CN114230616B - 一种癌细胞靶向的抗癌Pt配合物及其制备方法与应用 - Google Patents
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- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0086—Platinum compounds
- C07F15/0093—Platinum compounds without a metal-carbon linkage
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Abstract
Description
技术领域
本发明涉及抗癌化学药物技术领域,尤其是涉及一种癌细胞靶向的铂(IV)配合物及其制备方法与应用。
背景技术
四价铂Pt(IV)是铂经过氧化后得到的产物,与二价铂Pt(II)相比Pt(IV)是八面体构型,具有药代动力学惰性,可以提高在血液中的稳定性,延长铂的作用时间,提高抗肿瘤活性,为开发口服铂类药物提供了方向,Pt(IV)易于进行化学修饰,它的两个轴向部位可以引入不同的活性分子,在癌细胞中与二价铂Pt(II)产生协同作用,更好地发挥抗肿瘤的效果。
炎症与肿瘤的发生、发展具有相关性,它们通过内源性及外源性两条通路相互联系,炎症调节因子和效应细胞是肿瘤组织局部微环境的重要组成,肿瘤微环境中的炎症有多种促肿瘤作用,可以促进恶性细胞的增殖和存活,促血管新生和转移,削弱机体的获得性免疫反应,改变机体对激素和化疗药物的反应。
早在上世纪八十年代,硝基咪唑及其衍生物就已被作为肿瘤显像剂进行研究。由于该类化合物分子具有亲脂性,很容易通过弥散作用进入细胞。在细胞内多种硝基还原酶的作用下,有效基团(RNO2)发生还原,产生中性的自由基阴离子(RNO2 –•)。在正常氧浓度的细胞中,由于氧(还原电位为155 mV)比连接咪唑环的硝基(还原电位-554mV~ -389 mV)亲电子能力更强,自由基阴离子被氧化为RNO2,扩散到细胞外;而在乏氧细胞中,由于氧浓度较低,未发生氧化的自由基阴离子被进一步还原为羟胺(RNHOH),并与蛋白质等大分子发生共价结合而滞留在胞内。
发明内容
针对现有技术存在的上述问题,本发明提供了一种癌细胞靶向的抗癌Pt配合物及其制备方法与应用。本发明将乏氧靶向基团硝基咪唑和对氨基苯酚引入四价铂母核,设计合成了一系列新型四价铂类化合物,可作为对多种肿瘤有效的先导分子,解决了传统二价铂类药物存在的缺陷,也为四价铂类化合物的修饰开辟新的途径。此类源头上创新药物研究,对国民经济和社会发展及人民健康等都将具有重要的理论价值和实际意义。
本发明的技术方案如下:
一种癌细胞靶向的抗癌Pt配合物,所述配合物的结构如通式(1)或通式(2)所示:
顺铂、卡铂、庚铂、奈达铂、奥沙利铂和米铂均为常用的二价铂抗肿瘤药物,其均可氧化为结构相近的四价铂,作为四价铂抗肿瘤药物其化学性质相近。卡铂、庚铂、奈达铂、奥沙利铂和米铂均是在顺铂的基础上进行的改造,这些铂与顺铂具有相似的平面结构,两个惰性胺和两个离去基团,进入体内后水解活化,作用于DNA的碱基对发挥作用,以顺铂为代表的结构改造后的抗癌Pt配合物将于其他二价铂发挥相似的抗肿瘤疗效。
一种所述抗癌Pt配合物的制备方法,所述制备方法包括如下步骤:
将通式(4)所示化合物与2.0-4.0eq式(8)所示化合物加入到二甲亚砜中,加热到40-60 ℃,反应12-48h反应结束后,加入甲醇析晶,过滤收集固体,真空干燥,得到通式(1)所示配合物。
式(8)所示化合物的制备方法为:
(1)将对氨基酚与0.8-1.2eq氯乙酸甲酯或溴乙酸甲酯溶于水和乙醇的混合溶剂中,加入0.8-3.0eq碱,25-100℃下搅拌反应得到式(5)所示化合物;
(2)将氯甲酸苯酯和0.8-1.2eq 3-甲基-2-硝基咪唑-4-甲醇盐酸盐溶解在四氢呋喃中,加入0.8-3.0eq碱,0-80℃下搅拌反应得到式(6)所示化合物;
(3)将式(5)所示化合物和0.8-1.2eq式(6)所示化合物加入四氢呋喃中,加入0.8-3eq碱,0-100℃搅拌反应,反应完全后,加入1.0-3.0eq的氢氧化钠、氢氧化钾或氢氧化锂,0-100℃水解,得到式(7)所示化合物;
(4)将式(7)所示化合物溶解在二氯甲烷中,加入0.8-1.5eq N-羟基丁二酰亚胺、0.8-1.5eq N,N'-二环己基碳二亚胺,0-40℃下搅拌反应,过滤,滤液减压蒸干,得到式(8)所示化合物。
一种所述抗癌Pt配合物的制备方法,所述制备方法包括如下步骤:
将通式(4)所示化合物与2.0-4.0eq式(7)所示化合物、2.0-4.0eq O-苯并三氮唑-N ,N ,N′,N′-四甲基脲四氟硼酸TBTU、2.0-6.0eq三乙胺混合在DMF溶液中,搅拌混合均匀;加热到40-60 ℃搅拌反应,待反应结束后,过滤除去沉淀物,减压浓缩,然后加入甲醇,离心收集沉淀,然后用甲醇、乙醚洗涤沉淀,真空干燥即可得到通式(2)所示化合物。
通式(4)所示化合物的制备方法为:将通式(3)所示化合物与双氧水H2O2反应,获得通式(4)所示化合物;通式(3)所示化合物与双氧水的质量体积比为1:40-80g/mL;双氧水的浓度为30-35%。
一种所述抗癌Pt配合物在制备抗肿瘤药物中的应用。
本发明有益的技术效果在于:
本发明的Pt(IV)配合物将对氨基苯酚和乏氧靶向基团硝基咪唑与四价铂改造成一个分子,可提高铂类药物的抗肿瘤疗效,靶向肿瘤细胞,减少对正常细胞的毒副作用。其中:
1、炎症与肿瘤的发生、发展具有相关性,在抗癌的同时抗炎,会得到更高的抗肿瘤效果;
2、Pt(IV)配合物具有靶向肿瘤细胞作用,同时对正常细胞的毒副作用小;
3、Pt(IV)配合物对肿瘤细胞具有相对顺铂更高的细胞毒性。
本发明的Pt(IV)配合物的制备方法操作简单,目标产物产率高。
具体实施方式
下面实施例,对本发明进行具体描述。
实施例1
抗癌Pt(IV)配合物e的制备方法合成路线如下:
(1)式(5)化合物的制备
将1.00 g对氨基苯酚(a1,9.17 mmol)与0.995 g氯乙酸甲酯(9.17 mmol)加入到30ml乙醇溶液中,冰浴下滴加0.97g碳酸钠(9.17 mmol)的水溶液(10ml),加毕,升温至65oC反应过夜,TLC检测反应完全后,减压蒸除大部分乙醇,水相用柠檬酸水溶液调节至pH为5-6,乙酸乙酯萃取两次,合并有机相,有机相用无水硫酸钠干燥,过滤,减压蒸干,得到1.0g白色固体,即式(5)化合物,收率60%;1H-NMR (400 MHz, CDCl3): δ(ppm) 6.82-6.71 (m,2H), 6.68-6.57 (m, 2H), 4.56 (s, 2H), 3.79 (s, 3H), 3.45 (br, 2H).
(2)式(6)化合物的制备
将1.0 g化合物b1(5.16 mmol)和三乙胺1.6 g (15.48mmol)加入到20 ml四氢呋喃溶液中,冰浴下分批加入1.62 g氯甲酸苯酯(10.32 mmol),加毕,升温至常温反应过夜,TLC检测反应完全后,加入乙酸乙酯,水洗,有机相蒸干,柱层析(PE/EA),得到无色油状物1.1g,即式(6)化合物,收率77%,1H-NMR (400 MHz, DMSO-d6): δ(ppm) 7.33(s, 1H),7.32-7.30 (m, 2H), 7.24-7.18 (m, 3H), 5.58(s, 2H), 3.62 (s, 3H).
(3)式(7)化合物的制备
将0.927 g式(5)化合物 (5.12 mmol)与1.42 g式(6)化合物 (5.12 mmol)溶解在20 ml THF溶液中,加入1.55g三乙胺(15.36 mmol),25 oC下反应过夜,反应结束后,加入40mL乙酸乙酯,水洗,有机相减压蒸干,用20 ml甲醇溶解,加入0.25g LiOH的水溶液(5 ml),25 oC下反应过夜,反应结束后,1N HCl调节pH至5-6左右,减压蒸干,柱层析(DCM/MeOH),得到0.97g黄色固体,即式(7)化合物,收率54%,1H-NMR (400 MHz, DMSO-d6): δ(ppm) 12.10(br, 1H), 7.53(d, J=7.2Hz, 2H), 7.33(s,1H),6.83(d,J=7.2Hz, 2H), 6.51(br, 1H),5.45 (s, 2H), 4.57 (s, 2H), 3.72(s, 3H).
(4)式(8)化合物的制备
将0.50 g式(7)化合物 (1.43mmol)、0.18 g N-羟基丁二酰亚胺(1.57mmol)、0.32g N,N'-二环己基碳二亚胺(1.57mmol)溶解在10 ml DCM溶液中,25 oC下反应过夜,反应结束后,加入10 mL乙酸乙酯,过滤,母液减压蒸干,得到黄色固体,即式(8)化合物粗品,直接用于下一步。
(5)化合物e的制备
将式(8)化合物粗品、0.38 g配合物e1 (1.14mmol)加入 10 ml DMSO溶液中, 45oC下反应过夜,反应结束后,加入10 mL乙酸乙酯和50 mL甲基叔丁基醚,搅拌,倾出上层清液,加入10 mL甲醇,有固体析出,搅拌,过滤,收集固体,固体减压蒸干,得到褐色固体配合物e。
通过1H NMR、13C NMR、MS对所得的褐色固体产物进行表征,所得到的数据如下:
1H-NMR (400 MHz, DMSO-d6): δ(ppm) 7.53(d, J=7.2Hz, 2H), 7.33(s, 1H),6.83(d, J=7.2Hz, 2H), 6.51(br, 1H), 6.11-5.85(m, 6H), 5.45 (s, 2H), 4.57 (s,2H), 3.72(s, 3H).
13C-NMR (400 MHz, DMSO-d6): δ (ppm) 171.10, 156.20, 153.32, 152.35,137.99, 130.13, 127.73, 122.61, 114.63, 66.70, 56.96, 31.25.
ESI-MS (negative mode, m/z) found (calcd) for [M]‒: 664.21 (664.04).
由上述1H NMR、13C NMR、MS分析结果可以确认:本实施例成功制得了所述Pt(IV)配合物e。
实施例2
抗癌Pt(IV)配合物f的制备方法合成路线如下:
将283 mg化合物e1(0.85 mmol)与10 mL干燥的DMF混合,依次加入892 mg式(7)化合物c(2.55 mmol)、257mg三乙胺(2.55 mmol)和 817 mg TBTU (2.55 mmol),加毕,常温下搅拌48 h,反应结束后,过滤去除沉淀,将滤液浓缩至5 mL左右,加入甲醇析晶,过滤,滤饼用甲醇和乙醚各洗涤两次,减压烘干,得淡黄色固体化合物f。
通过1H NMR、13C NMR和MS对所得的淡黄色固体产物进行表征,所得到的数据如下:
1H-NMR (400 MHz, DMSO-d6): δ(ppm) 7.56(d, J=7.2Hz, 4H), 7.35(s, 2H),6.82(d, J=7.2Hz, 4H), 6.52(br, 2H), 6.11-5.85(m, 6H), 5.46 (s, 4H), 4.55 (s,4H), 3.73(s, 6H).
13C-NMR (400 MHz, DMSO-d6): δ (ppm) 171.16, 156.19, 153.32, 152.35,137.99, 130.13, 127.73, 122.61, 114.63, 66.70, 56.96, 31.25.
ESI-MS (negative mode, m/z) found (calcd) for [M]‒: 996.16 (996.11).
由上述1H NMR、13C NMR和MS结果可以确认:本实施例成功制得了所述Pt(IV)配合物f。
测试例体外抗肿瘤活性的测定
体外抗肿瘤活性测定采用MTT法(四甲基偶氮唑盐比色法)完成,选用人体3株癌细胞A2780、 HT-1080、 A549 和人体肾胚细胞Hek293,所有细胞株均在5%CO2浓度下,37℃饱和湿度的培养箱中培养。具体实验步骤如下:
S1、收集上述对数期细胞,调整细胞悬液的浓度,加入96孔板中,每孔细胞数约5000;
S2、将上述实验细胞置于CO2浓度为5%的细胞培养箱中,37℃培养12h;
S3、将实施例化合物和顺铂按一定梯度倍数用含10%FBS的培养基稀释,加入上述植入细胞的96孔板中,每个浓度设3个复孔,孵化48h;
S4、每孔加入20μL的MTT溶液(5mg/mL),继续孵化4h,吸取培养基,每孔加150μL的DMSO,摇床低速震荡10min;
S5、酶标仪570nm处检测每个孔的吸光度值;
S6、同时设置调零孔和对照组(培养基、DMSO),按以下公式计算细胞存活率:
其中,Abs(sample)为样品组细胞的吸光度值;Abs(blank)为空白对照组中液体的吸光度值;Abs(control)为未经过药物处理的对照组细胞的吸光度值;
S7、作出细胞存活率-浓度曲线,计算化合物的半抑制浓度(IC50),结果见表1。
表1为本发明实施例配合物以及顺铂对不同细胞的IC50值(48h)
由表1,可以看出本发明Pt(IV)配合物对卵巢癌细胞、人纤维肉瘤细胞、肺癌细胞毒性明显强于顺铂,尤其是配合物f对上述癌细胞毒性是顺铂的三倍左右。同时,对正常细胞人体肾胚细胞的毒性,明显小于顺铂,其中配合物f对正常细胞的毒性只有顺铂的四分之一左右,达到了治疗作用增强同时副作用降低的双重效果。
Claims (6)
3.根据权利要求2所述的癌细胞靶向的抗癌Pt配合物的制备方法,其特征在于,式(8)所示化合物的制备方法为:
(1)将对氨基酚与0.8-1.2eq氯乙酸甲酯或溴乙酸甲酯溶于水和乙醇的混合溶剂中,加入0.8-3.0eq碱,25-100℃下搅拌反应得到式(5)所示化合物;
(2)将氯甲酸苯酯和0.8-1.2eq 3-甲基-2-硝基咪唑-4-甲醇盐酸盐溶解在四氢呋喃中,加入0.8-3.0eq碱,0-80℃下搅拌反应得到式(6)所示化合物;
(3)将式(5)所示化合物和0.8-1.2eq式(6)所示化合物加入四氢呋喃中,加入0.8-3eq碱,0-100℃搅拌反应,反应完全后,加入1.0-3.0eq的氢氧化钠、氢氧化钾或氢氧化锂,0-100℃水解,得到式(7)所示化合物;
(4)将式(7)所示化合物溶解在二氯甲烷中,加入0.8-1.5eq N-羟基丁二酰亚胺、0.8-1.5eq N,N'-二环己基碳二亚胺,0-40℃下搅拌反应,过滤,滤液减压蒸干,得到式(8)所示化合物。
5.根据权利要求2或4所述的癌细胞靶向的抗癌Pt配合物的制备方法,其特征在于,通式(4)所示化合物的制备方法为:将通式(3)所示化合物与双氧水H2O2反应,获得通式(4)所示化合物;通式(3)所示化合物与双氧水的质量体积比为1:40-80g/mL;双氧水的浓度为30-35%。
6.一种权利要求1所述癌细胞靶向的抗癌Pt配合物在制备抗肿瘤药物中的应用。
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