CN117964630A - 一种no型卟啉-阿魏酸衍生物、制备方法及其用途 - Google Patents
一种no型卟啉-阿魏酸衍生物、制备方法及其用途 Download PDFInfo
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- CN117964630A CN117964630A CN202311231076.0A CN202311231076A CN117964630A CN 117964630 A CN117964630 A CN 117964630A CN 202311231076 A CN202311231076 A CN 202311231076A CN 117964630 A CN117964630 A CN 117964630A
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- pharmaceutically acceptable
- ferulic acid
- porphyrin
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Abstract
本发明公开了一种NO型卟啉‑阿魏酸衍生物,其具有优异的单线态氧产生能力且可有效释放NO。通过光动力性能、体外抗肿瘤活性等相关研究获得具有良好协同光动力‑化疗治疗作用的抗肿瘤药物。在光照条件下,本发明化合物对肿瘤细胞具有良好抑制作用。因而可以用做抗肿瘤药物的活性成分,具有良好的开发应用前景。
Description
技术领域
本发明涉及药物化学领域,具体地涉及一种NO型卟啉-阿魏酸衍生物、制备方法及其用途。
背景技术
光动力疗法(PDT)早在100多年前就已被发现,并已成为治疗癌症和包括感染在内的各种非恶性疾病的一种被广泛研究的疗法。到目前为止,此疗法已成功地用于治疗多种恶性肿瘤。PDT的基本要素可分为:光敏剂(PS)、特定激发光、分子氧。光敏剂在适当能量的波长光进行照射,形成激发单重态,然后转变为长寿命的激发三重态。这种三重态可以在氧气存在的情况下发生光化学反应,将能量传递给周围氧分子,形成活性氧(ROS),从而杀伤癌细胞、病原微生物和不需要的组织。同手术、放射治疗和药物治疗等更传统的癌症疗法相比,PDT具有非侵入性,副作用小等优点,在肿瘤治疗研究领域颇具吸引力。
随着PDT的发展,制备光敏剂,特别是卟啉类光敏剂是研究取得了令人瞩目的进展。大多数用于癌症治疗的光敏剂都具有以卟啉为基础的大环骨架,卟啉类化合物在光动力学研究中的主要优点包括:1)芳香族化合物的稳定性;2)对可见光的有效吸收;3)活性氧产率高;4)易于官能化修饰和结构多样性;5)三重态寿命较长和暗毒性较低。美国FDA批准的第一个上市的光敏药物Photofri就是经典的卟啉结构药物。
Li等(Chinese Chemical Letters,2007,18(11):1331-1334)设计合成了一种基于卟啉和5-氟尿嘧啶的新型潜在靶向抗癌药物,并采用MTT法对人肝癌细胞SMCC-7721的体外抗癌活性进行了评价。初步结果表明,耦合物的抗癌活性均达5-氟尿嘧啶抗癌活性的2倍以上。卟啉在无光照条件下对肿瘤细胞无杀伤作用,表明耦合物实际上是提高了5-氟尿嘧啶对肿瘤组织的靶向性,从而增强了抗癌活性。S.Weimin等(Bioorg Med Chem,2008,16(10):5665-5671)将5-氟尿酸/Boc-L-苯丙氨酸与氨基卟啉偶联,合成了一系列含5-氟尿嘧啶/L-苯丙氨酸的卟啉类化合物。体外抗癌活性研究结果表明,5-氟尿嘧啶和L-苯丙氨酸的引入能显著提高卟啉的光毒性。卟啉类化合物对肿瘤组织的高度选择性,为抗癌药物键连卟啉类化合物的研究拓宽了前景。
目前,阿魏酸(Ferulic acid,FA)及其钠盐已逐渐被证明具有良好的抗肿瘤活性,其已被证明对人肾腺癌(ACHN)、人膀胱癌(T24)、人乳腺癌(MDA-MB-231)和人骨肉瘤(143B和MG63)细胞具有抗癌活性。阿魏酸对不同的癌细胞系具有不同的作用方式,其作用方式包括改变癌细胞周期、诱导细胞凋亡和调节蛋白质产生等。例如,Nasr Bouzaiene N等人(EurJ Pharmacol.2015,766:99-105)报道了FA通过抑制DNA合成来抑制A549细胞系的增殖且在较高浓度下可使A549细胞的存活率降低至23%。Janicke等人(J Agric Food Chem,2005,53(17):6658-6665)研究结果显示,FA可通过影响细胞周期而对人类结肠内皮肿瘤细胞的增殖产生抑制作用。Luo等人(Med Sci Monit,2020,26:e920095)用阿魏酸处理Caski细胞,结果显示阿魏酸可下调Caski细胞中的PI3K/Akt信号通路,诱导Caski细胞凋亡。
由于阿魏酸结构中具有易于修饰的羟基和羧基,因此其易于被修饰从而获得一系列阿魏酸衍生物。近年来,越来越多的阿魏酸衍生物被相继报道,且该衍生物具有比阿魏更高的抗肿瘤活性及稳定性。Yue等人对阿魏酸结构中的羧基位进行结构修饰获得阿魏酸衍生物FXS-3。实验结果显示FXS-3可诱导A549细胞凋亡并将其细胞的周期阻滞在G0/G1期。Sawata等人将两个阿魏酸单体与白藜芦醇相连接,获得新型化合物UHA025。与白藜芦醇单体以及只与一个阿魏酸单体相连接的白藜芦醇相比,UHA025可通过增加肿瘤抑制因子p15的mRNA水平而对HCT-116细胞的3D增殖产生更强烈的抑制作用。Pellerito等人合成了三丁基锡(IV)阿魏酸TBT-F,可通过阻滞G2/M细胞周期,增加细胞膜通透性。
一氧化氮(NO)是一种最简单、用途最广泛的内源性分子,能够直接影响许多生物过程。当NO在肿瘤部位达到较高浓度时可通过抑制线粒体呼吸、影响肿瘤细胞周期停滞及产生肿瘤毒性等机制抑制肿瘤生长,被证明是一种有效的抗癌剂。此外,NO可促进细胞内GSH的代谢,破坏细胞内氧化还原平衡,升高细胞内ROS水平。值得关注的是,NO还可以与ROS相互反应并产生具有更强杀伤作用的过氧亚硝酸根阴离子(ONOO-)和其他活性氮物种(RNS),通过产生的亚硝化和氧化应激导致细胞凋亡、炎症反应、DNA脱氨、细胞功能抑制和线粒体呼吸损伤。然而,NO在体内半衰期短且不稳定,若直接输送到肿瘤部位效果不佳,因此越来越多的研究则集中于NO供体。目前有许多NO供体与其他抗肿瘤药物结合后产生的抗肿瘤活性高于NO供体本身及单一的抗肿瘤药物,表现出较好的开发前景。
目前,单一的光动力治疗已较难满足癌症治疗的需求,因此开发高效的联合治疗药物以实现对肿瘤的双模态及多模态治疗逐渐成为研究的焦点。前述研究表明卟啉及金属卟啉衍生物是光动力治疗一类极具发展潜力的光敏药物,其不仅对肿瘤具有特殊亲和力,且与抗癌药物的结合后可光照条件下产生优异的联合治疗效果。NO供体在肿瘤治疗方面也逐渐展现其独特的优势,特别是含有NO供体的天然产物可具有强于母体的抗肿瘤效果。因此,本发明基于前述有关卟啉-抗癌药物、NO供体-光敏剂/抗癌药物的研究,设计合成了一系列NO型卟啉-阿魏酸衍生物并研究其在癌症治疗方面的应用潜力。
发明内容
本发明所要解决的技术问题是:提供了一种NO型卟啉-阿魏酸衍生物,其具有良好的抑制肿瘤细胞的活性。
本发明的第一个方面,是提供一种式I或式II所示化合物及它们药学上可接受的盐,其具有如下结构::
其中,n选自1-8的整数;
m选自1-8的整数;
R1选自H,卤素,羟基,硝基,CN,C1-6烷基,C2-6烯基,C2-6炔基,C6-10芳基,C2-C10杂芳基;
R选自H,卤素,羟基,硝基,CN,C1-6烷基,C2-6烯基,C2-6炔基;
M选自Zn,Ni,Mn。
优选地,n选自1、2、3、4或5。
优选地,m选自1、2、3、4或5。
优选地,R1选自H,卤素,羟基,硝基,CN,C1-6烷基;更优选地,R1选自H或Cl;
优选地,R选自H,卤素,羟基,硝基,CN,C1-6烷基;更优选地,R选自H或甲基;
优选地,M选自Zn,Ni。
优选地,本发明化合物结构如下:
本发明的另一方面提供一种制备式I化合物的方法,其合成路线如下:
其中,n、m、R1、R的定义如前所述。
具体反应步骤如下:
在有机溶剂中,加入碱和卟啉衍生物5,加热搅拌,将阿魏酸衍生物4加入反应体系,直至反应完毕,经后处理得到式I化合物。
优选地,卟啉衍生物5与阿魏酸衍生物4的摩尔比为:1:(1-1.5),优选为1:1-1.2,更优选为1:1.2;
优选地,所述碱选自氢氧化钾、三乙胺或碳酸钾,更优选为三乙胺。
优选地,所述有机溶剂选自:二氯甲烷,氯仿,四氢呋喃,DMSO,DMF,甲醇,乙醇,异丙醇;更优选为DMF。
本发明的另一方面提供一种制备式II化合物的方法,其合成路线如下:
其中,n、m、R1、R和M的定义如前所述。
具体反应步骤如下:
将式I化合物用有机溶剂溶解,加入M金属盐,回流反应,TLC监控至反应完全,经后处理得到式II的卟啉-阿魏酸衍生物。
优选地,式I化合物与M金属盐的摩尔比为:1:3-7,优选为1:5;
优选地,所述M金属盐选自二水合醋酸锌、乙酸镍(II)四水合物。
本发明的另一方面提供一种药物组合物,其包含式I或式II所示的化合物或它们药学上可接受的盐,以及药学上可接受的载体。
本发明另一方面涉及一种式I或式II化合物及它们药学上可接受的盐或包含其药物组合物在制备抗癌药物中的用途;
优选地,所述癌症选自肺癌或肝癌;尤其是,人非小细胞肺癌细胞A549和人肝癌细胞HepG2。
与现有技术相比,本发明的有益效果是:
(1)本发明提供了一类新的具有抗癌活性的NO型卟啉-阿魏酸衍生物,拓宽了现有抗癌化合物的范围,可作为先导化合物继续优化;
(2)本发明化合物以卟啉分子为载体,利用其肿瘤组织聚集的效应,对肿瘤细胞具有靶向性,减少了对正常细胞的灭杀副作用。
(3)本发明的卟啉连阿魏酸类化合物可以实现光疗和化疗的协同治疗,除此之外,在卟啉中插入金属Zn或Ni也能够增强化合物的抗肿瘤活性。
定义:
在某些实施方案中,药学上可接受的形式是药学上可接受的盐,药学上可接受的盐在本领域中是熟知的。药学上可接受的盐的实例是诸如盐酸、氢溴酸、磷酸、硫酸、高氯酸、乙酸、草酸、顺丁烯二酸、酒石酸、柠檬酸、丁二酸或丙二酸、乙酸、丙酸、乙醇酸、丙酮酸、草酸、乳酸、三氟乙酸、甲烷磺酸、乙烷磺酸、对甲苯磺酸、水杨酸等与化合物形成盐的形式。
“药学上可接受的载体”或“药学上可接受的赋形剂”包括任何和所有溶剂、分散介质、包覆剂、抗细菌剂和抗真菌剂、等张剂和吸收延迟剂等。药学上可接受的载体或赋形剂不破坏公开的化合物的药理学活性,并且在以足以递送治疗量的化合物的剂量施用时是无毒的。药物活性物质的所述介质和试剂的使用在本领域中是熟知的。
附图说明
图1为化合物6a-6e(图1a)、7a-7e(图1b)、8a-8e(图1c)猝灭DPBF荧光强度变化。
具体实施方式
下面通过实施例来具体说明本发明的内容。在本发明中,以下实施例是为了更好地阐述本发明,并不是用来限制本发明的范围。下述实施例中所用的材料、试剂等,如无特殊说明,均可从商业途径得到。
实施例1 NO供体1的合成
在0℃的条件下,将1.1mL的浓硝酸和2.4mL的浓硫酸慢慢添加到15mL圆底烧瓶中,搅拌10分钟后添加1mL 5-溴-1-戊醇并继续搅拌1小时。反应完成后,将反应溶液与50mL冰水混合并利用CH2Cl2进行萃取。收集CH2Cl2并用无水Na2SO4除去CH2Cl2中所含的少量水分,减压除去CH2Cl2,可获得黄色的液体(化合物1)。
1:yield 98%.1H NMR(500MHz,Chloroform-d)δ4.46(t,J=6.6Hz,2H),3.41(t,J=6.7Hz,2H),1.92–1.85(m,2H),1.76–1.73(m,2H),1.59–1.50(m,2H)ppm。
实施例2阿魏酸衍生物3a-3e的合成
称取2.57mmol阿魏酸(500mg)放入150mL圆底烧瓶中,以CH2Cl2为溶剂并依次加入氯化亚砜和DMF。在40℃条件下反应1.5h后加入5.14mmol 2-溴乙醇(364.3μL)/3-溴-1-丙醇(464.8μL)/4-溴-1-丁醇(736.5μL,)/5-溴-1-戊醇(626.3μL)/6-溴-1-己醇(672.4μL),反应过程通过薄层色谱法进行监测。结束反应后,反应液中加入蒸馏水,以除去反应液中的多余的氯化亚砜和DMF。收集CH2Cl2并通过无水Na2SO4除水,减压旋除CH2Cl2得到粗产物。粗产物利用CH2Cl2洗脱,在硅胶层析柱上进行纯化。收集第一条带浓缩后即可获得黄色粘稠状液体(化合物3a-3e)。
实施例3含NO供体的阿魏酸衍生物4a-4e的合成
称取化合物1mmol 3a-3e(3a 301.1mg,3b 315.2mg,3c 329.2mg,3d 343.2mg,3e357.2mg)、691mg K2CO3于150mL三颈烧瓶中,以60mL丙酮作为溶剂,并加入0.5mmol 5-溴硝酸酯和500μL三乙胺,于60℃条件下冷凝回流。反应完成后,反应液抽滤后减压除去丙酮便可获得粗产物。粗产物同样利用CH2Cl2洗脱,通过硅胶层析柱对其纯化,收集第二条带并减压旋除CH2Cl2,得浅黄色固体,即化合物4a-4e。
4a:yield 32%.1HNMR(500MHz,DMSO-d6)δ7.62(d,J=15.9Hz,1H),7.38(d,J=1.9Hz,1H),7.24(dd,J=8.3,1.8Hz,1H),6.98(d,J=8.4Hz,1H),6.60(d,J=15.9Hz,1H),4.54(t,J=6.5Hz,2H),4.47(t,J=6.5Hz,2H),4.00(t,J=6.4Hz,2H),3.81(s,3H),3.73(t,J=6.4Hz,2H),1.79–1.70(m,2H),1.52–1.44(m,2H)ppm.
4b:yield 30%.1H NMR(500MHz,Chloroform-d)δ7.84(d,J=15.9Hz,1H),7.47(s,1H),7.29(dd,J=8.3,1.6Hz,1H),7.06(d,J=8.3Hz,1H),6.51(d,J=15.9Hz,1H),4.69(t,J=6.6Hz,2H),4.55(t,J=6.0Hz,2H),4.27(t,J=6.4Hz,2H),3.82(s,3H),3.73(t,J=6.6Hz,2H),2.42–2.52(m,2H),2.07–2.12(m,2H),1.99–2.05(m,2H),1.79–1.87(m,2H)ppm.
4c:yield 31%.1H NMR(500MHz,Chloroform-d)δ7.62(d,J=15.9Hz,1H),7.08(dd,J=8.3,1.7Hz,1H),7.05(d,J=1.7Hz,1H),6.85(d,J=8.3Hz,1H),6.30(d,J=15.9Hz,1H),4.48(t,J=6.6Hz,2H),4.23(t,J=6.3Hz,2H),4.06(t,J=6.4Hz,2H),3.84(s,3H),3.47(t,J=6.6Hz,2H),2.02–1.97(m,2H),1.93–1.86(m,4H),1.84–1.79(m,2H),1.66–1.60(m,2H)ppm.
4d:yield 33%.1H NMR(500MHz,Chloroform-d)δ7.62(d,J=15.9Hz,1H),7.08(dd,J=8.3,1.8Hz,1H),7.05(d,J=1.8Hz,1H),6.85(d,J=8.3Hz,1H),6.30(d,J=15.9Hz,1H),4.48(t,J=6.6Hz,2H),4.21(t,J=6.5Hz,2H),4.06(t,J=6.4Hz,2H),3.89(s,3H),3.44(t,J=6.7Hz,2H),1.93–1.87(m,4H),1.84–1.80(m,2H),1.76–1.72(m,2H),1.61–1.63(m,2H)ppm.
4e:yield 30%.1H NMR(500MHz,Chloroform-d)δ7.62(d,J=15.9Hz,1H),7.08(dd,J=8.3,1.8Hz,1H),7.05(d,J=1.8Hz,1H),6.85(d,J=8.3Hz,1H),6.30(d,J=15.9Hz,1H),4.48(t,J=6.6Hz,2H),4.20(t,J=6.6Hz,2H),4.06(t,J=6.4Hz,2H),3.82(s,3H),3.42(t,J=6.8Hz,2H),1.91–1.87(m,4H),1.83–1.80(m,2H),1.74–1.70(m,2H),1.65–1.58(m,2H),1.53–1.48(m,2H),1.47–1.42(m,2H)ppm.
实施例4卟啉母体5的合成
称取4.8848g(40mmol)对羟基苯甲醛、12.7344g(120mmol)苯甲醛置于250mL的三颈烧瓶中,以150ml的丙酸为溶剂,于130℃的环境下进行反应。将新蒸过的11.08mL(160mmol)吡咯添加到恒压滴液漏斗中,并以1滴/秒的速度滴加入反应液中,且滴定操作在30min内完成。继续加热回流90min后结束反应。通过旋转蒸发仪除去一半左右的丙酸,加入相同体积乙醇后放入温度为4℃的冰箱中。隔天对反应液进行抽滤,并用乙醇对其进行多次洗涤,可获得颜色为蓝紫色的粗产品。粗产物使用硅胶层析住纯化除去杂质后可得目标产物。
5:yield 8%.1H NMR(500MHz,DMSO-d6)δ8.89–8.85(m,8H),8.22(d,J=7.9Hz,6H),8.06(d,J=8.3Hz,2H),7.80–7.73(m,9H),7.16(d,J=8.3Hz,2H),-2.76(s,2H).
实施例5卟啉-阿魏酸(6a-6e)衍生物的合成
称取0.22mmol 4a-4e(4a 95.01mg,4b 98.18mg,4c 101.27mg,4d 104.36mg,4e107.44mg)、138mgK2CO3和126mg化合物5于150mL三颈烧瓶中,以60mL DMF作为溶剂并加入200μL三乙胺,于60℃条件下进行反应。薄层色谱法监测反应进程。反应结束后,抽滤,滤液加入蒸馏水并用CH2Cl2萃取。收集到的CH2Cl2通过无水Na2SO4除去其中存在水分,减压除去CH2Cl2后获得粗产物。粗产物以CH2Cl2为淋洗剂,利用硅胶柱纯化,收集第三条带,即可获得紫色固体(化合物6a-6e)。
6a:yield 80%;purity 98%;1H NMR(500MHz,Chloroform-d)δ8.88–8.84(m,8H),8.22(d,J=6.7Hz,6H),8.08(d,J=8.3Hz,2H),7.78–7.74(m,9H),7.67(d,J=15.9Hz,1H),7.21(d,J=8.3Hz,2H),7.11-7.06(m,2H),6.85(d,J=8.3Hz,1H),6.34(d,J=15.9Hz,1H),4.52(t,J=6.1Hz,2H),4.49(t,J=6.6Hz,2H),4.06(t,J=6.4Hz,2H),3.90(s,3H),3.59(t,J=6.1Hz,2H),1.93–1.87(m,2H),1.84–1.79(m,2H),1.65–1.62(m,2H),-2.78(s,2H)ppm;FT-IR(KBr,cm-1):3315(υNH),1705(υC=O),1277(υPh-O-C),1259(υC-O-C),1007(υpyrrole);HRMS-ESI:m/z calcd for C61H51N5O8 +982.3738[M+H]+,found 982.256.
6b:yield 83%;purity 95%;1H NMR(500MHz,Chloroform-d)δ8.89–8.84(m,8H),8.22(d,J=6.7Hz,6H),8.13(d,J=8.3Hz,2H),7.80–7.70(m,10H),7.30(d,J=8.4Hz,2H),7.13–7.09(m,2H),6.84(d,J=8.2Hz,1H),6.41(d,J=15.9Hz,1H),4.58(t,J=6.2Hz,2H),4.47(t,J=6.6Hz,2H),4.41(t,J=6.0Hz,2H),4.03(t,J=6.5Hz,2H),3.89(s,3H),2.43–2.38(m,2H),1.91–1.86(m,2H),1.83–1.77(m,2H),1.63–1.55(m,2H),-2.76(s,2H)ppm;FT-IR(KBr,cm-1):3315(υNH),1706(υC=O),1278(υPh-O-C),1254(υC-O-C),1001(υpyrrole).HRMS-ESI:m/z calcd for C62H53N5O8 +997.3894[M+H]+,found 997.4062.
6c:yield 82%;purity 96%;1H NMR(500MHz,Chloroform-d)δ8.89–8.83(m,8H),8.22(d,J=6.3Hz,6H),8.12(d,J=8.5Hz,2H),7.80–7.74(m,9H),7.69(d,J=15.9Hz,1H),7.29(d,J=8.5Hz,2H),7.10–7.07(m,2H),6.72(d,J=8.1Hz,1H),6.38(d,J=15.9Hz,1H),4.43–4.39(m,4H),4.33(t,J=5.7Hz,2H),3.90–3.87(m,5H),2.16–2.08(m,4H),1.80–1.69(m,4H),1.52–1.47(m,2H),-2.78(s,2H)ppm;FT-IR(KBr,cm-1):3315(υNH),1706(υC=O),1278(υPh-O-C),1252(υC-O-C),1001(υpyrrole);HRMS-ESI:m/z calcd for C63H55N5O8 +1010.4061[M+H]+,found 1010.4151.
6d:yield 82%;purity 96%;1H NMR(500MHz,Chloroform-d)δ8.89–8.83(m,8H),8.22(d,J=6.3Hz,6H),8.11(d,J=8.4Hz,2H),7.80–7.74(m,9H),7.67(d,J=15.9Hz,1H),7.28(d,J=8.5Hz,2H),7.10–7.07(m,2H),6.78(d,J=8.2Hz,1H),6.37(d,J=15.9Hz,1H),4.43(t,J=6.6Hz,2H),4.34(t,J=6.5Hz,2H),4.29(t,J=6.2Hz,2H),3.96(t,J=6.4Hz,2H),3.88(s,3H),2.09–2.03(m,2H),1.95–1.90(m,4H),1.85–1.73(m,6H),1.55–1.50(m,2H),-2.78(s,2H)ppm;FT-IR(KBr,cm-1):3314(υNH),1705(υC=O),1278(υPh-O-C),1256(υc-o-c),1001(υpyrrole);HRMS-ESI:m/z calcd for C64H57N5O8 +1024.4207[M+H]+,found1024.4316.
6e:yield 84%;purity 90%;1H NMR(500MHz,Chloroform-d)δ8.89–8.83(m,8H),8.22(d,J=6.5Hz,6H),8.10(d,J=8.3Hz,2H),7.80–7.73(m,9H),7.66(d,J=15.9Hz,1H),7.27(d,J=8.6Hz,2H),7.08–7.05(m,2H),6.70(d,J=8.1Hz,1H),6.36(d,J=15.9Hz,1H),4.34(t,J=6.6Hz,2H),4.30(t,J=6.6Hz,2H),4.27(t,J=6.4Hz,2H),3.86(s,3H),3.81(t,J=6.4Hz,2H),2.04–2.00(m,2H),1.88–1.83(m,2H),1.74–1.61(m,8H),1.44–1.39(m,2H),-2.77(s,2H)ppm;FT-IR(KBr,cm-1):3315(υNH),1705(υC=O),1278(υPh-O-C),1254(υC-O-C),1001(υpyrrole);HRMS-ESI:m/z calcd for C65H59N5O8 +1038.4364[M+H]+,found1038.4528.
实施例6卟啉-阿魏酸(7a-7e)衍生物的合成
化合物6a-6e以CH2Cl2为溶剂溶解于150mL三颈烧瓶中,并加入5倍当量的二水合醋酸锌,于40℃条件下进行反应。停止反应后将反应液与蒸馏水加入分液漏斗,摇晃分液漏斗以通过蒸馏水除去反应液中多余的金属盐,静置,收集有机层。收集到的有机层经过无水Na2SO4的除水处理后,减压除去溶剂得亮紫色晶体(化合物7a-7e)。
7a:yield 98%;purity 96%;1H NMR(500 MHz,Chloroform-d)δ8.99–8.94(m,8H),8.22(d,J=6.8 Hz,6H),8.08(d,J=8.0 Hz,2H),7.79–7.73(m,9H),7.64(d,J=15.9Hz,1H),7.20(d,J=8.1 Hz,2H),7.08–7.05(m,2H),6.83(d,J=8.3 Hz,1H),6.31(d,J=15.9 Hz,1H),4.51–4.47(m,4H),4.05(t,J=6.4 Hz,2H),3.89(s,3H),3.58(t,J=6.1 Hz,2H),1.93–1.87(m,2H),1.85–1.79(m,2H),1.64–1.60(m,2H)ppm.FT-IR(KBr,cm-1):1705(υC=O),1277(υPh-O-C),1259(υC-O-C),1002(υpyrrole);HRMS-ESI:m/z calcd for C61H49N5O8Zn+1044.2873[M+H]+,found 1044.1676.
7b:yield 98%;purity 95%;1H NMR(500 MHz,Chloroform-d)δ9.03–8.91(m,8H),8.22(d,J=6.9 Hz,6H),8.13(d,J=8.3 Hz,2H),7.79–7.73(m,9H),7.63(d,J=15.9Hz,1H),7.29(d,J=8.3 Hz,2H),7.10–7.06(m,2H),6.82(d,J=8.2 Hz,1H),6.35(d,J=15.9 Hz,1H),4.52–4.46(m,4H),4.39(t,J=6.0 Hz,2H),4.03(t,J=6.4 Hz,2H),3.88(s,3H),2.37(t,J=6.2 Hz,2H),1.91–1.87(m,2H),1.84–1.78(m,2H),1.63–1.57(m,2H)ppm.FT-IR(KBr,cm-1):1707(υC=O),1277(υPh-O-C),1257(υC-O-C),1002(υpyrrole);HRMS-ESI:m/z calcd forC62H51N5O8Zn+1059.3029[M+H]+,found 1059.3103.
7c:yield 97%;purity 96%;1H NMR(500 MHz,Chloroform-d)δ8.99–8.94(m,8H),8.22(d,J=6.5 Hz,6H),8.12(d,J=8.4 Hz,2H),7.80–7.73(m,9H),7.61(d,J=15.9Hz,1H),7.28(d,J=8.4 Hz,2H),7.07–7.03(m,2H),6.72(d,J=8.2 Hz,1H),6.32(d,J=15.9 Hz,1H),4.43(t,J=6.6 Hz,2H),4.36(t,J=6.0 Hz,2H),4.31(t,J=5.8 Hz,2H),3.91(t,J=6.4 Hz,2H),3.85(s,3H),2.13–2.04(m,4H),1.83–1.72(m,4H),1.56–1.53(m,2H)ppm.FT-IR(KBr,cm-1):1704(υC=O),1278(υph-O-C),1257(υC-O-C),1002(υpyrrole);HRMS-ESI:m/z calcd forC63H53N5O8Zn+1072.3186[M+H]+,found 1072.3384.
7d:yield 96%;purity 94%;1H NMR(500 MHz,Chloroform-d)δ8.99–8.94(m,8H),8.22(d,J=6.6 Hz,6H),8.11(d,J=8.3 Hz,2H),7.79–7.73(m,9H),7.61(d,J=15.9Hz,1H),7.28(d,J=8.4 Hz,2H),7.07–7.03(m,2H),6.76(d,J=8.3 Hz,1H),6.32(d,J=15.9 Hz,1H),4.45(t,J=6.6Hz,2H),4.30–4.27(m,4H),3.96(t,J=6.4Hz,2H),3.86(s,3H),2.08–2.02(m,2H),1.94–1.89(m,2H),1.85–1.74(m,6H),1.58–1.54(m,2H)ppm;FT-IR(KBr,cm-1):1705(υC=O),1278(υPh-O-C),1259(υC-O-C),1002(υpyrrole);HRMS-ESI:m/z calcdfor C64H55N5O8Zn+1086.3342[M+H]+,found 1086.3433.
7e:yield 98%;purity 97%;1H NMR(500MHz,Chloroform-d)δ8.99–8.94(m,8H),8.22(d,J=6.6Hz,6H),8.10(d,J=8.3Hz,2H),7.79–7.73(m,9H),7.60(d,J=15.9Hz,1H),7.27(d,J=7.8Hz,2H),7.05–7.01(m,2H),6.69(d,J=8.3Hz,1H),6.31(d,J=15.9Hz,1H),4.39(t,J=6.6Hz,2H),4.28–4.24(m,4H),3.85–3.83(m,5H),2.05–1.99(m,2H),1.86–1.81(m,2H),1.76–1.67(m,6H),1.64–1.59(m,2H),1.48–1.42(m,2H)ppm.FT-IR(KBr,cm-1):1705(υC=O),1278(υPh-O-C),1256(υC-O-C),1002(υpyrrole);HRMS-ESI:m/z calcd forC65H57N5O8Zn+1100.3499[M+H]+,found 1100.3702.
实施例7卟啉-阿魏酸(8a-8e)衍生物的合成
将化合物6a-6e以N,N-二甲基甲酰胺为溶剂溶于150mL三颈烧瓶中,加入5倍当量的乙酸镍(Ⅱ)四水合物,在125℃条件下进行冷凝回流。反应结束后,在反应液中加入蒸馏水,通过CH2Cl2萃取。收集CH2Cl2并用无水Na2SO4除去CH2Cl2中少量水分,旋除CH2Cl2后便得到粗产物。粗产物以CH2Cl2为展开剂通过硅胶柱的分离纯化后可得红棕色晶体(化合物8a-8e)。
8a:yield 52%;purity 86.93%;1H NMR(500MHz,Chloroform-d)δ8.78–8.74(m,8H),8.01(d,J=6.8Hz,6H),7.94(d,J=8.2Hz,2H),7.87(d,J=8.2Hz,2H),7.74–7.62(m,10H),7.15–7.10(m,2H),6.82(d,J=7.8 Hz,1H),6.45(d,J=16.0 Hz,1H),4.71(t,J=4.7Hz,2H),4.51–4.47(m,4H),4.03(t,J=6.3 Hz,2H),3.89(s,3H),2.06–2.01(m,2H),1.93–1.78(m,4H)ppm.FT-IR(KBr,cm-1):1707(υC=O),1277(υPh-O-C),1259(υC-O-C),1006(υpyrrole);HRMS-ESI:m/z calcd for C61H49N5O8Ni+1038.2935[M+H]+,found 1038.1083.
8b:yield 60%;purity 82.06%;1H NMR(500 MHz,Chloroform-d)δ8.78–8.73(m,8H),8.01(d,J=6.8 Hz,6H),7.92(d,J=8.3 Hz,2H),7.71–7.67(m,10H),7.22(d,J=8.4 Hz,2H),7.11–7.08(m,2H),6.84(d,J=8.2 Hz,1H),6.38(d,J=15.9 Hz,1H),4.55(t,J=6.2 Hz,2H),4.35(t,J=6.0 Hz,2H),4.20(t,J=6.5 Hz,2H),4.04(t,J=6.7 Hz,2H),3.89(s,3H),2.39–2.34(m,2H),1.91–1.86(m,2H),1.78–1.72(m,2H),1.64–1.62(m,2H)ppm;FT-IR(KBr,cm-1):1707(υC=O),1277(υPh-O-C),1261(υC-O-C),1006(υpyrrole);HRMS-ESI:m/z calcd forC62H51N5O8Ni+1052.3091[M+H]+,found 1052.1259.
8c:yield 54%;purity 84.42%;1H NMR(500 MHz,Chloroform-d)δ8.78–8.74(m,8H),8.01(d,J=6.8 Hz,6H),7.91(d,J=8.6 Hz,2H),7.72–7.65(m,10H),7.21(d,J=8.2 Hz,2H),7.09–7.06(m,2H),6.74(d,J=9.0 Hz,1H),6.36(d,J=15.9 Hz,1H),4.45–4.38(m,4H),4.27(t,J=7.5 Hz,2H),3.95–3.88(m,5H),2.11–2.03(m,4H),1.99–1.94(m,2H),1.82–1.73(m,4H)ppm.FT-IR(KBr,cm-1):1715(υC=O),1277(υPh-O-C),1261(υC-O-C),1006(υpyrrole);HRMS-ESI:m/z calcd for C63H53N5O8Ni+1066.3248[M+H]+,found 1066.3314.
8d:yield 58%;purity 85.83%.1H NMR(500 MHz,Chloroform-d)δ8.78–8.73(m,8H),8.01(d,J=6.7 Hz,6H),7.90(d,J=8.2 Hz,2H),7.72–7.64(m,10H),7.20(d,J=8.4 Hz,2H),7.09–7.06(m,2H),6.79(d,J=8.1 Hz,1H),6.35(d,J=15.9 Hz,1H),4.45(t,J=6.6 Hz,2H),4.32(t,J=6.4 Hz,2H),4.23(t,J=6.3 Hz,2H),3.98(t,J=6.4 Hz,2H),3.88(s,3H),2.05–1.99(m,4H),1.91–1.84(m,4H),1.79–1.74(m,4H)ppm.FT-IR(KBr,cm-1):1705(υC=O),1276(υPh-O-C),1260(υC-O-C),1006(υpyrrole);HRMS-ESI:m/z calcd forC64H55N5O8Ni+1080.3404[M+H]+,found 1080.3488.
8e:yield 56%;purity 95.32%.1H NMR(500MHz,Chloroform-d)δ8.79–8.74(m,8H),8.01(d,J=6.7Hz,6H),7.90(d,J=8.1Hz,2H),7.70–7.63(m,10H),7.20(d,J=8.3Hz,2H),7.09–7.06(m,2H),6.73(d,J=8.1Hz,1H),6.34(d,J=15.9Hz,1H),4.40(t,J=6.6Hz,2H),4.28(t,J=6.5Hz,2H),4.21(t,J=6.1Hz,2H),3.92–3.87(m,5H),2.01–1.96(m,2H),1.85–1.81(m,2H),1.77–1.67(m,8H),1.53–1.45(m,2H)ppm.FT-IR(KBr,cm-1):1704(υC=O),1277(υPh-O-C),1257(υC-O-C),1006(υpyrrole);HRMS-ESI:m/z calcd for C65H57N5O8Ni+1094.3561[M+H]+,found 1094.3645.
实施例8单线态氧检测
检测方法:分别精确称取待测化合物5、化合物6a-8e以及DPBF,三氯甲烷作溶剂,配制成8μmol/L的待测溶液和20μmol/L的DPBF溶液。将DPBF溶液与待测溶液等体积混合,在同一条件下测定DPBF加入待测溶液前后的荧光强度变化。将激发波长设置为418nm,采用1200nm/min的扫描速度进行200-800nm范围内的扫描。待测化合物在463nm处均无荧光。检测过程中,记录DPBF的荧光变化并整理成图,结果见说明书附图1。
DPBF荧光程度下降越快,信号值越低,表明单线态氧的含量越高。附图的结果显示,化合物5及化合物6a-8e可使DPBF的荧光强度在短时间内显著下降,且后者的DPBF的荧光下降程度更大。化合物6a-6e和化合物7a-7e可在50s的检测时间内不断减低DPBF的荧光强度,最终可降低至30以下。被化合物8a-8e处理后的DPBF荧光强度在10s内可降低至100左右,表明在激光照射下化合物8a-8e可在极短时间内迅速产生单线态氧。以上结果均表明,NO型卟啉-阿魏酸衍生物(化合物6a-8e)具有强于卟啉母体(化合物5)的单线态氧产生能力,可作为潜在的PDT治疗剂用于癌症的治疗。
实施例9体外抗肿瘤活性测试
人肝癌细胞HepG2和人非小细胞肺癌细胞A549均来自中国科学院上海生命科学研究院细胞资源中心。
在37℃、5%CO2的细胞培养箱中放入已复苏的A549细胞与HepG2细胞。当细胞生长所占体积达到培养瓶的体积的90%左右后,将瓶中的培养基吸出,并用PBS洗去残留的死细胞及培养基。往瓶中添加1mL的胰酶(Trypsin-EDTA)以对细胞进行消化,45秒后添加2mL培养液使其消化停止。用吸液枪对细胞进行吹扫,使其形成悬液,然后进行离心,并将离心后得到的细胞沉淀制备成细胞悬浮液待用。取6块96孔板,每两块为一组。每组设计光照组(即A组)和黑暗组(B组)。首先将PBS添加在每块96孔板的四周,每孔200μL。其次在加样槽中加入13ml培养基,取上述的细胞悬浮液185μL,混合后,将其以100μL/孔的体积接种到96孔板,然后将接种了细胞的96孔板放入环境温度为37℃、5%CO2的细胞培养器中,再进行24小时的培养。
每个实验药物配置成药物浓度为128μmol/L、64μmol/L、32μmol/L、16μmol/L的含药培养基。每组实验设计6个复孔的空白组和阴性对照组,3个复孔的阳性对照组及实验组。将96孔板取出后弃去原有培养基,并依次加入培养基(空白组)、含有DMAC的培养基(阴性对照组)、5-FU(阳性对照组)和含药培养基(实验组),最后在孔板表面对A、B组的孔板进行标记并继续放入培养箱培养。加药24小时后取出A组实验板用近红外灯照射10min,B组不作处理。细胞加药48h后,将5g/L MTT溶液以20μl/孔的方式分别添加到在两个实验组的A、B板中。培养4h后,取出96孔板并清除上清液,然后以150μl/孔的方式添加DMSO溶液,添加结束后需要用锡箔纸对孔板进行遮盖。将添加了DMSO的96孔板转移至摇床,10min后利用酶标仪检测其在490nm处的吸光度(OD值)。通过所得OD值计算出药物对癌细胞的体外抑制率(IC50值)。测试结果如下:
由上表可知,该系列对A549细胞也产生了不同程度细胞光毒性。通过对比可看出,大部分化合物对HepG2细胞具有更高的光毒性,且化合物7a-7c以及化合物8a在光照条件下对HepG 2细胞表现出优于5-fu的细胞抑制作用,其中化合物7a的作用最为显著(IC50=43.82±2.50)。值得注意的是,化合物7a及8a对A549细胞也表现出较强的光毒性,且二者对A549细胞的细胞毒性强于5-fu。
Claims (10)
1.一种式I或式II所示化合物及它们药学上可接受的盐,其具有如下结构::
其中,n选自1-8的整数;
m选自1-8的整数;
R1选自H,卤素,羟基,硝基,CN,C1-6烷基,C2-6烯基,C2-6炔基,C6-10芳基,C2-C10杂芳基;
R选自H,卤素,羟基,硝基,CN,C1-6烷基,C2-6烯基,C2-6炔基;
M选自Zn,Ni,Mn。
2.根据权利要求1所述的式I或式II所示化合物及它们药学上可接受的盐,其特征在于:R1选自H,卤素,羟基,硝基,CN,C1-6烷基;更优选地,R1选自H或Cl;
R选自H,卤素,羟基,硝基,CN,C1-6烷基;更优选地,R选自H或甲基。
3.根据权利要求1或2所述的式I或式II所示化合物及它们药学上可接受的盐,其特征在于:n选自1、2、3、4或5;
m选自1、2、3、4或5;
R1选自H或Cl;
R选自H或甲基;
M选自Zn或Ni。
4.根据权利要求1所述的式I或式II所示化合物及它们药学上可接受的盐,其特征在于,所述化合物结构如下:
5.一种制备如权利要求1所述的式I化合物的方法,其反应路线如下:
其中,n、m、R1、R的定义如权利要求1所述;
其中包括如下反应步骤:
在有机溶剂中,加入碱和卟啉衍生物5,加热搅拌,将阿魏酸衍生物4加入反应体系,直至反应完毕,经后处理得到式I化合物。
6.根据权利要求5所述的制备方法,其特征在于:
卟啉衍生物5与阿魏酸衍生物4的摩尔比为:1:(1-1.5);
所述碱选自氢氧化钾、三乙胺或碳酸钾;
所述有机溶剂选自:二氯甲烷,氯仿,四氢呋喃,DMSO,DMF,甲醇,乙醇,异丙醇中的一种或多种。
7.一种制备如权利要求1所述的式II化合物的方法,其反应路线如下:
其中,n、m、R1、R和M的定义如权利要求1所述;
其包括如下反应步骤:
将式I化合物用有机溶剂溶解,加入M金属盐,回流反应,TLC监控至反应完全,经后处理得到式II的卟啉-阿魏酸衍生物。
8.一种药物组合物,其包含权利要求1-4中任一项所述式I或式II化合物或它们药学上可接受的盐,以及药学上可接受的载体。
9.权利要求1-4中任一项所述的化合物或其药学上可接受的盐或权利要求8所述的药物组合物在制备治疗癌症的药物中的用途。
10.如权利要求9所述的用途,其中所述癌症选自肺癌或肝癌。
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