CN113072588B - 一类含有青蒿琥酯的四价铂配合物及其制备方法与应用 - Google Patents
一类含有青蒿琥酯的四价铂配合物及其制备方法与应用 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明公开了一类含有青蒿琥酯的四价铂配合物,结构如通式I或II所示:R为R1为支链或直链的饱和的C1~C20烷基、支链或直链的不饱和的C1~C20烷基。本发明提供的一类含有青蒿琥酯的四价铂配合物,对肝癌HepG2、肺癌A549、肠癌HCT116、乳腺癌MDA‑MB‑231和顺铂耐药肺癌均产生了较为明显的增殖抑制作用,部分化合物的抗肿瘤活性明显优于顺铂,可作为抗肿瘤的候选药物进行更加深入的研究。
Description
技术领域
本发明属于医药技术领域,具体涉及一类含有青蒿琥酯的四价铂配合物、制备方法及其在制备抗肿瘤药物中的应用。
背景技术
铂类抗肿瘤药物在临床上广泛用于恶性肿瘤的治疗。目前,美国FDA已批准三种铂类药物上市,包括顺铂、卡铂和奥沙利铂。顺铂临床上对卵巢癌、前列腺癌、睾丸癌、肺癌、鼻咽癌、食道癌、恶性淋巴瘤、头颈部鳞癌、甲状腺癌及成骨肉瘤等多种实体肿瘤均能显示疗效。卡铂是第二代铂类药物,为广谱抗肿瘤药,与其他抗肿瘤药无交叉耐药性,与顺铂有交叉耐药性,主要用于小细胞肺癌、卵巢癌、睾丸肿瘤、头颈部鳞癌等。奥沙利铂是第三代铂类药物,对大肠癌、卵巢癌有较好疗效,对胃癌、非霍奇金淋巴瘤、非小细胞肺癌、头颈部肿瘤有一定疗效。铂类抗肿瘤药物是我国肿瘤病人使用最为广泛的化疗药物,但长期使用易产生耐药性、并存在肾毒性、胃肠道不良反应、血液毒性等副作用。将二价的铂类药物氧化成四价铂,进一步在结构上引入其他抗肿瘤药效基团是近年来新型铂类抗肿瘤药物的热点研发领域。文献已报道抗炎药物如阿司匹林、萘普生等引入到四价铂中会发挥很好的协同抗肿瘤效果,具有毒副作用低、裸鼠体内抗肿瘤效果更优等优势。
青蒿琥酯临床上广泛用于恶性疟疾的治疗。近年来,青蒿琥酯也被报道有抗肿瘤活性。抗肿瘤机制表明青蒿琥酯结构中含有的过氧桥结构,能够产生氧自由基,提高肿瘤细胞内的活性氧,诱导肿瘤细胞铁死亡和诱导肿瘤细胞凋亡。目前,青蒿琥酯正进行I期临床实验用于转移性乳腺癌(NCT00764036)和II期临床试验用于结直肠癌(NCT03093129)的辅助治疗。尽管青蒿琥酯表现独特的抗肿瘤机制,但其抗肿瘤活性还比较低,对多种肿瘤细胞株的IC50为几十μM,难以单独开发成抗肿瘤药物。
公开号为CN105906667A的专利申请报道了R3为羟基取代或青蒿琥酯双取代的四价铂配合物,但它们的抗肿瘤活性较低,对测试的多株肿瘤细胞的IC50范围为6.72μM~30.3μM,总体表现与顺铂相当。
发明内容
本发明的目的是提供一类含有青蒿琥酯的四价铂配合物,此类化合物具有全新的骨架结构和优异的抗肿瘤活性,能够用于制备抗肿瘤药物。
本发明的第二个目的是提供一种所述含有青蒿琥酯的四价铂配合物的制备方法。
本发明的第三个目的是提供一种所述含有青蒿琥酯的四价铂配合物在制备抗肿瘤药物中的应用。
为了实现上述目的,本发明采用的技术方案如下:
本发明的第一方面提供了一类含有青蒿琥酯的四价铂配合物,结构如通式I或II所示:
R为
R1为支链或直链的饱和的C1~C20烷基、支链或直链的不饱和的C1~C20烷基。
术语烷基是指含1至20个碳原子的直链或支链饱和或不饱和脂肪烃基团,例如:甲基、乙基、丙基、异丙基、丁基、叔丁基、乙烯、丙烯等。
较优选的,所述通式I或II中,R1为-CH3、-CH2CH3、-CH(CH3)2、-(CH2)2CH3、-(CH2)4CH3、-(CH2)5CH3、-(CH2)6CH3、-(CH2)10CH3、-(CH2)12CH3、-(CH2)13CH3、-CH=CHCH3、-(CH2)7CH=CH(CH2)7CH3。
最优选的,所述含有青蒿琥酯的四价铂配合物为以下结构中的一种:
本发明的第二方面提供了一种所述含有青蒿琥酯的四价铂配合物的制备方法,包括以下步骤:
将化合物III中加入过量的30%的双氧水,在20~60℃的条件下反应1~4h,抽滤,滤液静置得到黄色针状固体即化合物IV;
将摩尔比为1:3的化合物V与丁二酸酐溶于乙腈溶剂中,室温搅拌反应过夜,柱层析纯化(石油醚:乙酸乙酯=5:1)制备得到青蒿琥酯即化合物VI;
将摩尔比为1:1.15:1.15的化合物VI、TBTU和三乙胺依次加入干燥的DMF中,室温搅拌1~30min,加入化合物IV,化合物IV与化合物VI的摩尔比为1:1.18,氮气保护下室温搅拌1~16h,反应结束后,蒸干溶剂,残留物用硅胶柱层析(DCM:MeOH=20:1)进行纯化,得到化合物VII;
将摩尔比为1:1.2的化合物VII和酸酐或异氰酸酯依次加入DMF中,在室温下搅拌反应1~16h;反应结束后,蒸干溶剂,残留物用硅胶柱层析进行纯化,得到化合物I;
将摩尔比为1:1.15:1.15的化合物VI、TBTU和三乙胺依次加入干燥DMF中,室温搅拌1~30min,加入化合物VIII,化合物VIII与化合物VI的摩尔比为1:1.18,氮气保护下室温搅拌1~16h,反应结束后,蒸干溶剂,残留物用硅胶柱层析进行纯化,得到化合物IX;
将摩尔比为1:1.2的化合物IX和酸酐或异氰酸酯依次加入DMF中,在室温下搅拌反应1~16h;反应结束后,蒸干溶剂,残留物用硅胶柱层析进行纯化,得到化合物II;
所述酸酐为乙酸酐、正己酸酐、正辛酸酐、月桂酸酐、肉豆蔻酸酐、棕榈酸酐、油酸酐;
所述异氰酸酯为异氰酸己酯。
本发明的第三方面提供了一种所述含有青蒿琥酯的四价铂配合物在制备抗肿瘤药物中的应用。
所述含有青蒿琥酯的四价铂配合物优选为化合物5、化合物6、化合物7或化合物8。
所述肿瘤为肺癌、肠癌、乳腺癌、肝癌、顺铂耐药的肺癌等恶性肿瘤。
由于采用上述技术方案,本发明具有以下优点和有益效果:
针对目前二价铂类抗肿瘤药物与青蒿琥酯在抗肿瘤治疗中存在副作用大、活性低等技术问题,本发明提供了一类含有青蒿琥酯的四价铂配合物,该配合物能够充分利用两者的优势,利用青蒿琥酯独特的抗肿瘤机制,解决铂类药物的耐药性,发挥优异的协同抗肿瘤效果。
本发明提供的一类含有青蒿琥酯的四价铂配合物,对肝癌HepG2、肺癌A549、肠癌HCT116、乳腺癌MDA-MB-231和顺铂耐药肺腺癌均产生了较为明显的增殖抑制作用,部分化合物的抗肿瘤活性明显优于顺铂,可作为抗肿瘤的候选药物进行更加深入的研究。如化合物6总体表现出最优的抗肿瘤活性,对肺癌A549、肝癌HepG2、肠癌HCT116和乳腺癌MDA-MB-231的半数抑制浓度IC50都低于1μM。此外,部分高活性化合物对顺铂耐药的A549肿瘤细胞仍表现优异的抗肿瘤活性。如化合物5、6和7对顺铂耐药的A549的IC50低于7μM,明显优于顺铂(IC50=44.77μM)。本发明提供的化合物具有全新的骨架结构,具有优异的抗肿瘤活性,可以进行抗肿瘤药物的开发。
本发明提供的含有青蒿琥酯的四价铂配合物的合成路线简单,合成原料易得、合成方法容易实现。
本发明的大部分化合物的体外抗肿瘤活性要明显优于文献CN105906667A报道的化合物1与2。如本申请的化合物5和6对肺癌A549的活性数据IC50分别为0.55μM和0.46μM,对肝癌HepG2的活性数据IC50分别为1.08μM和0.67μM。而文献CN105906667A报道的化合物1和化合物2对肺癌A549的活性数据分别为10.45μM和6.72μM,对肝癌HepG2的活性数据IC50分别为8.68μM和7.93μM。本申请的化合物5和6比该文献中的化合物的活性数据高出6.2~22.7倍。因此,本申请的化合物抗肿瘤活性有了明显提高。
具体实施方式
为了更清楚地说明本发明,下面结合优选实施例对本发明做进一步的说明。本领域技术人员应当理解,下面所具体描述的内容是说明性的而非限制性的,不应以此限制本发明的保护范围。
下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。
以下实施例制备的化合物的化学结构式、1H-NMR、13C-NMR和HRMS数据详见表1,其中编号1~9分别对应实施例1~9制备的化合物1~9。
表1.目标化合物1~8的化学结构式、1H-NMR、13C-NMR和HRMS数据
实施例1
化合物1的合成:
取1.0g顺铂即化合物III加入25mL 30%的双氧水,在60℃下反应2h,抽滤,滤液静置得到黄色针状固体0.95g氧铂即化合物IV,收率为85%。
将1.0g二氢青蒿素即化合物V(3.5mmol)与1.05g丁二酸酐(10.5mmol)溶于20mL乙腈溶剂中,室温搅拌反应过夜,柱层析纯化(石油醚:乙酸乙酯=5:1)制备得到青蒿琥酯即化合物VI,白色固体1.05g。
将青蒿琥酯即化合物VI(50mg,0.13mmol)、TBTU(48mg,0.15mmol)和三乙胺(15mg,0.15mmol)依次加入2mL干燥的DMF中,室温搅拌10min,加入氧铂即化合物IV(36mg,0.11mmol),氮气保护下室温搅拌12h。反应结束后,蒸干溶剂,残留物用硅胶柱层析(DCM:MeOH=20:1)进行纯化,得到化合物VII,白色固体(32mg,收率42%)。化合物VII的核磁数据与高分辨质谱数据如下。1H NMR(400MHz,DMSO-d6):0.78(d,J=7.0Hz,3H),0.89(d,J=6.2Hz,3H),0.94(m,1H),1.16-1.22(m,1H),1.29(s,3H),1.33(m,1H),1.46(br,2H),1.54-1.65(m,3H),1.82(br,1H),2.00(d,J=14.2Hz,1H),2.19(t,J=14.2Hz,1H),2.30(br,1H),2.55(br,4H),5.56(s,1H),5.67(d,J=9.7Hz,1H),5.92(br,6H).13C NMR(100MHz,DMSO-d6):δ11.83,20.03,21.02,24.16,25.49,29.96,30.74,31.62,33.67,35.87,35.94,44.56,51.10,79.85,90.56,91.57,103.55,171.37,179.18.HRMS(ESI positive)m/z calcd forC19H35Cl2N2O9Pt(M+H):700.1367;found 700.1371.
将化合物VII(30mg,0.042mmol)和乙酸酐(5.5mg,0.051mmol)依次加入2mL的DMF中,在室温下搅拌反应12小时。反应结束后,蒸干溶剂,残留物用硅胶柱层析(DCM:MeOH=20:1)进行纯化,得到淡黄色固体化合物1(25mg,收率78%)。
实施例2
化合物2的合成
参照实施例1的方法步骤,将化合物VII(30mg,0.042mmol)和正己酸酐(11mg,0.051mmol)在DMF(2mL)中反应,得到淡黄色固体化合物2(22mg,收率64%)。
实施例3
化合物3的合成
参照实施例1的方法步骤,将化合物VII(30mg,0.042mmol)与正辛酸酐(15mg,0.055mmol)在DMF(2mL)中反应,得到淡黄色固体化合物3(23mg,收率65%)。
实施例4
化合物4的合成
参照实施例1的方法步骤,将化合物VII(30mg,0.042mmol)与异氰酸己酯(6.5mg,0.051mmol)在DMF(2mL)中反应,得到淡黄色固体化合物4(28mg,收率79%)。
实施例5
化合物5的合成
参照实施例1的方法步骤,将化合物VII(30mg,0.042mmol)与月桂酸酐(21mg,0.055mmol)在DMF(2mL)中,60℃下搅拌12h。反应结束后,蒸干溶剂,残留物用硅胶柱层析(DCM/MeOH=20:1)进行纯化,得到淡黄色固体化合物5(23mg,收率61%)。
实施例6
化合物6的合成
参照实施例1的方法步骤,将化合物VII(30mg,0.042mmol)和肉豆蔻酸酐(22mg,0.051mmol)在DMF(2mL)中反应,得到淡黄色固体化合物6(19mg,收率49%)。
实施例7
化合物7的合成
参照实施例1的方法步骤,将化合物VII(30mg,0.042mmol)与棕榈酸酐(27mg,0.055mmol)在DMF(2mL)中反应,得到淡黄色固体化合物7(24mg,收率72%)。
实施例8
化合物8的合成
参照实施例1的方法步骤,将化合物VII(30mg,0.042mmol)与油酸酐(30mg,0.055mmol)在DMF(2mL)中反应,得到淡黄色固体化合物8(22mg,收率54%)。
实施例9
化合物9的合成
参照实施例1的方法步骤,将青蒿琥酯即化合物VI(50mg,0.13mmol)、TBTU(48mg,0.15mmol)和三乙胺(15mg,0.15mmol)依次加入2mL的干燥DMF中,室温搅拌10min。加入氧化卡铂即化合物VIII(45mg,0.11mmol),室温搅拌12h。反应结束后,蒸干溶剂,残留物用硅胶柱层析(DCM/MeOH=20:1)进行纯化,得到化合物IX,为白色固体36mg,收率42%。
参照实施例1的方法步骤,将化合物IX 30mg(0.0389mmol)与乙酸酐4.8mg(0.0467mmol)在2mL DMF中室温反应,制备得到化合物9,淡黄色固体(25mg,0.031mmol),收率为79%。
实施例10
本发明化合物的抗肿瘤活性试验
对本发明的化合物进行肿瘤细胞增殖抑制试验,试验方法采用常规的CKK-8法。
细胞株选用肺癌A549、肝癌HepG2、肠癌HCT116、乳腺癌MDA-MB-231和顺铂耐药的肺癌A549,均购自上海生命科学研究院细胞库。培养液为DMEM+10%NBS+双抗。
样品液配制:待测化合物用DMSO(Merck)溶解后,配成浓度为10mM的母液。用培养基稀释母液,配成药物的最终浓度分别为50μM、25μM、10μM、5μM、1μM、0.5μM、0.25μM和0.125μM。
公开号为CN105906667A的专利申请报道的R3为羟基取代或青蒿琥酯双取代的四价铂配合物,本申请经过制备得到,以同样的条件配成对照品溶液,在表2中化合物编号分别为10和11。其中化合物10即为实施例1中的中间体VII。经HPLC和1H-NMR检测,两个化合物的纯度大于98%。将抗肿瘤化合物顺铂、二氢青蒿素、青蒿琥酯及顺铂与青蒿琥酯1:1混合物以同样的条件配成对照品溶液。
化合物10和化合物11的结构如下所示:
96孔板每孔加入浓度为8×104个/mL的细胞悬液100μL,即8000个细胞/孔,置37℃、5%CO2培养箱内。24小时后,上层培养液吸掉,加入含有样品的培养液和对照品液,100μL/孔,37℃作用72小时。每孔加入CKK-8 10μL,置培养箱内,作用1小时后用MK-2全自动酶标仪测570nm OD值,计算半数抑制浓度IC50。
部分优选化合物的抗肿瘤活性详见表2,其中,样品1~9是指相应实施例中制备的含有青蒿琥酯的四价铂配合物,如化合物1表示在实施例1中所得到的化合物,同理类推。
表2.本发明部分化合物对肿瘤细胞的半数抑制浓度IC50(单位:μM)
表2中结果显示,本申请的化合物总体表现出广谱、优异的抗肿瘤活性,对肝癌HepG2、肺癌A549、肠癌HCT116、乳腺癌MDA-MB-231均产生了优异的增殖抑制作用。部分化合物的抗肿瘤活性强于顺铂。如化合物6总体表现出最优的抗肿瘤活性,对肺癌A549、肝癌HepG2、肠癌HCT116和乳腺癌MDA-MB-231的半数抑制浓度IC50都低于1μM。此外,部分高活性化合物对顺铂耐药的A549肿瘤细胞仍表现优异的抗肿瘤活性。如化合物5、6和7对顺铂耐药的A549的IC50低于7μM,明显优于顺铂(IC50=44.77μM)。此外,这类化合物的抗肿瘤活性要优于青蒿琥酯与顺铂的联用。大部分化合物的活性明显优于文献CN105906667A报道的化合物1和2(表2中对应化合物10与11)。因此,本发明提供的化合物具有全新的骨架结构,具有优异的抗肿瘤活性,可以进行抗肿瘤药物的开发。
本申请的全新结构类型的含有青蒿琥酯的四价铂配合物,抗肿瘤活性筛选发现,该类化合物的抗肿瘤活性要明显优于顺铂及青蒿琥酯与顺铂的联用,优于文献CN105906667A已报道的R3为羟基取代或青蒿琥酯双取代的四价铂配合物。如化合物5和6对测试的多种肿瘤细胞株的IC50范围分别为0.46μM~4.42μM和0.23μM~6.73μM。
本申请的大部分化合物的体外抗肿瘤活性要明显优于文献CN105906667A报道的化合物1与2。如本申请的化合物5和6对肺癌A549的活性数据IC50分别为0.55μM和0.46μM,对肝癌HepG2的的活性数据IC50分别为1.08μM和0.67μM。而文献CN105906667A报道的化合物1和化合物2对肺癌A549的活性数据分别为10.45μM和6.72μM,对肝癌HepG2的的活性数据IC50分别为8.68μM和7.93μM。本申请的化合物5和6比该文献中的化合物的活性数据高出6.2~22.7倍。因此,本申请的化合物抗肿瘤活性有了明显提高。
以上所述仅是本发明的较佳实施例而已,并非对本发明作任何形式上的限制,虽然本发明已以较佳实施例揭露如上,然而并非用以限定本发明,任何熟悉本专利的技术人员在不脱离本发明技术方案范围内,当可利用上述提示的技术内容作出些许更动或修饰为等同变化的等效实施例,但凡是未脱离本发明技术方案的内容,依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与修饰,均仍属于本发明方案的范围内。
Claims (4)
1.一类含有青蒿琥酯的四价铂配合物,其特征在于,所述含有青蒿琥酯的四价铂配合物为以下结构中的一种:
2.一种权利要求1所述的含有青蒿琥酯的四价铂配合物在制备抗肿瘤药物中的应用。
3.根据权利要求2所述的含有青蒿琥酯的四价铂配合物在制备抗肿瘤药物中的应用,其特征在于,所述肿瘤为肺癌、肠癌、乳腺癌、肝癌。
4.根据权利要求3所述的含有青蒿琥酯的四价铂配合物在制备抗肿瘤药物中的应用,其特征在于,所述肿瘤为顺铂耐药的肺癌。
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CN105906667A (zh) * | 2016-04-26 | 2016-08-31 | 中国科学院长春应用化学研究所 | 一种具有抗癌活性的化学物质及其制备方法与应用 |
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1520823A (zh) * | 2003-02-12 | 2004-08-18 | 恒 沈 | 一种新型的抗肿瘤药物复方制备方法 |
CN105906667A (zh) * | 2016-04-26 | 2016-08-31 | 中国科学院长春应用化学研究所 | 一种具有抗癌活性的化学物质及其制备方法与应用 |
CN109021026A (zh) * | 2018-07-18 | 2018-12-18 | 浙江大学 | 顺铂药物前体、制备方法和应用 |
Non-Patent Citations (2)
Title |
---|
Towards rational design of RAD51-targeting prodrugs: platinumIV–artesunate conjugates with enhanced cytotoxicity against BRCA-proficient ovarian and breast cancer cells;Shuren Zhang et al.;《Chem. Commun.》;第54卷;第11717-11720页 * |
作为抗肿瘤药物的小分子四价铂;谭晓晓 等;《化学进展》;第30卷(第6期);第831-846页 * |
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