合产物a。将单氯代混合物a接着与无水醋酸钠反应生成13位和14位乙酯化产物混合物b。将b进一步在KOH条件下水解,即可制得13-β-榄香醇和14-β-榄香醇混合物c(比例为6∶1)。将混合物c通过HPLC制备分离的方法,得到单一的13-β-榄香醇d。最后将d与二氢吡啶片段进行连接得到目标产物e。
药理试验证明,本发明的13-β-榄香烯吡啶衍生物对胶质瘤细胞具有较好的选择性,相比于榄香烯有着更好的抗肿瘤作用,可以用于进一步制备抗胶质瘤药物。下面是本发明部分化合物的体外抗人类多种肿瘤增殖活性的药理实验结果:
实验设备与试剂
仪器 超净工作台(苏州艾可林净化设备有限公司)
恒温CO2培养箱(日本SANYO)
酶联免疫检测仪(美国BIO-RAD)
倒置生物显微镜(日本OLYMPUS)
试剂 青、链霉素混合液(南京凯基生物科技发展有限公司)
胰蛋白酶消化液(南京凯基生物科技发展有限公司)
PBS(南京凯基生物科技发展有限公司)
MTT(BIOSHARP)
DMSO(SIGMA)
细胞株 人胶质瘤细胞U251、U87、SHG44、人乳腺癌细胞
MCF-7。
实验方法
1.细胞消化、计数、制成浓度为5×104个/mL的细胞悬液,96孔板中每孔加入100μl细胞悬液(每孔5×103个细胞);
2. 96孔板置于37℃,5%CO2培养箱中培养24小时;
3.用完全培养基稀释药物至所需浓度,每孔加入100μL相应的含药培养基;
4. 96孔板置于37℃,5%CO2培养箱中培养72小时;
5.MTT法:
1)将96孔板进行MTT染色,λ=490nm,测定OD值。
2)每孔加入20μL MTT(5mg/mL),在培养箱继续培养4小时;
3)弃去培养基,每孔加入150μL DMSO溶解,摇床10分钟轻轻混匀;λ=490nm,酶标仪读出每孔的OD值。
6.计算抑制率。
实验结果
表1化合物对3种人类胶质瘤细胞株及人乳腺癌细胞细胞的抗增殖活性IC50值(μM)
样品 | U251 | U87 | SHG44 | MCF-7 |
β-榄香烯 | 198.6 | 186.4 | 143.2 | 163.8 |
化合物1 | 23.3 | 17.8 | 68.2 | 90.5 |
化合物2 | 12.2 | 15.4 | 65.5 | 110.5 |
化合物3 | 23.6 | 36.7 | 11.2 | 122.7 |
化合物4 | 37.3 | 43.6 | 57.8 | 120.6 |
化合物5 | 36.3 | 24.7 | 65.2 | 120.6 |
化合物6 | 10.4 | 17.8 | 37.3 | 126.5 |
化合物7 | 24.1 | 28.9 | 63.2 | 114.2 |
化合物8 | 15.4 | 18.4 | 32.9 | 76.3 |
下面是本发明部分化合物的体内抗肿瘤活性的药理实验结果:
实验方法
由上海斯莱克实验动物有限责任公司提供,周龄为4周,体重14-17g的雌性Balb/c裸鼠80只,SPF实验室培养。胰酶消化单层培养的U251细胞并计数,以不含牛血清的DMEM培养基清洗2次,采用瘤细胞悬液接种方法制作动物模型,裸鼠予乙醚麻醉后,选择裸鼠头部顶枕区,用无菌注射针头钻孔,将吸有5μL细胞悬液的微量进样器垂直硬脑膜表面插入,旋转缓慢进针2mm,回抽有阻力,无脑脊液吸出,10min内缓慢注入,待细胞沉积后,缓慢拔针。80只荷瘤鼠随机分为10组,每组8只,于接种后8天给药。衍生物溶于DMSO,再滴入poloxamer母液,最后加生理盐水至所需剂量。DMSO终浓度为1%,poloxamer终浓度为2%。各组裸鼠给药,模型组注射等量溶媒,每天注射1次,静脉注射,持续28天,每组注射10mg/kg的衍生物。给药28天结束后处死裸鼠,开颅取脑,测量移植瘤的最长径(L)和与之垂直的最宽径(W),根据公式V=L*W2/2计算肿瘤体积。计算肿瘤生长抑制率(%),用SPSS 17.0对结果进行分析,组间用t检验进行统计学分析处理,公式为:
实验结果
表2化合物的体内抗肿瘤活性
具体实施方式
以下通过实施例形式展示具体的实施方式,对本发明内容进行进一步的详细说明,但不应当将此理解为本发明上述主题的范围仅限于以下的实施例,凡是基于本发明上述内容在本领域内所能实现的技术均应属于本发明的内容。
实施例1 13-β-榄香醇的制备
将β-榄香烯(2.04g,10.0mmol)溶于乙酸(2mL)和二氯甲烷(8mL)的混合溶液中,冰浴条件下缓慢滴入NaClO溶液(1.6M,11.3mL,18.0mmol),冰浴条件下反应6h。分液,水层以二氯甲烷萃取(3×20mL),合并二氯甲烷层,分别以饱和NaHCO3溶液、H2O和饱和NaCl溶液洗涤,无水Na2SO4干燥。浓缩后以石油醚柱层析,分离得到β-榄香烯、13-氯-β-榄香烯、14-氯-β-榄香烯混合物,以及13,14-二氯-β-榄香烯,产物为无色液体。
将β-榄香烯、13-氯-β-榄香烯、14-氯-β-榄香烯混合物(3.00g,约含13-氯-β-榄香烯、14-氯-β-榄香烯共10.0mmol)溶于无水DMF(15mL)中,加入无水NaOAc(2.22g,30.0mmol),120℃条件下反应7h。反应完毕后,硅藻土过滤,滤饼以石油醚洗涤,滤液中加入H2O(15mL),以石油醚萃取(3×20mL),合并有机层,无水Na2SO4干燥。浓缩后,以石油醚∶乙酸乙酯=30∶1(V∶V)硅胶柱层析,得到13-β-榄香醇乙酸酯和14-β-榄香醇乙酸酯混合物,淡黄色液体,产率82%。
将13-β-榄香醇乙酸酯和14-β-榄香醇乙酸酯混合物(2.62g,10.0mmol)溶于氯仿(8mL)和甲醇(8mL)的混合溶液中,加入KOH(1.68g,30.0mmol),回流反应2h。过滤,滤饼以甲醇洗涤,滤液浓缩,以石油醚∶乙酸乙酯=10∶1(V∶V)硅胶柱层析,得13-β-榄香醇和14-β-榄香醇混合物,无色液体,产率90%。
采用HPLC制备方法分离13-β-榄香醇和14-β-榄香醇混合物,手性柱型号为CHIRALPAKAD-H,流动相为正己烷∶乙醇=98∶2(V∶V),流速为1mL/min,检测波长为UV214nm,室温条件下分离混合物,得到13-β-榄香醇。无色液体,产率62%.1H NMR(CDCl3,300MHz)δ:1.01(s,3H),1.41-1.67(m,6H),1.71(s,3H),1.97-2.05(m,2H),4.13(s,2H),4.59(s,1H),4.82(t,J=1.7Hz,1H),4.88(s,1H),4.91-4.94(m,2H),5.05(d,J=1.3Hz,1H),5.81(dd,J1=17.8Hz,J2=10.5Hz,1H).13C NMR(CDCl3,300MHz)δ:153.7,150.0,147.4,112.1,109.9,107.9,65.1,52.7,41.4,39.8,39.7,33.2,27.2,24.7,16.5.
实施例2化合物1的制备
将13-β-榄香醇与二氢吡啶甲酸溶于二氯甲烷中,加入EDCI与DMAP,室温搅拌过夜,以石油醚∶乙酸乙酯=3∶1(V∶V)硅胶柱层析,得目标化合物1,无色液体,产率79%。1HNMR(CDCl3,300MHz)δ:1.04(s,3H),1.40-1.62(m,6H),1.73(s,3H),1.88(d,J=5.4Hz,3H),1.93-2.01(m,2H),2.84(m,2H),3.42(s,3H),4.66(s,2H),4.81(s,1H),4.89(s,1H),4.91(d,J=4.3Hz,1H),5.01(s,1H),5.09(s,1H),5.23(m,1H),5.54(s,1H),5.87(m,1H).
实施例3化合物2的制备
参考实施例2的操作步骤,得目标化合物2,无色液体,产率64%。1H NMR(CDCl3,300MHz)δ:1.01(s,3H),1.40-1.61(m,6H),1.70(s,3H),1.82(d,J=5.1Hz,3H),1.98-2.01(m,2H),2.83(m,2H),3.40(s,3H),4.69(s,2H),4.80(s,1H),4.94(s,1H),4.98(d,J=4.3Hz,1H),5.03(s,1H),5.09(s,1H),5.53(m,1H),5.64(s,1H),5.92(m,1H).
实施例4化合物3的制备
参考实施例2的操作步骤,得目标化合物3,无色液体,产率72%。1H NMR(CDCl3,300MHz)δ:0.93(s,3H),1.46-1.69(m,6H),1.79(s,3H),1.72(d,J=5.4Hz,3H),1.99-2.03(m,2H),2.79(m,2H),3.52(s,3H),4.72(s,2H),4.86(s,1H),4.92(s,1H),4.98(d,J=4.2Hz,1H),5.05(s,1H),5.13(s,1H),5.58(s,1H),5.82(m,1H).
实施例5化合物4的制备
参考实施例2的操作步骤,得目标化合物4,无色液体,产率61%。1H NMR(CDCl3,300MHz)δ:1.08(s,3H),1.42-1.55(m,6H),1.83(s,3H),1.89(d,J=5.4Hz,3H),1.98-2.01(m,2H),2.62(s,3H),2.94(m,2H),3.59(s,3H),4.52(s,2H),4.84(s,1H),4.92(s,1H),4.95(d,J=4.3Hz,1H),5.06(s,1H),5.09(s,1H),5.58(m,1H),5.72(s,1H),5.91(m,1H).
实施例6化合物5的制备
参考实施例2的操作步骤,得目标化合物5,无色液体,产率74%。1H NMR(CDCl3,300MHz)δ:0.89(s,3H),1.44-1.62(m,6H),1.78(s,3H),1.78(d,J=5.4Hz,3H),1.98-2.01(m,2H),2.40(m,3H),2.83(m,2H),3.80(m,2H),4.78(s,2H),4.70(s,1H),4.91(s,1H),4.98(d,J=4.2Hz,1H),5.12(s,1H),5.18(s,1H),5.64(m,1H),5.79(s,1H),5.93(m,1H).
实施例7化合物6的制备
参考实施例2的操作步骤,得目标化合物6,无色液体,产率82%。1H NMR(CDCl3,300MHz)δ:1.08(s,3H),1.42-1.60(m,6H),1.77(s,3H),1.89(d,J=5.4Hz,3H),1.99-2.07(m,2H),2.88(m,2H),4.05(s,2H),4.69(s,2H),4.78(s,1H),4.89(s,1H),4.92(d,J=4.2Hz,1H),5.76(s,1H),5.08(s,1H),5.43(m,1H),5.59(s,1H),5.82(m,1H),7.45-7.63(m,5H).
实施例8化合物7的制备
参考实施例2的操作步骤,得目标化合物7,无色液体,产率49%。1H NMR(CDCl3,300MHz)δ:1.07(s,3H),1.40-1.59(m,6H),1.74(s,3H),1.89(d,J=5.4Hz,3H),1.93-2.01(m,2H),2.84(m,2H),3.04(m,4H),3.58(s,3H),4.66(s,2H),4.83(s,1H),4.89(s,1H),4.91(d,J=4.3Hz,1H),5.01(s,1H),5.17(s,1H),5.13(m,1H),5.53(s,1H),5.89(m,1H).
实施例9化合物8的制备
参考实施例2的操作步骤,得目标化合物9,无色液体,产率52%。1H NMR(CDCl3,300MHz)δ:1.07(s,3H),1.40-1.58(m,6H),1.71(s,3H),1.87(d,J=5.4Hz,3H),1.93-2.01(m,2H),2.84(m,2H),3.58(s,3H),3.65(m,4H),4.66(s,2H),4.83(s,1H),4.89(s,1H),4.91(d,J=4.2Hz,1H),5.01(s,1H),5.35(s,1H),5.32(m,1H),5.65(s,1H),5.84(m,1H).
实施例10
取上述配方,用常规方法制备成片剂。
Claims (4)
1.一种含有二氢吡啶结构的β-榄香烯衍生物及其药用盐,其选自如下化合物:
2.一种药物组合物,其特征在于,所述组合物由权利要求1所述的含有二氢吡啶结构的β-榄香烯衍生物及其药用盐和药学上可被接受的赋形剂组成。
3.权利要求1中所述的含有二氢吡啶结构的β-榄香烯衍生物及其药用盐在制备抗胶质瘤药物中的应用。
4.权利要求2所述的药物组合物在制备抗胶质瘤药物中的应用。
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CN114573504A (zh) * | 2022-02-28 | 2022-06-03 | 杭州师范大学 | 一种含N-OH键的β-榄香烯衍生物及其制备方法和应用 |
CN115010642A (zh) * | 2022-06-17 | 2022-09-06 | 沈阳药科大学 | β-榄香烯酰亚胺类衍生物及其应用 |
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CN110627615A (zh) * | 2019-09-29 | 2019-12-31 | 杭州师范大学 | β-榄香烯氧化物及制备方法和用途 |
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CN114573504B (zh) * | 2022-02-28 | 2023-11-14 | 杭州师范大学 | 一种含N-OH键的β-榄香烯衍生物及其制备方法和应用 |
CN115010642A (zh) * | 2022-06-17 | 2022-09-06 | 沈阳药科大学 | β-榄香烯酰亚胺类衍生物及其应用 |
CN115010642B (zh) * | 2022-06-17 | 2023-05-26 | 沈阳药科大学 | β-榄香烯酰亚胺类衍生物及其应用 |
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