CN117143076A - 喹喔啉修饰的萘酰亚胺-多胺缀合物及其制备方法和应用 - Google Patents
喹喔啉修饰的萘酰亚胺-多胺缀合物及其制备方法和应用 Download PDFInfo
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- CN117143076A CN117143076A CN202311124402.8A CN202311124402A CN117143076A CN 117143076 A CN117143076 A CN 117143076A CN 202311124402 A CN202311124402 A CN 202311124402A CN 117143076 A CN117143076 A CN 117143076A
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- Prior art keywords
- quinoxaline
- acid
- naphthalimide
- polyamine
- modified
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Abstract
本发明属于药物合成技术领域,具体涉及一种喹喔啉修饰的萘酰亚胺‑多胺缀合物及其制备方法和应用。本发明的喹喔啉修饰的萘酰亚胺‑多胺缀合物,为式Ⅰ所示的化合物或其药学上可接受的盐:本发明提供的上述化合物,采用喹喔啉对萘酰亚胺的萘环6‑位直接进行结构修饰,制备药效团,然后将该药效团与多胺缀合。试验证实,喹喔啉修饰基团具有良好的生物安全性,并且上述化合物对于多种肿瘤细胞的生长具有显著的抑制作用,同时能够有效抑制肿瘤细胞转移。因此,本发明能够为开发安全高效的抗肿瘤药物提供理论依据和物质基础。
Description
技术领域
本发明属于药物合成技术领域,具体涉及一种喹喔啉修饰的萘酰亚胺-多胺缀合物及其制备方法和应用。
背景技术
喹喔啉,别名1,4-二氮萘,化学式为C8H6N2,常用作有机合成试剂和抗结核药物吡嗪酰胺的中间体。近年来,喹喔啉因具有广泛的生理活性,在药学及药理学领域引起了十分广泛的关注。研究学者通过对喹喔啉进行结构修饰和改造开发合成了大量的新结构化合物,如能抑制癌症干细胞的醌霉素A(Quinomycin A),其结构上拥有一对特征性喹喔啉结构片段,可选择性插入到DNA分子的碱基对之间,通过抑制DNA的复制和转录发挥抗肿瘤活性。另外,FDA批准上市治疗丙型肝炎的药物艾诺全(Mavyret)的主要成分为格卡瑞韦(glecaprevir),也含有喹喔啉片段。2019年FDA批准上市用于铂类化疗期间或化疗后出现局部晚期或转移性尿路上皮癌药物厄达替尼(Erdafitinib)的核心结构骨架也是喹喔啉。因此喹喔啉结构基团被验证具有良好的生理活性。
萘酰亚胺类化合物作为抗肿瘤试剂,目前已有多种化合物分子进入临床研究,代表性化合物氨萘菲特曾进入临床三期研究,但由于氨萘菲特的萘环5-位的氨基被乙酰化后会产生不可预知的毒性,导致其未能成功上市。因此该类化合物合成及氨萘菲特的结构修饰一直是药物化学家们研究的热点之一。多胺为一种具有多种生理活性的含氮小分子,其与萘酰亚胺的缀合物已被证明具有体内外的抗肿瘤活性,并且多胺能有效定位至细胞亚器,其存在能赋予萘酰亚胺药效团一定新的生理活性。
公布号为CN112300125A的发明专利申请公开了一种萘酰亚胺-多胺缀合物及其制备方法和用途,其采用苯基吡唑、氨基-喹唑啉对萘酰亚胺-多胺中萘环的不同位进行结构修饰,同时证实了所得化合物对于MDA-MB-231(乳腺癌细胞)、HCT-116(人结肠癌细胞)、HepG2(人肝癌细胞)三种肿瘤细胞株的抗肿瘤效果。
然而,长期试验探究发现,针对萘酰亚胺-多胺缀合物进行结构修饰时,不同的萘环修饰位置、不同的修饰药效基团、不同的多胺种类,均会对化合物的抗肿瘤活性和作用效果造成不可预估的影响。而探索更多新型结构的萘酰亚胺-多胺缀合物,提高其对于不同肿瘤细胞的抗肿瘤效果,对新型抗肿瘤药物的研发以及相关疾病的研究治疗具有重要意义。
发明内容
本发明的目的之一在于提供一种喹喔啉修饰的萘酰亚胺-多胺缀合物,其对于Sun739、MCF-7、PC-12、HepG2肿瘤细胞的生长具有显著的抑制作用,并且能够有效抑制肿瘤细胞的迁移。
本发明的目的之二在于提供一种喹喔啉修饰的萘酰亚胺-多胺缀合物的制备方法,其合成路径新颖,产物得率高。
本发明的目的之三在于提供一种喹喔啉修饰的萘酰亚胺-多胺缀合物的应用,利用喹喔啉修饰的萘酰亚胺-多胺缀合物制备的相关药物,能够起到有效的肿瘤细胞抑制活性,并且能够有效抑制肿瘤细胞迁移。
本发明的目的之一,采用如下技术方案实现:
一种喹喔啉修饰的萘酰亚胺-多胺缀合物,为式Ⅰ所示的化合物或其药学上可接受的盐:
式Ⅰ中,m为1、2或3;R选自 中的一种。
基于进一步提高化合物对肿瘤细胞抑制活性的考虑,作为进一步优选的方案,m为2,R为或者,m为3,R为/>
进一步地,所述药学上可接受的盐为盐酸盐、硫酸盐、马来酸盐、磷酸盐、枸橼酸盐、氢溴酸盐、醋酸盐、苯磺酸盐、酒石酸盐、碳酸盐、柠檬酸盐、苹果酸盐、甲磺酸盐、硬脂酸盐、戊酸盐、硝酸盐中的一种或多种。
本发明的目的之二,采用如下技术方案实现:
喹喔啉修饰的萘酰亚胺-多胺缀合物的制备方法,目标产物为式Ⅰ所示的化合物药学上可接受的盐时,制备方法包括如下步骤:
步骤(1):将与乙酰氯反应,然后分离纯化,得到/>
步骤(2):将与重铬酸钾反应,过滤,得到/>
步骤(3):将与N-溴代琥珀酰亚胺反应,然后分离纯化,得到
步骤(4):将与/>反应,过滤,得到/>
步骤(5):将与胺链R′NH2反应,纯化后得到/>
步骤(6):将与酸混合进行反应,过滤,得到式Ⅰ所示的化合物药学上可接受的盐;
目标产物为式Ⅰ所示的化合物时,制备方法除包括所述步骤(1)~步骤(6)外,还包括将步骤(6)所得式Ⅰ所示化合物药学上可接受的盐进行中和反应以得到式Ⅰ所示的化合物的步骤;
其中,所述胺链R′NH2选自 中的一种。
优选地,步骤(1)中反应在二氯甲烷中进行;步骤(2)中反应在冰醋酸中进行;步骤(3)中反应在乙腈中进行;步骤(4)中反应在含有10%吡啶的四氢呋喃溶液中进行;步骤(5)中反应在乙醇中进行;步骤(6)中反应在无水乙醇中进行。
作为进一步优选的方案,步骤(3)中,与N-溴代琥珀酰亚胺的反应摩尔比为2︰1;步骤(4)中,/>与/>的反应摩尔比为1︰1。
将化合物进行成盐反应制备得到药学上可接受的盐,有助于液态药物剂型的制备,能够提高化合物的溶解度以及生物利用度。优选地,步骤(6)中,所述酸为盐酸、硫酸、马来酸、磷酸、枸橼酸、氢溴酸、醋酸、苯磺酸、酒石酸、碳酸、柠檬酸、苹果酸、甲磺酸、硬脂酸、戊酸、硝酸中的一种或多种。
进一步地,步骤(6)中,所述酸为浓度为4mol/L的盐酸。
本发明的目的之三,采用如下技术方案实现:
如上所述的喹喔啉修饰的萘酰亚胺-多胺缀合物在制备抗肿瘤药物中的应用。
优选地,所述抗肿瘤药物为抑制肿瘤细胞生长或迁移的药物。
进一步地,所述肿瘤细胞为Sun739细胞、MCF-7细胞、PC-12细胞、HepG2细胞中的一种或多种。
本发明的有益效果在于:
(1)本发明的喹喔啉修饰的萘酰亚胺-多胺缀合物,采用喹喔啉对萘酰亚胺的萘环6-位直接进行结构修饰,同时缀合多胺基团,由此构建得到了一类新型的萘酰亚胺-多胺缀合物。本发明的化合物,由于不含氨萘菲特萘环的5-位氨基,能够避免氨萘菲特中5-位氨基被乙酰化后产生的不可预知毒性,同时喹喔啉修饰基团也具有良好的生物安全性。并且试验证实本发明提供的喹喔啉修饰的萘酰亚胺-多胺缀合物,对于多种肿瘤细胞的生长活性具有显著的抑制作用。因此,本发明能够为开发安全高效的抗肿瘤药物提供理论依据和物质基础。
(2)本发明的喹喔啉修饰的萘酰亚胺-多胺缀合物的制备方法,以苊为原料,通过邻苯二胺与萘酰亚胺萘环6-位乙酰基环化,合成喹喔啉修饰的萘酰亚胺新药效团,然后与多胺进行缀合,设计得到喹喔啉修饰的萘酰亚胺-多胺缀合物。本发明的上述制备方法,合成路径新颖,条件温和,制备得到的化合物在保持萘酰亚胺类化合物的活性的同时,也兼具了喹喔啉类化合物的特性,改善了原有分子的生物学活性,提高了目标分子的抗肿瘤活性。
(3)本发明以喹喔啉修饰萘酰亚胺萘环制备新药效团,然后与多胺缀合设计合成喹喔啉修饰的萘酰亚胺-多胺缀合物,对其进行抗肿瘤活性评价试验证实:本发明化合物对Sun739(人肝癌细胞)、MCF-7(人乳腺癌细胞)、PC-12(大鼠肾上腺嗜铬细胞瘤细胞)和HepG2(人肝癌细胞)多种肿瘤细胞的增殖均显示出明显的抑制活性。并且,动物试验证实,本发明化合物能够有效抑制肿瘤细胞的迁移,而且不会对动物体重和脏器指数产生不良影响。因此本发明提供的化合物能够用于抗肿瘤药物的制备,也能够为开发新的抗肿瘤药物或抗肿瘤先导化合物提供更多的结构选择。
附图说明
图1为本发明实施例3化合物对肝癌细胞HepG2迁移能力的影响结果图;
图2为本发明实施例3化合物以及对照组化合物作用后,H22肝癌小鼠的肺转移图片、以及肺转移抑制率、肺转移结节数的结果图;
图3为本发明实施例3化合物以及对照组化合物对H22肝癌小鼠治疗7天后生长体重和器官指数的影响结果图。
具体实施方式
以下结合具体实施例对本发明的技术方案做进一步详细说明,但本发明的保护范围并不局限于此。以下实施例中采用的原料和试剂,若无特殊说明,均为可通过市售渠道获得的常规材料。
以下实施例提及的喹喔啉修饰的萘酰亚胺-多胺缀合物,为式Ⅰ所示的化合物或其药学上可接受的盐:
式Ⅰ中,m为1、2或3;R选自 中的一种。
具体地,以下实施例1~7提供的喹喔啉修饰的萘酰亚胺-多胺缀合物,为式Ⅰ所示的化合物的盐酸盐形式,结构式记为:
m为1、2或3;R选自
中的一种;·XHCl表示化合物连接的盐酸基团,X表示盐酸的数目,X的数值取1、2或3。
由于赋予化合物抗肿瘤活性的是化合物自身固有的结构,是否成盐以及成盐的种类只是改变了化合物的溶解性,不影响化合物的本质活性。因此,在其他的实施例中,喹喔啉修饰的萘酰亚胺-多胺缀合物,也可直接为式Ⅰ所示的化合物。在另外的实施例中,喹喔啉修饰的萘酰亚胺-多胺缀合物,也可以是式Ⅰ所示的化合物的硫酸盐、马来酸盐、磷酸盐、枸橼酸盐、氢溴酸盐、醋酸盐、苯磺酸盐、酒石酸盐、碳酸盐、柠檬酸盐、苹果酸盐、甲磺酸盐、硬脂酸盐、戊酸盐、硝酸盐中的一种或多种,其在保证溶解性能的基础上能够达到与盐酸盐相似的应用效果。
以下实施例1~7的喹喔啉修饰的萘酰亚胺-多胺缀合物(即式Ⅰ所示的化合物的盐酸盐)的制备方法,具体的工艺路线图如下:
各实施例化合物的制备方法主要包括如下步骤:
步骤(1):将与乙酰氯反应,然后分离纯化,得到/>
步骤(2):将与重铬酸钾反应,过滤,得到/>
步骤(3):将与N-溴代琥珀酰亚胺反应,然后分离纯化,得到
步骤(4):将与/>反应,过滤,得到/>
步骤(5):将与胺链R′NH2反应,纯化后得到
步骤(6):将与盐酸混合进行反应,过滤,得到式Ⅰ所示的化合物的盐酸盐;
其中,所述胺链R’NH2选自 中的一种。
实施例1
本实施例的喹喔啉修饰的萘酰亚胺-多胺缀合物,为式Ⅰ所示的化合物的盐酸盐,m为2,R为X为2。具体结构式如下:
本实施例的喹喔啉修饰的萘酰亚胺-多胺缀合物的制备方法,具体步骤如下:
一、中间产物5(胺链R′NH2 )的合成
实施例1涉及的中间产物5的合成路线图如下。其他实施例中涉及的胺链R′NH2可参照下述实施例1的合成路线及步骤合成,部分常见结构也可通过市售渠道进行购买。
(1)取无水碳酸钾2.01g(15mmol),吗啉0.92g(10mmol)置于含有25mL乙腈的烧瓶中,室温搅拌15min后升温至45℃,然后分批加入3-溴丙基邻苯二甲酰亚胺1.79g(8mmol)并保持此温度反应12h。然后减压浓缩,残余物氯仿萃取,饱和Na2CO3水溶液洗涤,收集有机层,无水Na2SO4干燥,过滤减压浓缩得淡黄色油状物,柱层析分离(洗脱剂:V二氯甲烷:V甲醇=100:3),得到中间产物2。
(2)取1.00g(2.05mmol)中间产物2溶于30mL无水乙醇中,加水合肼0.52g(12.5mmol),室温搅拌12h,减压蒸除溶剂,残余物先用二氯甲烷萃取,再用质量分数10%的Na2CO3水溶液洗涤,收集有机层,浓缩得中间产物3,不需分离直接用于下步反应。
(3)取无水碳酸钾2.01g(15mmol)和1.96g(10mmol)中间产物3于25mL乙腈中,室温搅拌15min后升温至45℃,然后分批加入3-溴丙基邻苯二甲酰亚胺1.79(8mmol)并保持此温度反应12h。然后减压浓缩,残余物氯仿萃取,饱和Na2CO3水溶液洗涤,收集有机层,无水Na2SO4干燥,过滤,减压浓缩得淡黄色油状物。此油状物于30mL甲醇和15mmol(3.27g)二碳酸二叔丁酯混合液中,室温搅拌过夜后减压蒸除溶剂,残余物氯仿萃取,水洗,柱层析分离(洗脱剂V二氯甲烷:V甲醇=100:3),得到中间产物4。
(4)取1.00g(2.05mmol)中间产物4于30mL无水乙醇中,加水合肼0.52g(12.5mmol),室温搅拌12h,减压蒸除溶剂,残余物先用二氯甲烷萃取,再用质量分数10%的Na2CO3水溶液洗涤,收集有机层,浓缩得中间产物5(即胺链R′NH2 ),不需分离直接用于下步反应。
二、目标化合物的合成
目标化合物的合成路线如下:
(5)取6.48mmol(1g)苊(市售品)和1.30g(8.72mmol)无水AlCl3于干燥烧瓶中,加入二氯甲烷20mL,冰浴下搅拌15min后缓慢滴加6.80mmol(4.86mL)乙酰氯与5mL二氯甲烷混合溶液,加毕室温反应2h后倒入冰水中,二氯甲烷萃取水洗,收集有机层无水硫酸钠干燥,减压浓缩,残余物硅胶柱分离(洗脱剂V石油醚:V乙酸乙酯=6:1)纯化得棕色固体,收率62.32%,记为中间产物12。
(6)取1.96g(10.0mmol)中间产物12和7.45g(25.0mmol)的K2Cr2O7于25mL冰醋酸中,加热至回流反应6h冷至室温,反应液倒入50mL冰水中,减压抽滤,水洗至中性,干燥得淡黄色固体,产率81.57%,记为中间产物13。
(7)取1.20g(5.0mmol)中间产物13和0.88g(2.5mmol)N-溴代丁二酰亚胺(NBS)于25mL乙腈中,25℃下搅拌15min后加入对甲苯磺酸1.90g(10.0mmol),然后升温至回流反应5h后,减压蒸出溶剂,残余物硅胶柱分离(洗脱剂V石油醚:V乙酸乙酯=5:1)提纯得黄色固体,产率77.41%,记为中间产物14。
(8)取5mmol(0.54g)邻苯二胺和5mmol(1.59g)中间产物14于15mL的10%吡啶的THF溶液中,室温搅拌6h后有大量固体析出,反应结束,减压抽滤,THF洗涤,收集固体干燥得中间产物15,收率62.82%,不需纯化直接用于下步反应。
(9)取2.0mmol(0.652g)中间产物15于20mL乙醇中,加入中间体5(胺链)共2.5mmol,加热回流5h后减压蒸除溶剂,残余物硅胶柱分
离(洗脱剂:V二氯甲烷:V甲醇=100:3)纯化得中间产物16。
(10)取2mmol上步所得中间产物16溶于10mL重蒸无水乙醇中,缓慢滴加4M盐酸乙醇溶液,加毕后室温搅拌12h至有大量固体析出,减压抽滤,滤饼用无水乙醇洗涤,干燥滤饼即得式Ⅰ所示的化合物的盐酸盐,对应于实施例1的喹喔啉修饰的萘酰亚胺-多胺缀合物。
实施例1的喹喔啉修饰的萘酰亚胺-多胺缀合物为淡黄色固体,产率为57.34%。核磁表征结果为:1H NMR(500MHz,D2O):δ(ppm)7.84(s,1H,Ar-H),7.56(dd,J=18.81,7.34Hz,2H,Ar-H),7.45(d,J=6.83Hz,1H,Ar-H),7.17(t,J=7.41Hz,1H,Ar-H),7.09-6.95(m,2H,Ar-H),6.87(q,J=7.21,5.70Hz,2H,Ar-H),6.70(d,J=7.82Hz,1H,Ar-H),4.08(d,J=13.44Hz,2H,1×N-CH2),3.78(t,J=12.40Hz,4H,1×N-CH2),3.54(d,J=12.51Hz,2H,1×N-CH2),3.32-3.25(m,2H,1×N-CH2),3.18-3.06(m,4H,2×CH2),2.28-2.13(m,2H,1×CH2),1.93(q,J=7.51Hz,2H,1×CH2).13C NMR(125MHz,D2O):δ(ppm)164.0,163.6,149.5,143.9,139.2,137.9,131.9,131.1,130.9,130.7,129.9,129.0,128.0,127.5,126.7,126.6,126.3,120.6,119.7,63.8,53.8,51.9,45.6,44.6,20.5.ESI-MS m/z:664.81[M-2HCl+H]+.Elemental Analysis for C30H33Cl2N5O3:C 61.84%,H 5.71%,N 12.02%;found:C60.51%,H 5.79%,N 12.94%.
实施例2
本实施例的喹喔啉修饰的萘酰亚胺-多胺缀合物,为式Ⅰ所示的化合物的盐酸盐,m为2,R为X为1。具体结构式如下:
本实施例的喹喔啉修饰的萘酰亚胺-多胺缀合物的制备方法,制备步骤与实施例1的步骤(5)~(10)基本相同,区别仅在于:步骤(9)中采用代替其它合成及提纯方法同实施例1。
实施例2的喹喔啉修饰的萘酰亚胺-多胺缀合物为灰色固体,产率为72.15%。核磁表征结果为:1H NMR(500MHz,CDCl3):δ(ppm)9.20(s,1H,Ar-H),8.75(d,J=7.20Hz,1H,Ar-H),8.68(d,J=8.55Hz,1H,Ar-H),8.62(d,J=7.50Hz,1H,Ar-H),8.24-8.26(m,2H,Ar-H),8.06(d,J=7.50Hz,1H,Ar-H),7.89-7.91(m,2H,Ar-H),7.80(t,J=7.30Hz,1H,Ar-H),4.30(t,J=6.30Hz,2H,1×N-CH2),3.61(t,J=4.45Hz,4H,1×O-CH2),2.53(t,J=7.01Hz,2H,1×N-CH2),2.46(brs,4H,2×N-CH2),1.99-2.00(m,2H,1×CH2).13C NMR(125MHz,CDCl3):δ(ppm)163.7,163.4,151.9,145.7,141.7,141.5,140.6,131.9,131.3,130.8,130.7,130.3,129.8,129.6,129.5,129.2,128.9,123.3,122.7,53.6,45.2,38.3,28.4,27.7.ESI-MS m/z:453.20[M+H]+.Elemental Analysis forC27H24N4O3:C 71.67%,H 5.35%,N 12.38%;found:C71.485,H 5.06%,N 12.54%.
实施例3
本实施例的喹喔啉修饰的萘酰亚胺-多胺缀合物,为式Ⅰ所示的化合物的盐酸盐,m为3,R为X为2。具体结构式如下:
本实施例的喹喔啉修饰的萘酰亚胺-多胺缀合物的制备方法,制备步骤与实施例1的步骤(5)~(10)基本相同,区别仅在于:步骤(9)中采用代替其它合成及提纯方法同实施例1。
实施例3的喹喔啉修饰的萘酰亚胺-多胺缀合物为棕色固体,产率为50.2%。核磁表征结果为:1H NMR(500MHz,D2O):δ(ppm)7.91(s,1H,Ar-H),7.60(dd,J=7.01Hz,17.58Hz,2H,Ar-H),7.46(d,1H,J=5.52Hz,Ar-H),7.24(t,J=6.45Hz,1H,Ar-H),7.13(t,1H,J=6.48Hz,Ar-H),7.02(d,J=6.45Hz,1H,Ar-H),6.94(d,2H,J=5.35Hz,Ar-H),6.79(d,1H,J=6.32Hz,Ar-H),3.72(brs,10H,5×N-CH2),3.34(t,J=7.95Hz,2H,1×N-CH2),1.81-1.84(m,2H,1×CH2),1.50-1.53(m,2H,1×CH2).13C NMR(125MHz,D2O):δ(ppm)163.9,163.4,149.5,143.9,139.2,137.9,137.7,131.8,131.0,130.9,130.7,129.8,128.9,128.0,127.4,126.6,126.1,120.6,119.7,56.5,48.5,40.8,39.4,24.0,20.9.ESI-MS m/z:466.25[M-HCl+H]+.Elemental Analysis for C28H29Cl2N5O2:C62.45%,H 5.43%,N13.01%;found:C 62.28%,H 5.17%,N 12.88%.
实施例4
本实施例的喹喔啉修饰的萘酰亚胺-多胺缀合物,为式Ⅰ所示的化合物的盐酸盐,m为2,R为X为1。具体结构式如下:/>
本实施例的喹喔啉修饰的萘酰亚胺-多胺缀合物的制备方法,制备步骤与实施例1的步骤(5)~(10)基本相同,区别仅在于:步骤(9)中采用代替其它合成及提纯方法同实施例1。
实施例4的喹喔啉修饰的萘酰亚胺-多胺缀合物为棕色固体,产率为45.23%。核磁表征结果为:1H NMR(500MHz,DMSO-d6):δ(ppm)9.32(s,1H,Ar-H),8.67(d,J=8.55Hz,1H,Ar-H),8.62(d,1H,J=7.50Hz,Ar-H),8.55(d,J=7.15Hz,1H,Ar-H),8.19-8.23(m,3H,J=6.48Hz,Ar-H),8.00(brs,2H,NH2·HCl-H),7.95-7.97(m,2H,Ar-H),7.89(t,1H,J=7.80Hz,Ar-H),4.15(t,J=6.60Hz,2H,1×N-CH2),2.88-2.91(m,2H,1×N-CH2),1.99-2.05(m,2H,1×CH2).13C NMR(125MHz,DMSO-d6):δ(ppm)164.1,163.9,152.4,146.8,141.6,141.5,140.9,132.8,131.5,131.4,130.5,123.0,129.9,129.6,129.5,128.6,128.5,123.5,122.9,37.8,37.5,26.4.ESI-MS m/z:383.16[M-HCl+H]+.Elemental Analysis forC23H19ClN4O2:C 65.95%,H 4.57%,N 13.38%;found:C65.76%,H 4.31%,N 13.07%.
实施例5
本实施例的喹喔啉修饰的萘酰亚胺-多胺缀合物,为式Ⅰ所示的化合物的盐酸盐,m为2,R为X为2。具体结构式如下:
本实施例的喹喔啉修饰的萘酰亚胺-多胺缀合物的制备方法,制备步骤与实施例1的步骤(5)~(10)基本相同,区别仅在于:步骤(9)中采用代替/>其它合成及提纯方法同实施例1。
实施例5的喹喔啉修饰的萘酰亚胺-多胺缀合物为棕色固体,产率为57.43%,1HNMR(500MHz,D2O):δ(ppm)7.86(s,1H,Ar-H),7.58-7.62(m,2H,Ar-H),7.49(d,1H,J=6.85Hz,Ar-H),7.21(t,J=7.05Hz,1H,Ar-H),7.08(t,J=6.65Hz,1H,Ar-H),7.01(d,J=6.75Hz,1H,Ar-H),6.88-6.93(m,2H,Ar-H),6.71(d,1H,J=7.55Hz,Ar-H),3.86(brs,2H,1×N-CH2),3.25(t,J=7.95Hz,2H,1×N-CH2),3.17-3.21(m,4H,2×N-CH2),2.16-2.22(m,2H,1×CH2),1.98-2.00(m,2H,1×CH2).13C NMR(125MHz,D2O):δ(ppm)164.0,163.5,149.5,143.8,139.1,137.8,131.8,131.1,130.9,130.7,129.9,129.0,127.9,127.4,126.7,126.6,126.2,120.6,119.7,45.5,44.8,37.4,36.6,24.3,23.8.ESI-MS m/z:440.23[M-2HCl+H]+.Elemental Analysis for C26H27Cl2N5O2:C60.94%,H 5.31%,N 13.67%;found:C 61.21%,H 5.56%,N 13.94%.
实施例6
本实施例的喹喔啉修饰的萘酰亚胺-多胺缀合物,为式Ⅰ所示的化合物的盐酸盐,m为2,R为X为3。具体结构式如下:
本实施例的喹喔啉修饰的萘酰亚胺-多胺缀合物的制备方法,制备步骤与实施例1的步骤(5)~(10)基本相同,区别仅在于:步骤(9)中采用代替/>其它合成及提纯方法同实施例1。
实施例6的喹喔啉修饰的萘酰亚胺-多胺缀合物为棕色固体,产率43.22%,1H NMR(500MHz,D2O):δ(ppm)7.94(s,1H,Ar-H),7.71(d,J=7.95Hz,1H,Ar-H),7.67(d,1H,J=6.65Hz,Ar-H),7.57(d,J=7.05Hz,1H,Ar-H),7.28(t,J=7.05Hz,1H,Ar-H),7.17(t,J=7.00Hz,1H,Ar-H),7.10(d,J=7.00Hz,1H,Ar-H),7.01(t,J=7.25Hz,1H,Ar-H),6.96(d,J=7.95Hz,1H,Ar-H),6.82(d,J=7.75Hz,1H,Ar-H),3.90(brs,2H,1×N-CH2),3.13-3.23(m,10H,5×N-CH2),2.12-2.16(m,2H,2×CH2),1.98-2.03(m,2H,1×CH2),1.86(t,J=7.05Hz,4H,2×CH2).13C NMR(125MHz,D2O):δ(ppm)164.1,163.7,149.6,143.9,139.2,138.0,131.9,131.2,130.9,130.7,129.9,129.1,128.0,127.1,126.8,126.6,126.3,120.7,119.7,47.1,47.1,45.4,44.6,37.5,36.7,36.6,24.3,23.8,22.9.ESI-MS m/z:440.23[M-3HCl+H]+.Elemental Analysis for C26H27Cl2N5O2:C60.94%,H 5.31%,N13.67%;found:C 61.21%,H 5.56%,N 13.94%.
实施例7
本实施例的喹喔啉修饰的萘酰亚胺-多胺缀合物,为式Ⅰ所示的化合物的盐酸盐,m为1,R为X为1。具体结构式如下:
本实施例的喹喔啉修饰的萘酰亚胺-多胺缀合物的制备方法,制备步骤与实施例1的步骤(5)~(10)基本相同,区别仅在于:步骤(9)中采用N,N-二甲基乙二胺代替其它合成及提纯方法同实施例1。
实施例7的喹喔啉修饰的萘酰亚胺-多胺缀合物为灰色固体,产率为78.36%。核磁表征结果为:1H NMR(500MHz,D2O):δ(ppm)8.22(s,1H,Ar-H),7.92(d,J=7.30Hz,2H,Ar-H),7.88(d,1H,J=7.40Hz,Ar-H),7.48-7.51(m,1H,Ar-H),7.38-7.41(m,1H,Ar-H),7.33(d,J=7.40Hz,1H,Ar-H),7.29(d,J=8.20Hz,1H,Ar-H),7.16-7.19(m,2H,Ar-H),3.90(t,J=6.50Hz,2H,1×N-CH2),3.48(t,J=6.80Hz,2H,1×N-CH2),3.07(s,6H,2×CH3).13C NMR(125MHz,D2O):δ(ppm)164.5,164.0,150.0,144.3,139.7,138.8,138.6,132.3,131.6,131.1,130.4,129.2,128.1,127.7,127.4,127.1,126.9,121.0,120.1,55.0,43.4,35.3.ESI-MS m/z:397.18[M-HCl+H]+.Elemental Analysis for C24H21ClN4O2:C 66.59%,H 4.89%,N 12.94%;found:C 66.87%,H 4.68%,N 13.25%.
对比例1
对比例1的化合物,与实施例3化合物的区别在于:不采用喹喔啉修饰,化合物结构如下:
对比例2
对比例2的化合物,与实施例3化合物的区别在于:参考现有技术CN112300125A的部分基团,采用氨基-喹唑啉修饰萘酰亚胺-多胺缀合物中萘环的5-位,结构式如下:
对比例3
对比例3的化合物,具体结构如下:
对比例4
对比例4的化合物,具体结构如下:
/>
对比例5
对比例5的化合物,具体结构如下:
试验例1体外生物活性评价
化合物体外抑制肿瘤细胞生长活性测定:选择实施例1~7制备的喹喔啉修饰的萘酰亚胺-多胺缀合物,以及对比例1~5的化合物,并以氨萘菲特作为对照组,分别取对数生长期的Sun739(人肝癌细胞)、MCF-7(人乳腺癌细胞)和PC-12(大鼠肾上腺嗜铬细胞瘤细胞)和HepG2(人肝癌细胞)四种肿瘤细胞株,以每孔5000-8000个细胞埋入96孔板,90μL/孔。培养24h后,加入10、50、100、300、500μM的样品,对每个细胞株,每个浓度都有四个复孔,在37℃,5v%CO2条件下培养48h后,加MTT 50μL(即噻唑蓝),继续培养4h后弃上清,每孔加入100μL的DSMO,轻轻振荡15min,用酶标仪在570nm波长处测其吸光度A值。按下面的公式计算被测物对不同肿瘤细胞生长的抑制率,实验重复三次。结果如表1所示。
其中,肿瘤细胞生长抑制率(%)=(OD对照-OD实验)/(OD对照-OD空白)×100%
表1各实施例和对比例化合物对肿瘤细胞的生长抑制活性
由表1可知,实施例1~实施例7的化合物分别对Sun739(人肝癌细胞)、MCF-7(人乳腺癌细胞)和PC-12(大鼠肾上腺嗜铬细胞瘤细胞)和HepG2(人肝癌细胞)四种肿瘤细胞的细胞毒作用方面起着不同程度的作用。相比对照药物氨萘菲特,本发明的化合物在体外对多种肿瘤细胞的增殖显示出更明显的抑制活性。其中实施例1、3化合物对四种测试肿瘤细胞株的抑制能力均显著优于阳性对照氨萘菲特;实施例2、4化合物在高浓度下对四种测试肿瘤细胞株的抑制能力高于氨萘菲特,低浓度下和氨萘菲特相当;实施例5化合物对Sun739和PC-12两种肿瘤细胞株的抑制能力优于氨萘菲特,其中在30μM时对Sun739的抑制能力是氨萘非特的三倍。由此可知,以喹喔啉修饰萘酰亚胺萘环后提高了其与多胺缀合物的生理活性,此外在母核相同的情况下,酰亚胺侧链对活性也有不同程度的影响。
进一步由实施例3和对比例1~5对比可知,本发明采用喹喔啉修饰萘环6-位所得化合物,相较于未进行修饰的对比例1的化合物,以及采用现有技术中的氨基-喹唑啉修饰的对比例2化合物,以及对比例3~5采用其他基团修饰的化合物,能够显著提高化合物对肿瘤细胞活性的抑制作用。
综合而言,本发明提供的喹喔啉修饰的萘酰亚胺-多胺缀合物,能够有效抑制所测试肿瘤细胞株的活性,具有优良的成药性的潜力。
试验例2对肝癌细胞HepG2的运动能力的影响
在96孔板底部孔的中间用Marker笔画一条直线,取对数生长期的肝癌细胞HepG2用胰酶消化、离心、混悬,然后用移液枪吸取10μL滴在提前准备好的计数板上,显微镜下计数,然后以每孔46000个细胞接种于提前在孔底中间画有直线的96孔板中,于二氧化碳培养箱培养12小时,当细胞铺满96孔板底部约80%-90%时,用提前消毒过得牙签进行划痕。划后用血清RPMI 1640培养基洗一遍,然后加入无血清培养基90μL及不同浓度的本发明实施例3的化合物,使实施例3化合物的终浓度分别为2.5、5、7.5μM。显微镜下拍照,此时的时间记为0h,此时的宽度为W0;将细胞与二氧化碳培养箱中培养48小时,此时的时间记为48小时,宽度记为W48。根据如下公式计算迁移率:迁移率=[(W48-W0)/W0]×100%。结构如图1所示。图1中,*p<0.01,**p<0.01表示统计学分析结果具有显著差异。
由图1可知,实施例3化合物在处理HepG2细胞48h后,可显著减少细胞的迁移距离,抑制肿瘤细胞的划痕伤口愈合,且随着浓度的增加,其对肿瘤细胞迁移的抑制能力越强,存在剂量依赖性。
试验例3对H22肝癌小鼠肺转移以及体重、脏器指数的影响
将H22细胞腹腔注射于昆明种小鼠体内,7天后可见小鼠腹部有明显腹水,乙醚麻醉小鼠后颈椎脱臼处死,无菌条件下取生长良好的腹水,无菌生理盐水洗三次,台盼蓝法检测细胞活力(将0.1mL的0.2%台盼蓝染液加入到0.9mL细胞液中)并计活细胞数。以生理盐水稀释成单细胞悬液(1×107个/mL)备用。昆明小鼠尾部酒精消毒后尾静脉注射0.2mL肿瘤细胞悬液。次日,荷瘤小鼠随机分为3组,每组8只,分别为生理盐水组、本发明实施例3(3mg/kg,最大耐受量5mg/kg)组,氨萘非特(Amonafide,5mg/kg)组。每组小鼠均自由饮食,每日定时称量体重,为确保所有小鼠在给药前肿瘤平均生长,将其接种肿瘤后培养10天以创建肺转移小鼠模型。第十一天尾静脉给药(iv,0.1mL/10g小鼠体重/d),连续7天。第8天称重后乙醚麻醉以颈椎脱臼法处死小鼠,用解剖显微镜计数各肺叶的转移集落数,以下列公式计算肺转移抑制率:抑制率(%)=(1-治疗组平均肺集落数/对照组平均肺集落数)×100%。结果如图2所示。
由图2可知,本发明实施例3处理过的小鼠显示极少的肺转移结节,其肺转移抑制率高达62.65%;但生理盐水组小鼠肺部可看到较多的肿瘤转移结节;相比较而言,阳性对照氨萘非特在一定程度上降低了肺转移结节数,但效果显著低于本发明实施例3的化合物。
进一步地,分别称取小鼠的心、肝、脾、肺、肾重量,按以下公式计算小鼠脏器指数:OI=脏器重量/第8d小鼠体重,并记录小鼠每日体重差,小鼠每日体重差=第(n+1)天小鼠体重-第n天小鼠体重。所有实验均用PRISM软件进行统计学分析,实验所得数据采用均数±标准差(x±SD)表示。组间差异用Student’s t test检验或单因素方差分析(ANOVA)检测。p<0.05表示显著性差异,p<0.01表示极显著性差异。结果如图3所示。
进一步由图3可知,与生理盐水组相比,本发明实施例3化合物组和氨萘菲特组小鼠各脏器均无实质性变化,各个脏器指数均无明显改变。生理盐水组小鼠每日体重差异相对较大,氨萘非特组体重变化趋缓,但整体有所降低,而本发明实施例3组处理后,小鼠体重整体有所增加。
分析上述结果可知,本发明实施例3化合物,采用喹喔啉修饰萘酰亚胺的萘环6-位,同时以哌嗪为末端取代基的胺链修饰酰亚胺侧链,分子中引入了多个杂环氮原子及自由胺基上的氮原子,这是本发明实施例3化合物抗肿瘤活性优于氨萘菲特的原因。并且试验证实,本发明实施例3化合物在发挥肺转移抑制能力的同时,对小鼠的体重及脏器指数没有明显影响,也暗示本发明的喹喔啉修饰的萘酰亚胺药效团具有较低的毒性,生物安全性高。
综上可知,本发明提供的喹喔啉修饰的萘酰亚胺-多胺缀合物,采用喹喔啉对萘酰亚胺的萘环6-位直接进行结构修饰,同时缀合多胺基团。本发明的上述化合物,由于不含氨萘菲特萘环的5-位氨基,能够避免氨萘菲特中5-位氨基被乙酰化后产生的不可预知毒性,同时喹喔啉修饰基团也具有良好的生物安全性。进一步试验证实本发明提供的喹喔啉修饰的萘酰亚胺-多胺缀合物,对于多种肿瘤细胞的生长活性具有显著的抑制作用,并且能够抑制肿瘤细胞的迁移,且不会动物体重及脏器指数产生影响。因此,本发明能够为开发安全高效的抗肿瘤药物提供理论依据和物质基础。
Claims (10)
1.一种喹喔啉修饰的萘酰亚胺-多胺缀合物,其特征在于,为式Ⅰ所示的化合物或其药学上可接受的盐:
式Ⅰ中,m为1、2或3;R选自 中的一种。
2.如权利要求1所述的喹喔啉修饰的萘酰亚胺-多胺缀合物,其特征在于,m为2,R为或者,m为3,R为/>
3.如权利要求1所述的喹喔啉修饰的萘酰亚胺-多胺缀合物,其特征在于,所述药学上可接受的盐为盐酸盐、硫酸盐、马来酸盐、磷酸盐、枸橼酸盐、氢溴酸盐、醋酸盐、苯磺酸盐、酒石酸盐、碳酸盐、柠檬酸盐、苹果酸盐、甲磺酸盐、硬脂酸盐、戊酸盐、硝酸盐中的一种或多种。
4.如权利要求1所述的喹喔啉修饰的萘酰亚胺-多胺缀合物的制备方法,其特征在于,目标产物为式Ⅰ所示的化合物药学上可接受的盐时,制备方法包括如下步骤:
步骤(1):将与乙酰氯反应,然后分离纯化,得到/>
步骤(2):将与重铬酸钾反应,过滤,得到/>
步骤(3):将与N-溴代琥珀酰亚胺反应,然后分离纯化,得到
步骤(4):将与/>反应,过滤,得到/>
步骤(5):将与胺链R′NH2反应,纯化后得到
步骤(6):将与酸混合进行反应,过滤,得到式Ⅰ所示的化合物药学上可接受的盐;
目标产物为式Ⅰ所示的化合物时,制备方法除包括所述步骤(1)~步骤(6)外,还包括将步骤(6)所得式Ⅰ所示化合物药学上可接受的盐进行中和反应以得到式Ⅰ所示的化合物的步骤;
其中,所述胺链R′NH2选自 中的一种。
5.根据权利要求4所述的喹喔啉修饰的萘酰亚胺-多胺缀合物的制备方法,其特征在于,步骤(1)中的反应在二氯甲烷中进行;步骤(2)中的反应在冰醋酸中进行;步骤(3)中的反应在乙腈中进行;步骤(4)中的反应在含有10%吡啶的四氢呋喃溶液中进行;步骤(5)中的反应在乙醇中进行;步骤(6)中的反应在无水乙醇中进行;步骤(3)中,与N-溴代琥珀酰亚胺的反应摩尔比为2︰1;步骤(4)中,/>与/>的反应摩尔比为1︰1。
6.根据权利要求4所述的喹喔啉修饰的萘酰亚胺-多胺缀合物的制备方法,其特征在于,步骤(6)中,所述酸为盐酸、硫酸、马来酸、磷酸、枸橼酸、氢溴酸、醋酸、苯磺酸、酒石酸、碳酸、柠檬酸、苹果酸、甲磺酸、硬脂酸、戊酸、硝酸中的一种或多种。
7.根据权利要求4或6所述的喹喔啉修饰的萘酰亚胺-多胺缀合物的制备方法,其特征在于,步骤(6)中,所述酸为浓度为4mol/L的盐酸。
8.如权利要求1所述的喹喔啉修饰的萘酰亚胺-多胺缀合物在制备抗肿瘤药物中的应用。
9.如权利要求8所述的喹喔啉修饰的萘酰亚胺-多胺缀合物在制备抗肿瘤药物中的应用,其特征在于,所述抗肿瘤药物为抑制肿瘤细胞生长或迁移的药物。
10.如权利要求9所述的喹喔啉修饰的萘酰亚胺-多胺缀合物在制备抗肿瘤药物中的应用,其特征在于,所述肿瘤细胞为Sun739细胞、MCF-7细胞、PC-12细胞、HepG2细胞中的一种或多种。
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