CN116947875A - 一种靶向线粒体的鱼藤醇-丙二酸-地喹氯铵化合物及其制备方法和应用 - Google Patents
一种靶向线粒体的鱼藤醇-丙二酸-地喹氯铵化合物及其制备方法和应用 Download PDFInfo
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Abstract
本发明属于药物化学技术领域,具体涉及一种靶向线粒体的鱼藤醇‑丙二酸‑地喹氯铵化合物及其制备方法和应用。所述鱼藤醇‑丙二酸‑地喹氯铵化合物具有如下结构式。本发明以丙二酸为桥连分子,通过将鱼藤酮衍生物‑鱼藤醇与线粒体靶向分子‑地喹氯铵进行共价结合,得到一种抗癌前药分子‑鱼藤醇‑丙二酸‑地喹氯铵。该前药能够促使药物在癌细胞内线粒体中的富集,并鉴于地喹氯铵具有明显的促癌细胞凋亡功能,在鱼藤醇及地喹氯铵的协同作用,促使癌细胞内产生大量活性氧,从而表现出较高的抗癌活性,并实现高效低毒抗癌。
Description
技术领域
本发明属于药物化学技术领域,具体涉及一种靶向线粒体的鱼藤醇-丙二酸-地喹氯铵化合物及其制备方法和应用。
背景技术
鱼藤酮类衍生物是一类从鱼藤属等植物中提取出来的具有杀虫活性的异黄酮类化合物,自1932年以来,已从鱼藤酮属等植物中提取分离出47种鱼藤酮类化合物。这种化合物因为可以抑制还原型烟酰胺腺嘌呤二核甘酸(NADH)而阻断线粒体呼吸,从而具有杀虫活性。研究表明,鱼藤酮能减少环境污染,刺激植物生长,有效延缓害虫的耐药性。但是,鱼藤酮在日光、氧气、高温等条件下容易分解失效,使得它的应用受到极大的限制。为了降低鱼藤酮的局限性,可以对其进行结构改造或者化学修饰,构造靶向前药。设计高效低毒的鱼藤酮类衍生物,改善其生物活性是目前亟待解决的问题。
近年来研究发现鱼藤酮对多种肿瘤细胞具有抑制作用,包括肺癌,乳腺癌,胃癌等、胰腺癌、结肠癌肿瘤细胞。作为一种抗癌物质,鱼藤酮可诱导多种癌细胞发生凋亡,包括人乳腺癌细胞、B淋巴细胞、早幼粒白血病细胞、人神经母细胞瘤细胞、肺癌细胞等,因此,靶向线粒体的鱼藤酮抗癌作用机制是一个非常值得深入探讨的研究课题,而鱼藤酮也被认为是一个非常有前景的抗癌先导化合物。然而,当鱼藤酮剂量在大于有效浓度时,可产生对心脏、肺及神经系统的损害,并且还会引起帕金森综合症,这样对鱼藤酮的实际应用带来巨大的障碍。因此,如何对鱼藤酮进行结构改造或者化学修饰,一方面考虑增加其稳定性,另一方面则是在保留其抗癌活性的同时使其具有肿瘤靶向性,以降低其对机体其他组织尤其是对神经系统的毒副作用,改善其生物活性是目前亟待解决的问题。
发明内容
为了解决上述问题,本发明提供一种靶向线粒体的鱼藤醇-丙二酸-地喹氯铵化合物及其制备方法和应用,本发明以丙二酸为桥连分子,通过将鱼藤酮衍生物-鱼藤醇与线粒体靶向分子-地喹氯铵进行共价结合,得到一种抗癌前药分子-鱼藤醇-丙二酸-地喹氯铵。该前药能够促使药物在癌细胞内线粒体中的富集,并鉴于地喹氯铵具有明显的促癌细胞凋亡功能,在鱼藤醇及地喹氯铵的协同作用,促使癌细胞内产生大量活性氧,从而表现出较高的抗癌活性,并实现高效低毒抗癌。
本发明是通过以下技术方案解决上述技术问题的。
本发明的第一个目的是提供一种靶向线粒体的鱼藤醇-丙二酸-地喹氯铵化合物,所述鱼藤醇-丙二酸-地喹氯铵化合物具有如下结构式:
本发明的第二个目的是提供上述靶向线粒体的鱼藤醇-丙二酸-地喹氯铵化合物的制备方法,其特征在于,包括以下步骤:
S1、将鱼藤酮溶解于第一溶剂中,加入硼氢化钠室温反应,反应结束后搅拌状态下加入水,得到化合物1;
S2、将丙二酸置于容器中,在保护气体氛围下加入1,4-二氧六环,滴加氯化亚砜并进行第一次油浴反应,反应结束后去除溶剂得到残渣,向残渣中加入化合物1溶液,滴加三乙胺并进行第二次油浴反应,反应结束后去除溶剂、洗涤、干燥得到化合物2;
S3、将化合物2、1-(3-二甲胺基丙基)-3-乙基碳二亚胺和1-羟基苯并三唑置于容器中,在保护气体氛围下加入第二溶剂,进行第一次活化反应,反应结束后加入地喹氯铵溶液,调节体系pH为9,进行第三次油浴反应,反应结束后过滤、浓缩、重结晶、干燥得到靶向线粒体的鱼藤醇-丙二酸-地喹氯铵化合物。
优选的,S1中,所述鱼藤酮、第一溶剂、硼氢化钠和水的质量体积比为270-330mg:8-12mL:120-140mg:8-12mL。
优选的,S1中,所述室温反应的时间为3-5h,所述第一溶剂为甲醇。
优选的,S2中,所述丙二酸、1,4-二氧六环、氯化亚砜、化合物1和三乙胺的质量体积比为40-60mg:10-12mL:100-110μL:230-240mg:60-70μL;化合物1溶液为化合物和N,N-二甲基甲酰胺以质量体积比为237mg:10mL混合得到。
优选的,S2中,所述第一次油浴反应的温度为100-120℃,反应的时间为12-15h;所述第二次油浴反应的温度为60-80℃,时间为12-15h。
优选的,S3中,所述化合物2、1-(3-二甲胺基丙基)-3-乙基碳二亚胺、1-羟基苯并三唑、第二溶剂和地喹氯铵的质量体积比70-80mg:120-140mg:120-130mg:25-30mL:65-80mg;地喹氯铵溶液是地喹氯铵和甲醇以质量体积比为76mg:7mL混合得到;所述第二溶剂为甲醇。
优选的,S3中,所述第一次活化反应的温度为0-4℃,时间为4-6h;调节体系pH采用N,N-二异丙基乙胺调节pH为9;所述第三次油浴反应的温度为37℃,时间为20-24h。
本发明的第三个目的是提供上述靶向线粒体的鱼藤醇-丙二酸-地喹氯铵化合物在制备治疗和/或预防癌症药物中应用。
优选的,所述癌症包括肺癌、宫颈癌、肝癌、乳腺癌、胰腺癌或结肠癌。
本发明与现有技术相比具有如下有益效果:
(1)本发明以丙二酸为桥连分子,通过将鱼藤酮衍生物-鱼藤醇与线粒体靶向分子-地喹氯铵进行共价结合,得到一种抗癌前药分子-鱼藤醇-丙二酸-地喹氯铵。该前药能够促使药物在癌细胞内线粒体中的富集,并鉴于地喹氯铵具有明显的促癌细胞凋亡功能,在鱼藤醇及地喹氯铵的协同作用,促使癌细胞内产生大量活性氧,从而表现出较高的抗癌活性。另外,由于癌细胞的细胞膜膜电位远远高于正常细胞,从而使得带有正电荷的地喹氯铵能够在细胞跨膜电位的推动下,更容易进入癌细胞胞质,使得该前药具有肿瘤靶向功能,最终实现高效低毒抗癌。
(2)本发明从原料鱼藤酮着手,采用还原反应得到其衍生物鱼藤醇。随后通过酯化反应与丙二酸共价连接,得到鱼藤醇-丙二酸中间产物。而该中间产物质中另一个游离的羧基在合适的条件下会进一步与地喹氯铵上的氨基反应,生成鱼藤醇-丙二酸-地喹氯铵前药分子。
附图说明
图1为本发明实施例1化合物1的氢谱图;
图2为本发明实施例1化合物1的碳谱图;
图3为本发明实施例1化合物1的质谱图;
图4为本发明实施例1化合物2的氢谱图;
图5为本发明实施例1化合物2的碳谱图;
图6为本发明实施例1化合物2的质谱图;
图7为本发明实施例1鱼藤醇-丙二酸-地喹氯铵化合物的氢谱图;
图8为本发明实施例1鱼藤醇-丙二酸-地喹氯铵化合物的碳谱图;
图9为本发明实施例1鱼藤醇-丙二酸-地喹氯铵化合物的质谱图;
图10为本发明鱼藤醇-丙二酸-地喹氯铵化合物对三种人类癌细胞系作用后的细胞存活率图。
具体实施方式
下面将结合本发明实施例中的附图,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
需要说明的是,本发明中所使用的专业术语只是为了描述具体实施例的目的,并不是旨在限制本发明的保护范围,除非另有特别说明,本发明以下各实施例中用到的各种原料、试剂、仪器和设备均可通过市场购买得到或者通过现有方法制备得到。
一种靶向线粒体的鱼藤醇-丙二酸-地喹氯铵化合物,所述鱼藤醇-丙二酸-地喹氯铵化合物具有如下结构式:
本发明的第二个目的是提供上述靶向线粒体的鱼藤醇-丙二酸-地喹氯铵化合物的制备方法,包括以下步骤:
S1、将鱼藤酮溶解于第一溶剂中,加入硼氢化钠室温反应,反应结束后搅拌状态下加入水,得到化合物1;
S2、将丙二酸置于容器中,在保护气体氛围下加入1,4-二氧六环,滴加氯化亚砜并进行第一次油浴反应,反应结束后减压蒸馏去除溶剂得到残渣,向残渣中加入化合物1溶液,滴加三乙胺并进行第二次油浴反应,反应结束后减压蒸馏去除溶剂、洗涤、干燥得到化合物2;
S3、将化合物2、1-(3-二甲胺基丙基)-3-乙基碳二亚胺和1-羟基苯并三唑置于容器中,在保护气体氛围下加入第二溶剂,进行第一次活化反应,反应结束后加入地喹氯铵溶液,调节体系pH为9,进行第三次油浴反应,反应结束后过滤、浓缩、重结晶、干燥得到靶向线粒体的鱼藤醇-丙二酸-地喹氯铵化合物。
其合成反应方程式如下:
实施例1
靶向线粒体的鱼藤醇-丙二酸-地喹氯铵化合物的制备方法,包括以下步骤:
S1、将300mg鱼藤酮溶解于10mL甲醇中,然后加入127mg的硼氢化钠,然后在室温下搅拌4h,反应溶液逐渐变澄清,之后向反应溶液中一边搅拌一边逐滴滴加10mL的二次水,溶液由澄清逐渐变浑浊,析出大量白色固体,后经抽滤、60℃真空干燥12h得到白色粉末状固体,得到化合物1;
化合物1的氢谱如图1所示,1H NMR(500MHz,DMSO-d6)δ7.26(s,1H),7.05(s,1H),6.37(s,2H),5.64(s,1H),5.18(s,1H),5.01(s,2H),4.86(s,2H),4.46(s,1H),4.17(s,1H),3.64(d,J=28.0Hz,6H),3.39(d,J=4.7Hz,1H),3.22–3.09(m,1H),2.80(dd,J=15.6,7.8Hz,1H),1.69(s,3H).
化合物1的碳谱如图2所示,13C NMR(126MHz,DMSO)δ160.59,149.88,149.06,148.92,144.50,143.04,128.18,117.94,114.06,111.87,111.47,101.54,100.77,85.85,70.54,66.53,66.22,56.61,55.83,49.07,40.50,40.34,40.17,40.00,39.84,39.67,39.50,36.97,31.90,17.52.
化合物1的质谱如图3所示,HR-MS:396.1(M+Na+).
其合成反应方程式如下:
S2、取丙二酸50mg(0.48mmol)加入到25mL棕色三颈圆底烧瓶中,在氮气保护下加入10mL 1,4-二氧六环,油浴105℃加热,冷凝回流,滴加104μL氯化亚砜(1.44mmol),反应4h后,减压蒸馏去除溶剂;向残渣和237mg(0.6mmol)化合物1中加入10mL无水DMF(N,N-二甲基甲酰胺),滴加66μL TEA(三乙胺0.48mmol),油浴60℃加热,冷凝回流12h;结束后,减压蒸馏除去溶剂,残留物通过0.5mol/L的盐酸酸洗3次,之后用甲醇溶解,旋蒸蒸干溶剂,最后60℃真空干燥12h,得到棕黄色粉末(化合物2);
化合物2的氢谱如图4所示,1H NMR(500MHz,DMSO-d6)δ7.28(s,2H),7.03(d,J=2.4Hz,2H),6.99(d,J=8.0Hz,2H),6.55(s,2H),6.47(d,J=8.1Hz,2H),5.41-5.31(m,2H),5.27(t,J=8.7Hz,2H),5.10(d,J=2.2Hz,2H),4.96(t,J=1.8Hz,2H),4.62(dd,J=9.9,5.4Hz,2H),4.09(dd,J=10.9,9.9Hz,4H),3.84(s,6H),3.80(s,6H),3.50(q,J=7.0Hz,6H),3.30(dd,J=15.7,9.6Hz,2H),2.94(dd,J=15.7,7.8Hz,2H),2.10-2.00(m,1H),1.79(s,5H),1.32-1.28(m,3H),1.23(dt,J=14.0,7.1Hz,3H),1.12(t,J=7.0Hz,9H).
化合物2的碳谱如图5所示,13C NMR(126MHz,DMSO)δ161.07,150.64,149.47,149.07,145.04,144.21,127.16,123.42,117.29,112.91,112.66,112.17,110.90,106.57,103.05,101.61,86.16,71.05,67.54,56.54,56.49,56.11,31.44,19.02,17.56.
化合物2的质谱如图6所示,HR-MS:482.1(M+H+).
其合成反应方程式如下:
S3、取化合物275mg(0.24mmol),EDCI 136mg(1-(3-二甲胺基丙基)-3-乙基碳二亚胺和1-羟基苯并三唑0.69mmol),HOBT 124mg(1-羟基苯并三唑0.29mmol)加入到50mL棕色三颈圆底烧瓶中,在氮气保护下加入25mL甲醇,冰水浴搅拌活化5h。之后向体系中注入7mL用甲醇溶解的地喹氯铵76mg(0.14mmol),900μL DIPEA(N,N-二异丙基乙胺)调节体系PH为9,37℃油浴加热,反应24h。反应结束后,过滤去除滤渣,得黄色滤液,旋蒸浓缩,冰乙醚重结晶,抽滤干燥,得黄色粉末,即为鱼藤醇-丙二酸-地喹氯铵化合物;
鱼藤醇-丙二酸-地喹氯铵化合物的氢谱如图7所示,1H NMR(500MHz,DMSO-d6)δ8.93(d,J=16.2Hz,2H),8.49(d,J=8.3Hz,1H),8.14(d,J=9.0Hz,1H),8.04-7.97(m,1H),7.71(t,J=7.6Hz,1H),7.22(s,3H),6.97(d,J=2.4Hz,3H),6.93(d,J=8.0Hz,3H),6.75(s,1H),6.50(s,3H),6.42(d,J=8.0Hz,3H),5.33-5.25(m,3H),5.22(t,J=8.7Hz,3H),5.04(s,3H),4.90(t,J=1.8Hz,3H),4.56(dd,J=9.9,5.4Hz,3H),4.44(t,J=8.2Hz,2H),4.03(t,J=10.4Hz,3H),3.78(s,9H),3.74(s,9H),3.25(dd,J=15.7,9.6Hz,5H),3.08(qd,J=7.3,4.8Hz,1H),2.89(dd,J=15.6,7.9Hz,3H),2.72(s,3H),2.04-1.94(m,1H),1.73(s,8H),1.44(d,J=8.8Hz,2H),1.34(d,J=7.7Hz,1H),1.30(s,2H),1.26-1.14(m,5H),0.85(t,J=6.8Hz,1H).
鱼藤醇-丙二酸-地喹氯铵化合物的碳谱如图8所示,13C NMR(126MHz,DMSO-d6)δ161.06,155.40,150.62,149.46,149.06,145.03,144.20,127.17,126.34,123.42,117.29,112.92,112.66,112.18,110.89,106.54,104.46,103.06,101.60,86.15,71.04,67.53,56.53,56.11,48.36,31.44,29.44,29.13,28.52,26.35,21.99,17.57.
鱼藤醇-丙二酸-地喹氯铵化合物的质谱如图9所示,HR-MS:991.3(M+H+).
其合成反应方程式如下:
实施例2
鱼藤醇-丙二酸-地喹氯铵化合物的细胞毒性测试。
将不同浓度的中间产物以及鱼藤醇-丙二酸-地喹氯铵化合物与细胞共同孵育48h,用四甲基偶氮唑盐比色法检测其对人肺癌细胞(A549)、人宫颈癌细胞(HeLa)、人肝癌细胞(HepG-2)三种癌细胞的杀伤作用。中间产物以及最终产物鱼藤醇-丙二酸-地喹氯铵化合物以剂量依赖的方式逐渐降低细胞活力。IC50为50%抑制浓度,即细胞存活量为对照样本一半时所对应的浓度,半数抑制越低,说明药物对细胞的毒性越高。
图10为本发明鱼藤醇-丙二酸-地喹氯铵化合物对三种人类癌细胞系作用后的细胞存活率图。IC50值用GraphPadPrism 9.0计算。纵轴提供活细胞分数(%),横轴提供log[浓度](μM)。细胞处理48h。通过MTT测试评估细胞毒性。这些结果来自三个独立试验中的一个有代表性的试验。数据以平均值±SD表征。图10中,A为化合物1对A549、HeLa、HepG-2三种癌细胞的存活率图,B为鱼藤醇-丙二酸-地喹氯铵对A549、HeLa、HepG-2三种癌细胞的存活率图。
从图10中结果可以分析得出,(1)对于A549、HeLa、HepG-2三种癌细胞来说,无论哪种癌细胞,细胞存活率都是随着药物浓度的增大而降低,可见细胞存活率与给药浓度之间存在明显的剂量依赖性关系;(2)通过观察不同药物对癌细胞的抑制效果,可以看出来鱼藤醇-丙二酸-地喹氯铵化合物的细胞毒性最强,而中间产物的细胞毒性更弱。这是因为最终产物不仅偶联了鱼藤醇,而且还有地喹氯铵,两种药物均可以靶向癌细胞中的线粒体,一定程度上可以起到协同作用,增强了药物的毒性。癌细胞种类不同,各种药物分子对细胞的抑制率也不同。比如,鱼藤醇-丙二酸-地喹氯铵化合物对HepG-2细胞的抑制作用相较于A549细胞更明显,这可能是由于该前药对HepG-2细胞与对A549等其他细胞促使凋亡的机制不同,从而导致不同的结果。但从总体来看,该前药对几种癌细胞都具有良好的抑制效果。
需要说明的是,本发明中涉及数值范围时,应理解为每个数值范围的两个端点以及两个端点之间任何一个数值均可选用,由于采用的步骤方法与实施例相同,为了防止赘述,本发明描述了优选的实施例。尽管已描述了本发明的优选实施例,但本领域内的技术人员一旦得知了基本创造性概念,则可对这些实施例做出另外的变更和修改。所以,所附权利要求意欲解释为包括优选实施例以及落入本发明范围的所有变更和修改。
显然,本领域的技术人员可以对本发明进行各种改动和变型而不脱离本发明的精神和范围。这样,倘若本发明的这些修改和变型属于本发明权利要求及其等同技术的范围之内,则本发明也意图包含这些改动和变型在内。
Claims (10)
1.一种靶向线粒体的鱼藤醇-丙二酸-地喹氯铵化合物,其特征在于,所述鱼藤醇-丙二酸-地喹氯铵化合物具有如下结构式:
2.一种权利要求1所述的靶向线粒体的鱼藤醇-丙二酸-地喹氯铵化合物的制备方法,其特征在于,包括以下步骤:
S1、将鱼藤酮溶解于第一溶剂中,加入硼氢化钠室温反应,反应结束后搅拌状态下加入水,得到化合物1;
S2、将丙二酸置于容器中,在保护气体氛围下加入1,4-二氧六环,滴加氯化亚砜并进行第一次油浴反应,反应结束后去除溶剂得到残渣,向残渣中加入化合物1溶液,滴加三乙胺并进行第二次油浴反应,反应结束后去除溶剂、洗涤、干燥得到化合物2;
S3、将化合物2、1-(3-二甲胺基丙基)-3-乙基碳二亚胺和1-羟基苯并三唑置于容器中,在保护气体氛围下加入第二溶剂,进行第一次活化反应,反应结束后加入地喹氯铵溶液,调节体系pH为9,进行第三次油浴反应,反应结束后过滤、浓缩、重结晶、干燥得到靶向线粒体的鱼藤醇-丙二酸-地喹氯铵化合物。
3.根据权利要求2所述的靶向线粒体的鱼藤醇-丙二酸-地喹氯铵化合物的制备方法,其特征在于,S1中,所述鱼藤酮、第一溶剂、硼氢化钠和水的质量体积比为270-330mg:8-12mL:120-140mg:8-12mL。
4.根据权利要求2所述的靶向线粒体的鱼藤醇-丙二酸-地喹氯铵化合物的制备方法,其特征在于,S1中,所述室温反应的时间为3-5h,所述第一溶剂为甲醇。
5.根据权利要求2所述的靶向线粒体的鱼藤醇-丙二酸-地喹氯铵化合物的制备方法,其特征在于,S2中,所述丙二酸、1,4-二氧六环、氯化亚砜、化合物1和三乙胺的质量体积比为40-60mg:10-12mL:100-110μL:230-240mg:60-70μL;化合物1溶液为化合物和N,N-二甲基甲酰胺以质量体积比为237mg:10mL混合得到。
6.根据权利要求2所述的靶向线粒体的鱼藤醇-丙二酸-地喹氯铵化合物的制备方法,其特征在于,S2中,所述第一次油浴反应的温度为100-120℃,反应的时间为12-15h;所述第二次油浴反应的温度为60-80℃,时间为12-15h。
7.根据权利要求2所述的靶向线粒体的鱼藤醇-丙二酸-地喹氯铵化合物的制备方法,其特征在于,S3中,所述化合物2、1-(3-二甲胺基丙基)-3-乙基碳二亚胺、1-羟基苯并三唑、第二溶剂和地喹氯铵的质量体积比70-80mg:120-140mg:120-130mg:25-30mL:65-80mg;所述地喹氯铵溶液是地喹氯铵和甲醇以质量体积比为76mg:7mL混合得到;所述第二溶剂为甲醇。
8.根据权利要求2所述的靶向线粒体的鱼藤醇-丙二酸-地喹氯铵化合物的制备方法,其特征在于,S3中,所述第一次活化反应的温度为0-4℃,时间为4-6h;调节体系pH采用N,N-二异丙基乙胺调节pH为9;所述第三次油浴反应的温度为37℃,时间为20-24h。
9.一种权利要求1所述的靶向线粒体的鱼藤醇-丙二酸-地喹氯铵化合物在制备治疗和/或预防癌症药物中应用。
10.根据权利要求9所述的应用,其特征在于,所述癌症包括肺癌、宫颈癌、肝癌、乳腺癌、胰腺癌或结肠癌。
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