CN116554182A - 一种卟啉-丁香酚衍生物、制备方法及其用途 - Google Patents
一种卟啉-丁香酚衍生物、制备方法及其用途 Download PDFInfo
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- CN116554182A CN116554182A CN202310508392.1A CN202310508392A CN116554182A CN 116554182 A CN116554182 A CN 116554182A CN 202310508392 A CN202310508392 A CN 202310508392A CN 116554182 A CN116554182 A CN 116554182A
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Abstract
本发明公开了一种具有抗肿瘤活性的卟啉‑丁香酚衍生物,使用DPBF检测了单线态氧的产率,体外抗肿瘤活性测试显示本发明化合物具有良好的活性。本发明的卟啉连香豆素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***金属Zn也能够增强化合物的抗肿瘤活性。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,具体地涉及一种卟啉-丁香酚衍生物、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。
本发明人前期对卟啉类化合物已经进行了大量的研究,例如将卟啉与白杨素、氨基酸进行键连,合成了一系列具有良好抗癌活性的新型PDT类化合物,但前期工作主要集中在卟啉键连抗癌活性药物来增强药物抗肿瘤活性方面,对如何提高卟啉类化合物的1O2产生能力来增强抗肿瘤活性的相关研究甚少。
丁香酚是一种苯丙酸类衍生物,是丁香中具有生物活性的分类成分,常温下为淡黄色粘稠油状液。目前正在研究丁香酚对癌细胞系和动物模型的抗癌活性,并且丁香酚诱导黑色素瘤、皮肤肿瘤、白血病和肥大细胞凋亡等的分子机制也已被证实。丁香酚在体内和体外研究中都被认为是一个很有前途的候选药物。
李诗杰等人(Thorac Cancer,2018.9(1):p.25-29)研究观察到丁香酚对人肺癌的化疗活性,实验中发现低浓度的丁香酚可以抑制致癌细胞的迁移和侵袭,阻碍肺癌细胞的可持续性,并阻止转移。在较大的浓度(1000M)下,丁香酚对正常细胞和肺癌细胞表现出致命的影响。而且丁香酚处理后肺癌细胞中磷酸AKT和基质金属蛋白酶(MMP-2)的表达水平均降低。其中MMPs是锌酶的一个关键家族,负责降解与肿瘤转移密切相关的细胞外基质成分。在包括肺癌在内的各种疾病中,过度的MMP表达可能有助于组织破坏过程的发病。Petrocelli等人利用丁香酚对NCM-460细胞(上皮结肠)和对结直肠癌(CRC)细胞系的抗癌作用进行了研究,确定丁香酚具有明确抗肿瘤活性,选择性靶向转化的结肠细胞。处理72h后,Caco-2和SW-620细胞中丁香酚均能激活细胞死亡、坏死和细胞周期减慢,而NCM-460细胞则不能。近年来,多项研究表明丁香酚具有抗癌活性,其不仅可以抑制癌细胞,还可以抑制肿瘤微环境中的基质细胞,也慢慢成为了许多学者的研究热点。
卟啉化合物是研究较为热门的药物,具有很好的研究前景与抗肿瘤潜力,丁香酚的抗癌活性研究也慢慢受到广泛关注。本发明设计合成了一类新型的卟啉-丁香酚衍生物,通过丁香酚与卟啉的结合,利用卟啉的肿瘤靶向作用与生成的单线态氧的能力,加上丁香酚的抗癌活性,能够发挥出药物的抗肿瘤效果。在具有良好的抗肿瘤活性的同时,还具有更小的毒副作用。
发明内容
本发明所要解决的技术问题是:提供了一种卟啉-丁香酚衍生物,能够特异性地抑制肿瘤细胞,对人体正常细胞无灭杀活性。
本发明人在前期工作的基础上,为了得到具有靶向抑制的卟啉-丁香酚衍生物,进行了大量的工作,设计并合成了一系列卟啉-丁香酚衍生物,筛选出了与EGFR激酶能够较好地结合的化合物,并考量了化合物对细胞周期、细胞凋亡、细胞迁移和人正常血管内皮细胞的毒性等因素,最终筛选得到了本发明的化合物。
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;
R1选自H,卤素,羟基,硝基,CN,C1-6烷基,C2-C6烯基,C2-C6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-C6烯基,C2-C6炔基;
M选自Zn,Ni,Mn。
优选地,n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。
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、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1,加热搅拌,将丁香酚衍生物2加入反应体系,直至反应完毕,经后处理得到式I的卟啉-丁香酚衍生物。
优选地,卟啉衍生物1与丁香酚衍生物2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;更优选为二氯甲烷。
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、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-丁香酚衍生物。
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。
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卟啉连香豆素衍生物,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)本发明的卟啉连香豆素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***金属Zn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卟啉化合物4及6a-6e的荧光强度随光照时间的变化趋势图。
图2卟啉化合物5及7a-7e的荧光强度随光照时间的变化趋势图。
图3卟啉化合物4及8a-8e的荧光强度随光照时间的变化趋势图。
图4卟啉化合物5及9a-9e的荧光强度随光照时间的变化趋势图。
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丁香酚衍生物的合成
称取154μL(1mmol)丁香酚,691mg(5mmol)K2CO3,166mg(1mmol)KI于100mL圆底烧瓶中,加入10mLDMF作为溶剂,使其充分溶解,于60℃下回流搅拌20min,随后向反应体系中缓慢滴加0.33mL(3mmol)溴乙酸乙酯/0.39mL(3mmol)2-溴丙酸乙酯/0.43mL(3mmol)4-溴丁酸乙酯/0.47mL(3mmol)5-溴戊酸乙酯/0.53mL(3mmol)6-溴己酸乙酯,TLC点板监测,直至反应完全,停止加热,静置冷却,将反应液倒入分液漏斗中,加入适量二氯甲烷萃取,水洗,放出下层有机层,无水Na2SO4除水,减压旋蒸,得淡黄色油状液体。然后将黄色液体加入圆底烧瓶,适量甲醇溶解,调节pH至10-11,60℃下水解1.5h,结束反应,静置,向反应体系中加入10%HCl调节pH至2-3,减压旋蒸,析出白色固体,
加水抽滤,用适量去离子水冲洗滤饼,得丁香酚衍生物3a-3e。产率:75~90%
3a:1H NMR(500MHz,Chloroform-d)δ6.87(d,J=8.0Hz,1H),6.76-6.73(m,2H),5.99–5.89(m,1H),5.12–5.05(m,2H),4.65(s,2H),3.89(s,3H),3.35(d,J=6.6Hz,2H).
3b:1HNMR(500MHz,DMSO-d6)δ12.11(s,1H),6.80(d,J=2.0Hz,1H),6.73(d,J=8.2Hz,1H),6.65(d,J=8.1Hz,1H),5.97-5.91(m,1H),5.10–5.00(m,2H),4.69-4.65(m,1H),3.75(s,3H),3.28(d,J=6.5Hz,2H),1.47(d,J=6.7Hz,3H).
3c:1H NMR(500MHz,DMSO-d6)δ12.16(s,1H),6.85(d,J=8.1Hz,1H),6.77(s,1H),6.66(d,J=8.1Hz,1H),5.99–5.87(m,1H),5.10–4.99(m,2H),3.91(t,J=6.5Hz,2H),3.73(s,3H),3.28(d,J=6.8Hz,2H),2.37(t,J=7.3Hz,2H),1.92-1.87(m,2H).
3d:1H NMR(500MHz,DMSO-d6)δ12.06(s,1H),6.89–6.62(m,3H),6.03–5.84(m,1H),5.08-5.01(m,2H),3.90(t,J=6.3Hz,2H),3.73(s,3H)3.29(d,J=7.0Hz,2H),2.35–
2.22(m,2H),1.78–1.61(m,4H).
3e:1H NMR(500MHz,DMSO-d6)δ11.99(s,1H),6.86(d,J=8.1Hz,1H),6.77(d,J=1.9Hz,1H),6.67(dd,J=8.2,1.9Hz,1H),6.00–5.88(m,1H),5.10–4.99(m,2H),3.89(t,J=6.5Hz,2H),3.73(s,3H),3.29(d,J=6.7Hz,2H),2.23(t,J=7.3Hz,2H),1.74–1.64(m,2H),1.61–1.51(m,2H),1.46–1.36(m,2H)。
实施例2母体化合物卟啉的合成
准确称取6.13mL(60mmol)苯甲醛和2.48g(20mmol)对羟基苯甲醛于500mL三颈烧瓶中,加入120mL丙酸作为溶剂,135℃下搅拌至体系达到微沸状态,用恒压漏斗缓慢滴加5.2mL(80mmol)新蒸吡咯,时间控制在30min左右,待吡咯滴加完成后,回流1h。停止反应,趁热减压旋蒸出2/3丙酸,加入100mL无水乙醇,放入冰箱中4℃冷藏24h,减压抽滤,干燥,得黑紫色固体粗品,随后用展开剂(二氯甲烷:正己烷=2:1)过硅胶柱进行纯化,搜集第二条色带,减压旋蒸,即得卟啉化合物4。产率:8%
4:1H NMR(500MHz,Chloroform-d)δ8.86(d,J=12.2Hz,8H),8.25–8.21(m,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).
准确称取8.4g(60mmol)对氯苯甲醛和2.48g(20mmol)对羟基苯甲醛于500mL三颈烧瓶中,加入120mL丙酸作为溶剂,135℃下搅拌至体系达到微沸状态,用恒压漏斗缓慢滴加5.2mL(80mmol)新蒸吡咯,时间控制在30min左右,待吡咯滴加完成后,回流1h。停止反应,趁热减压旋蒸出2/3丙酸,加入100mL无水乙醇,放入冰箱中4℃冷藏24h,减压抽滤,干燥,得黑紫色固体粗品,随后用展开剂(二氯甲烷:正己烷=2:1)过硅胶柱进行纯化,搜集第二条色带,减压旋蒸,即得卟啉化合物5。产率:8%
5:1H NMR(500MHz,Chloroform-d)δ8.92–8.80(m,8H),8.14(d,J=7.8Hz,6H),8.06(d,J=8.6Hz,2H),7.75(d,J=8.4Hz,6H),7.22(d,J=8.6Hz,2H),-2.84(s,2H).
实施例3卟啉-丁香酚衍生物的合成
准确称取44.4mg(2mmol)3a/47.2mg(2mmol)3b/50.0mg(2mmol)3c/52.8mg(2mmol)3d/55.6mg(2mmol)3e丁香酚衍生物于50mL单颈烧瓶中,适量二氯甲烷溶解,加入1mL氯化亚砜,3滴DMF作催化剂,反应3h,减压旋蒸除去溶剂,加入15mL二氯甲烷重新溶解,再次减压旋蒸,加入适量二氯甲烷溶解待用。另取圆底烧瓶,加入0.63g化合物4或0.73g化合物5,416μL(5mmol)三乙胺,30mL二氯甲烷溶解,将上述待用的二氯甲烷溶液缓慢滴加至反应体系中,40℃下回流30min,待反应结束后,减压旋蒸,得粗产品,粗品展开剂(二氯甲烷:正己烷:乙酸乙酯=20:10:1)过硅胶柱纯化,收集第二条色带,减压旋蒸,得化合物6a-6e和化合物7a-7e。
将制得的化合物6a-6e和化合物7a-7e用适量二氯甲烷溶解,并向其中加入100mg二水合醋酸锌,40℃下回流搅拌1h,待反应结束后,加入适量去离子水洗去反应体系中的金属盐,有机层用无水Na2SO4除水,减压旋蒸,得***晶体。即目标化合物8a-8e和9a-9e。
本发明共合成了20个丁香酚-卟啉化合物,均通过核磁共振氢谱、质谱确证结构。
6a:Yield:65.3%,1HNMR(500MHz,Chloroform–d)δ8.85(s,8H),8.22(d,J=6.4Hz,8H),7.81–7.74(m,9H),7.46(d,J=8.0Hz,2H),7.10(d,J=8.2Hz,1H),6.85–6.80(m,2H),6.05–5.95(m,1H),5.15–5.08(m,4H),3.97(s,3H),3.39(d,J=6.7Hz,2H),-2.80(s,2H).Purity:98.74%,HRMS:C56H43N4O4 for[M+H]+,calculated 835.3284,found835.3245.
6b:Yield:59.5%,1H NMR(500MHz,Chloroform-d)δ8.87(s,8H),8.24(d,J=6.7Hz,8H),7.80–7.75(m,9H),7.48(d,J=7.8Hz,2H),7.12(d,J=8.1Hz,1H),6.86–6.81(m,2H),6.05–5.97(m,1H),5.16–5.08(m,3H),3.98(s,3H),3.41(d,J=6.7Hz,2H),1.98(d,J=6.8Hz,3H),-2.77(s,2H).Purity:96.02%,HRMS:C57H45N4O4 for[M+H]+,calculated849.3440,found 849.3498.
6c:Yield:68.4%,1H NMR(500MHz,Chloroform-d)δ8.89–8.88(m,8H),8.24(d,J=7.0Hz,8H),7.82–7.76(m,9H),7.52(d,J=7.9Hz,2H),6.94(d,J=7.9Hz,1H),6.79–6.77(m,2H),6.04–5.96(m,1H),5.14–5.07(m,2H),4.25(t,J=6.1Hz,2H),3.94(s,3H),3.38(d,J=6.7 Hz,2H),3.03(t,J=7.3 Hz,2H),2.45–2.40(m,2H),-2.76(s,2H).Purity:99.33%,HRMS:C58H47N4O4 for[M+H]+,calculated 863.3596,found 863.3578.
6d:Yield:62.7%,1H NMR(500 MHz,Chloroform-d)δ8.87–8.86(m,8H),8.23(d,J=7.1 Hz,8H),7.81–7.74(m,9H),7.49(d,J=7.5 Hz,2H),6.89(d,J=8.4 Hz,1H),6.76–6.75(m,2H),6.02–5.94(m,1H),5.12–5.05(m,2H),4.18–4.14(m,2H),3.91(s,3H),3.36(d,J=6.7 Hz,2H),2.86(t,J=6.8 Hz,2H),2.14–2.08(m,4H),-2.78(s,2H).Purity:98.89%,HRMS:C59H49N4O4 for[M+H]+,calculated 877.3752,found 877.3777.
6e:Yield:64.0%,1H NMR(500 MHz,Chloroform-d)δ8.87–8.86(m,8H),8.22(d,J=7.2 Hz,8H),7.81–7.74(m,9H),7.49(d,J=7.5 Hz,2H),6.90–6.83(m,2H),6.74–6.73(m,1H),6.02–5.92(m,1H),5.11–5.04(m,2H),4.11–4.07(m,2H),3.89(s,3H),3.35(d,J=6.7Hz,2H),2.80(s,2H),2.03–1.97(m,4H),1.75–1.73(m,2H),-2.78(s,2H).Purity:99.34%,HRMS:C60H51N4O4 for[M+H]+,calculated 891.3908,found 891.3882.
7a:Yield:74.3%,1H NMR(500 MHz,Chloroform-d)δ8.86–8.84(m,8H),8.20(d,J=8.1 Hz,2H),8.13(d,J=7.8 Hz,6H),7.75(d,J=8.2 Hz,6H),7.53(d,J=8.1 Hz,2H),7.06(d,J=8.2 Hz,1H),6.85–6.80(m,2H),6.04–5.95(m,1H),5.14–5.09(m,4H),3.98(s,3H),3.40(d,J=6.8 Hz,2H),-2.86(s,2H).Purity:91.48%,HRMS:C56H40Cl3N4O4 for[M+H]+,calculated 937.2115,found 937.2093.
7b:Yield:42.6%,1H NMR(500 MHz,Chloroform-d)δ8.86–8.84(m,8H),8.19(d,J=8.0 Hz,2H),8.13(d,J=7.9 Hz,6H),7.75(d,J=7.8 Hz,6H),7.47(d,J=7.9 Hz,2H),7.10(d,J=8.1 Hz,1H),6.85–6.80(m,2H),6.05–5.96(m,1H),5.15–5.08(m,3H),3.97(s,3H),3.40(d,J=6.6 Hz,2H),1.97(d,J=6.9 Hz,3H),-2.86(s,2H).Purity:92.21%,HRMS:
C57H42Cl3N4O4 for[M+H]+,calculated 951.2271,found 951.2366.
7c:Yield:41.5%,1H NMR(500 MHz,Chloroform-d)δ8.89–8.84(m,8H),8.20(d,J=8.0 Hz,2H),8.14(d,J=7.8 Hz,6H),7.75(d,J=7.8 Hz,6H),7.51(d,J=7.9 Hz,2H),6.94(d,J=8.2 Hz,1H),6.78–6.76(m,2H),6.03–5.94(m,1H),5.13–5.07(m,2H),4.25(t,J=6.2
Hz,2H),3.93(s,3H),3.37(d,J=6.6 Hz,2H),3.02(t,J=7.3 Hz,2H),2.44–2.39(m,2H),
-2.85(s,2H).Purity:97.47%,HRMS:C58H44Cl3N4O4 for[M+H]+,calculated965.2427,found965.2505.
7d:Yield:43.5%,1H NMR(500 MHz,Chloroform-d)δ8.89–8.84(m,8H),8.20(d,J=8.4 Hz,2H),8.14(d,J=8.0 Hz,6H),7.75(d,J=8.2 Hz,6H),7.50(d,J=8.4 Hz,2H),6.90(d,J=8.5 Hz,1H),6.77–6.75(m,2H),6.02–5.94(m,1H),5.12–5.04(m,2H),4.16(t,J=5.8Hz,2H),3.91(s,3H),3.36(d,J=6.7 Hz,2H),2.89–2.83(m,2H),2.14–2.07(m,4H),-2.85(s,2H).Purity:97.79%,HRMS:C59H46Cl3N4O4 for[M+H]+,calculated 979.2583,found979.2535.
7e:Yield:44.3%,1H NMR(500 MHz,Chloroform-d)δ8.84(s,8H),8.21(d,J=8.0Hz,2H),8.14(d,J=7.8 Hz,6H),7.75(d,J=7.8 Hz,6H),7.50(d,J=7.8 Hz,2H),6.88–6.84(m,2H),6.74(s,1H),6.01–5.92(m,1H),5.10–5.06(m,2H),4.11–4.07(m,2H),3.89(s,3H),3.34(d,J=6.7 Hz,2H),2.80(t,J=8.0 Hz,2H),2.03–1.97(m,4H),1.78–1.71(m,2H),-2.85(s,2H).Purity:99.14%,HRMS:C60H48Cl3N4O4 for[M+H]+,calculated 993.2739,found 993.2746.
8a:Yield:89.9%,1H NMR(500 MHz,Chloroform-d)δ8.95(s,8H),8.22(d,J=7.2Hz,8H),7.80–7.73(m,9H),7.50(d,J=8.0 Hz,2H),7.04(d,J=8.0 Hz,1H),6.84–6.80(m,2H),6.04–5.95(m,1H),5.14–5.08(m,4H),3.97(s,3H),3.39(d,J=6.8 Hz,2H).Purity:97.70%,HRMS:C56H41N4O4Zn for[M+H]+,calculated 897.2419,found 897.2414.
8b:Yield:91.0%,1H NMR(500 MHz,Chloroform-d)δ8.95(s,8H),8.22(d,J=6.8Hz,8H),7.80–7.73(m,9H),7.45(d,J=8.6 Hz,2H),7.10(d,J=8.1 Hz,1H),6.85–6.78(m,2H),6.04–5.94(m,1H),5.13–5.08(m,3H),3.96(s,3H),3.39(d,J=6.8 Hz,2H),1.95(d,J=6.9Hz,3H).Purity:98.82%,HRMS:C57H43N4O4Zn for[M+H]+,calculated 911.2575,found 911.2551.
8c:Yield:92.3%,1H NMR(500 MHz,Chloroform-d)δ8.96–8.95(m,8H),8.22(d,J=6.0 Hz,8H),7.80–7.74(m,9H),7.49(d,J=7.9 Hz,2H),6.93(d,J=8.3 Hz,1H),6.77–6.75(m,2H),6.02–5.94(m,1H),5.12–5.06(m,2H),4.23(t,J=6.3 Hz,2H),3.91(s,3H),3.36(d,J=6.8 Hz,2H),3.00(t,J=7.3 Hz,2H),2.43–2.38(m,2H).Purity:99.72%,HRMS:
C58H45N4O4Zn for[M+H]+,calculated 925.2731,found 925.2690.
8d:Yield:94.1%,1H NMR(500 MHz,Chloroform-d)δ8.97–8.95(m,8H),8.22(d,J=6.5 Hz,8H),7.80–7.73(m,9H),7.47(d,J=8.4 Hz,2H),6.88(d,J=8.3 Hz,1H),6.75–6.74(m,2H),6.01–5.93(m,1H),5.12–5.03(m,2H),4.18–4.12(m,2H),3.90(s,3H),3.35(d,J=6.7 Hz,2H),2.85(t,J=6.8 Hz,2H),2.12–2.07(m,4H).Purity:99.30%,HRMS:
C59H47N4O4Zn for[M+H]+,calculated 939.2887,found 939.2863.
8e:Yield:86.4%,1H NMR(500 MHz,Chloroform-d)δ8.96–8.95(m,8H),8.22(d,J=6.1 Hz,8H),7.80–7.73(m,9H),7.48(d,J=8.7 Hz,2H),6.86(d,J=8.2 Hz,1H),6.74–6.73(m,2H),6.00–5.92(m,1H),5.10–5.04(m,2H),4.09(t,J=6.6 Hz,2H),3.88(s,3H),3.34(d,J=6.7 Hz,2H),2.79(t,J=7.4 Hz,2H),2.02–1.96(m,4H),1.77–1.72(m,2H).
Purity:99.57%,HRMS:C60H49N4O4Zn for[M+H]+,calculated 953.3043,found953.3129.
9a:Yield:85.0%,1H NMR(500 MHz,Chloroform-d)δ8.96–8.94(m,8H),8.20(d,J=8.0 Hz,2H),8.14(d,J=7.9 Hz,6H),7.75(d,J=7.9 Hz,6H),7.52(d,J=8.1 Hz,2H),7.04(d,J=8.0 Hz,1H),6.84–6.78(m,2H),6.04–5.96(m,1H),5.15–5.07(m,4H),3.97(s,3H),3.39(d,J=6.7 Hz,2H).Purity:94.43%,HRMS:C56H38Cl3N4O4Zn for[M+H]+,calculated
999.1250,found 999.1365.
9b:Yield:93.2%,1H NMR(500 MHz,Chloroform–d)δ8.96-8.94(m,8H),8.19(d,J=6.6 Hz,2H),8.14(d,J=8.5 Hz,6H),7.75(d,J=8.0 Hz,6H),7.46(d,J=8.2 Hz,2H),7.10(d,J=8.2 Hz,1H),6.84–6.78(m,2H),6.04–5.96(m,1H),5.13–5.08(m,3H),3.96(s,3H),3.39(d,J=6.9 Hz,2H),1.96(d,J=6.9 Hz,3H).Purity:97.33%,HRMS:C57H40Cl3N4O4Zn for[M+H]+,calculated 1013.1406,found 1013.1512.
9c:Yield:93.2%,1H NMR(500 MHz,Chloroform-d)δ8.98–8.94(m,8H),8.20(d,J=7.9 Hz,2H),8.14(d,J=8.5 Hz,6H),7.75(d,J=7.8 Hz,6H),7.50(d,J=7.9 Hz,2H),6.93(d,J=8.3Hz,1H),6.77–6.76(m,2H),6.02–5.94(m,1H),5.12–5.06(m,2H),4.24(t,J=6.2Hz,2H),3.92(s,3H),3.36(d,J=6.7Hz,2H),3.01(t,J=7.3Hz,2H),2.43–2.38(m,2H).Purity:99.61%,HRMS:C58H42Cl3N4O4Zn for[M+H]+,calculated 1027.1562,found1027.1631.
9d:Yield:87.8%,1H NMR(500MHz,Chloroform-d)δ8.98–8.94(m,8H),8.20(d,J=8.3Hz,2H),8.14(d,J=8.2Hz,6H),7.75(d,J=8.2Hz,6H),7.48(d,J=8.3Hz,2H),6.88(d,J=8.3Hz,1H),6.75–6.74(m,2H),6.01–5.94(m,1H),5.11–5.06(m,2H),4.17–4.11(m,2H),3.90(s,3H),3.35(d,J=6.8Hz,2H),2.88–2.81(m,2H),2.14–2.07(m,4H).
Purity:99.49%,HRMS:C59H44Cl3N4O4Zn for[M+H]+,calculated 1041.1718,found1041.1700.
9e:Yield:93.8%,1H NMR(500MHz,Chloroform-d)δ8.98–8.94(m,8H),8.20(d,J=7.9Hz,2H),8.14(d,J=8.2Hz,6H),7.75(d,J=7.8Hz,6H),7.49(d,J=8.1Hz,2H),6.86(d,J=8.7Hz,1H),6.74–6.73(m,2H),6.00–5.92(m,1H),5.10–5.03(m,2H),4.09(t,J=6.7Hz,2H),3.88(s,3H),3.34(d,J=6.7Hz,2H),2.79(t,J=7.5Hz,2H),2.02–1.96(m,4H),1.77–1.70(m,2H).Purity:99.64%,HRMS:C60H46Cl3N4O4Zn for[M+H]+,calculated1055.1874,found 1055.1819.
实施例4单线态氧检测
1,3-二苯基苯并呋喃(DPBF)为一种单线态氧检测探针,可以检测卟啉化合物产生的单线态氧的速率和产量。DPBF结构如下所示,当存在单线态氧的情况下,会与单线态氧发生反应,生成二苯甲酰苯(DBB),产生的DBB不存在吸收,造成DPBF的结构改变而使得荧光信号的改变。因此,可以通过DPBF在463nm附近的荧光强度来判断单线态氧的生成能力,进一步来评价光动力疗法的效果。DPBF与1O2的反应机理如下:
DPBF溶液配制:精密称取1.35mg的DPBF,以1ml的氯仿作为溶剂溶解,稀释至250ml,配制成浓度为20μmol/L的溶液,避光保存待用。
标准样品溶液配制:称取适量标准化合物,以氯仿作为溶剂溶解,梯度稀释,配制成浓度为8μmol/L的溶液,避光放置待用。
待测化合物溶液配制:称取适量不同待测化合物,以氯仿作为溶剂溶解,梯度稀释,配制成浓度为8μmol/L的溶液,同样避光放置待用。
溶液配制好后,分别吸取等体积的DPBF溶液、标准溶液以及待测溶液,将DPBF溶液分别与标准溶液以及待测溶液摇匀混合,使用荧光分光光度计分别测定各组的初始吸光度,随后通过418nm的激光照射,产生单线态氧,然后每隔10s测定DPBF在463nm处的荧光强度。由于DPBF本身也会发生吸光度随时间而衰减的情况,因此也要对DBPF也进行荧光测定,将DPBF的浓度等体积稀释至10μmol/L测定,同时也要注意实验过程中控制溶液配制以及操作的时间。测试结果如说明书附图1-4所示。
考虑到DPBF本身在设置的光照刺激下有影响,因此进行了DPBF空白组的测试,发现DPBF也会存在一定的分解,但依旧保持较高的强度;随后将丁香酚原料与DPBF进行了混合检测,发现丁香酚的加入对DPBF荧光并没有影响;而加入合成的丁香酚-卟啉衍生物后DPBF的荧光发生明显变化,强度显著降低。DPBF荧光变化大小代表了物质的单线态氧的生成能力,荧光强度降得越低,说明单线态氧的产生能力越强,趋势下降越快,说明生成速率越快。
从图中可以发现卟啉母体以及目标化合物都有很好的单线态氧生成能力,卟啉母体与丁香酚-卟啉衍生物相比,单线态氧的生成能力没有太大差别,表明,丁香酚的键入,对卟啉的共轭体系没有影响。总体来说,相比于6、7系列的化合物,金属螯合后的8、9系列的化合物最开始的降低趋势比6、7系列的略大,说明其单线态氧的产生能力要略强于未金属化的化合物。
实施例5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。
5.1试剂配制
PBS溶液配制:将PBS磷酸盐缓冲剂倒入洁净的1L烧杯中,用量筒量取蒸馏水定容至1L刻度线,使用灭菌后的玻璃瓶对其进行分装,随后转入高压灭菌锅140℃灭菌,灭菌后的PBS溶液放置在4℃的冰箱中保存待用。
MTT探针溶液的配制:准确称取50mg MTT粉末,用灭菌后的PBS溶液10ml进行溶解,避光处理的同时使用超声机超声促进溶解,在经过紫外照射后的超洁净工作台上,用0.22μm的滤膜过滤除菌,随后进行分装密封,放置于-20℃的冰箱中避光保存待用。
培养基配制:胎牛血清和DMEM以1:9的比例配制并混合,在混合液中加入1%的青、链霉素混合液,混合均匀即得,封口膜封装保存待用。注意要现配现用。
5.2细胞复苏及培养
将装有A549细胞(非小细胞肺癌)/HepG2细胞(人肝癌细胞)的冻存管从-80℃冰箱中取出,把冻存管的2/3浸入到装有约37℃的温水中,轻轻摇晃冻存管,使肿瘤细胞充分解冻。待细胞解冻之后,转移至经过紫外光照射后的超洁净工作台,用移液枪将细胞转移到15mL的离心管中,放入离心机中离心五分钟后取出,去掉上清液。往细胞沉淀中加入1~2mL的培养基,吹打,使得细胞分散均匀。往新取的细胞培养瓶中加入3mL的培养基,用移液枪将细胞悬浮液转移至细胞培养瓶中,随后放置于5%CO2,37℃的恒温细胞培养箱中进行培养。
当在显微镜下观察到细胞长满培养瓶时,弃去原有培养基,吸取2~3mL的PBS溶液进行清洗,重复清洗3次,弃去PBS溶液,用移液枪吸掉残留的PBS溶液,接着吸取1mL的胰酶,消化30s(显微镜下观察到细胞变圆即可),迅速往培养瓶中加入2mL的培养基,移液枪吹打,制成细胞悬浮液后,转移至离心管再次离心,弃去上清液,加入3mL的培养基混匀成细胞悬浮液。往两个细胞培养瓶中加入3mL的培养基,将前面得到的细胞悬浮液分别转移至两个培养瓶中,混匀,放置于细胞培养箱中进行培养。
当在显微镜下观察到细胞长满培养瓶时,弃去原有培养基,吸取2~3mL的PBS溶液进行清洗,重复清洗3次,弃去PBS溶液,用移液枪吸掉残留的PBS溶液,接着吸取1mL的胰酶,消化30s(显微镜下观察到细胞变圆即可),迅速往培养瓶中加入2mL的培养基,移液枪吹打,制成细胞悬浮液后,转移至离心管再次离心,弃去上清液,加入3mL的培养基混匀成细胞悬浮液。另取加样槽加入13mL的培养基,吸取200μL的细胞混悬液加入至加样槽中,使用排枪吹打混匀。取96孔板,四周每孔加200μL的PBS溶液,吸取100μL含细胞的培养基加入到96孔板的其余孔中,放置于细胞培养箱中培养24h。
5.3细胞加药及OD值的测定
取出96孔板,弃去培养基。目标化合物浓度设置为128μmol/L、64μmol/L、32μmol/L、16μmol/L,每个浓度设三个复孔,往每孔中加入150μL的含药培养基。再设置两个对照组:空白组(培养基组)和阴性对照组(含DMAC的培养基组),两组均设置6个复孔。标记好A板(光照组)和B板(黑暗组),随后放置于培养箱中培养。24h后取出A、B板,用近红外光照射A板10min,B板不进行光照。光照结束后,每块孔板的复孔加入20μL新配的MTT溶液,放入培养箱继续培养4h。随后取出A、B板,弃去培养基,每个复孔加入150μL的DMSO,放置于摇床上摇晃10min后,使用酶标仪在490nm波长处测定其吸收值(OD值)。通过GraphPad Prism 6.0软件计算化合物的IC50值,每组实验平行进行三次。IC50结果=平均值±标准偏差。测试结果如下:
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由上班可知,本发明大部分卟啉-丁香酚衍生物对HepG2细胞和A549细胞的抑制作用要强于丁香酚原料,卟啉母体化合物4和化合物5。其中金属化后的目标化合物基本要比free-base卟啉化合物的活性要强,说明丁香酚与卟啉结合起到了很好的协同抗肿瘤作用。在光照条件下,化合物9a和9c对HepG2细胞的作用以及化合物8a、8c和9a对A549细胞的作用明显要强的多,表现出较好的光动力治疗作用。
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;
R1选自H,卤素,羟基,硝基,CN,C1-6烷基,C2-C6烯基,C2-C6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-C6烯基,C2-C6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:n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。
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: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。
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、R1、R的定义如权利要求1所述;
其中包括如下步骤:在有机溶剂中,加入碱和卟啉衍生物1,加热搅拌,将丁香酚衍生物2加入反应体系,直至反应完毕,经后处理得到式I的卟啉-丁香酚衍生物。
6.根据权利要求5所述的制备方法,其特征在于:
其中:卟啉衍生物1与丁香酚衍生物2的摩尔比为:1:(1-1.5),优选为1:1-1.2,更优选为1:1.2;
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、R1、R和M的定义如权利要求1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-丁香酚衍生物。
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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