CN109053782A - 多功能靶向免疫小分子抗癌药枸橼酸Bestazomib及其制备方法与应用 - Google Patents
多功能靶向免疫小分子抗癌药枸橼酸Bestazomib及其制备方法与应用 Download PDFInfo
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- CN109053782A CN109053782A CN201810902222.0A CN201810902222A CN109053782A CN 109053782 A CN109053782 A CN 109053782A CN 201810902222 A CN201810902222 A CN 201810902222A CN 109053782 A CN109053782 A CN 109053782A
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Abstract
本发明公开了一种多功能靶向免疫小分子抗癌药枸橼酸Bestazomib及其制备方法与应用,所述多功能靶向免疫小分子抗癌药枸橼酸Bestazomib的结构如下:本发明的多功能靶向免疫小分子抗癌药枸橼酸Bestazomib对APN/CD13具有抑制活性,同时对肿瘤蛋白酶体也具有抑制活性,可用于恶性肿瘤治疗药物的开发。
Description
技术领域
本发明涉及药物化学技术领域,具体涉及一种多功能靶向免疫小分子抗癌药枸橼酸Bestazomib及其制备方法与应用。
背景技术
氨肽酶N(APN/CD13)是一种II型跨膜锌离子依赖性金属蛋白酶,属于M1家族的Gluzincins亚族,以同源二聚体糖蛋白的形式结合于细胞膜(Nucleic Acids Res.,1999,27(1):325-331)。APN在多种组织的细胞表面都有表达,例如中枢神经系统突触细胞、滑膜液成纤维细胞、活化的内皮细胞、肝细胞、肠粘膜上皮细胞、胎盘、骨髓始祖细胞、单核细胞、破骨细胞等,尤其在肾脏和肠刷状缘细胞大量富集(Haema.,2003,4(6):453-461)。此外,相比较于正常细胞,APN在多种肿瘤细胞如黑色瘤、卵巢癌、前列腺癌、结肠癌、胰腺癌、乳腺癌、肺癌等细胞表面高水平表达。
近年来,全世界多个实验室大量实验研究已经证明:氨肽酶N(APN/CD13)是人肝癌干细胞表面生物标志物,与肝癌的化疗耐药,复发和转移密切相关(J Clin Invest2010,120,3326-3339);APN/CD13已被证明介导肿瘤微环境中新生血管的生成(PNAS2007,104(11):4588-4593;2012,109(5):1637-1642)。APN/CD13在肿瘤微环境中起重要作用,它通过影响肿瘤组织微环境中某些细胞因子的水平,促进肿瘤组织微血管的生成而加速肿瘤的生长,还能阻止放化疗引起肿瘤组织内癌细胞的活性氧自由基(ROS)的产生而导致其化疗耐药,进而导致免疫功能的缺失。
乌苯美司(Ubenimex,Bestatin)是从网状橄榄链霉菌(Streptomycesolivoreticuli)培养液中分离所得的一种二肽类化合物,于1987年在日本上市作为免疫增强剂用于白血病的治疗;乌苯美司于1998年在国内上市,商品名百士欣。Bestatin具有明显的免疫调节功能和显著的抗肿瘤活性。Bestatin对免疫系统的影响主要体现在它能有效的增强T、B淋巴细胞的功能,同时提高自然杀伤细胞(NK)的杀伤活力。此外,它还可以通过促进集落刺激因子的合成,刺激骨髓细胞的再生及分化,达到调节、增强、兴奋和恢复机体的免疫功能的作用。Bestatin可抑制小鼠黑色瘤高转移株B16BL6侵袭;也能够抑制HUVECs形成管腔结构(Cancer letter,2004,216(1):35-42)。在小鼠移植瘤实验中发现,Bestatin可以抑制肿瘤细胞转移和肿瘤诱发的血管生成(Bio.Pharm,Bull.,1996,19(1):6-10)。Ubenimex作为一个小分子免疫增强剂,在临床上与传统化疗药辅佐治疗各类癌症如白血病、多发性骨髓瘤、骨髓增生异常综合症及其他实体瘤等,证明安全有效。但是,单药使用疗效甚微(Science,2000)。
硼替佐米(Bortezomib,MG-341),是由美国Millennium公司研发的蛋白酶体抑制剂,2003年经FDA批准上市,临床用于治疗多发性骨髓瘤和复发、难治性套细胞淋巴瘤。硼替佐米在体外对多种恶性肿瘤细胞有明显的增殖抑制作用,而且在一系列血液系统恶性肿瘤及小细胞肺癌、前列腺癌、胰腺癌等实体肿瘤中均具有明显的抗肿瘤效应。但由于口服生物利用度低和稳定性的原因,硼替佐米只能注射给药。
枸橼酸伊莎佐米(Ixazomib Citrate,MLN9708),由武田制药公司研发,是一种口服的、具有高选择性的蛋白酶体抑制剂,于2015年11月20日首次在美国获得批准上市,用于治疗既往至少接受过一线治疗的多发性骨髓瘤。与已上市的蛋白酶体抑制剂相比,Ixazomib具有以下优势:Ixazomib对硼替佐米等一代抑制剂耐药的多发性骨髓瘤患者仍有效;Ixazomib是口服的蛋白酶体抑制剂,每周只需服用一次;与硼替佐米相比,Ixazomib具有较低的外周神经毒性。
由于现有的恶性肿瘤治疗药物其功能和靶点较为单一,恶性肿瘤的化学治疗一般需要多药联合治疗,尤其是用传统细胞毒类化疗药与生物免疫佐剂或抑制新生血管生长的靶向激酶抑制剂类药物联合用药,已成为肿瘤临床化疗的优选方案。但是,在联合用药的过程中,肿瘤患者需要接受多种、大量的药物治疗,使其面临药物相互作用所导致危险的几率更大,而且还增加了治疗成本。因此,设计开发多功能型抗癌药物,成为近年来药物化学新药设计领域的研究热点。
发明内容
针对上述现有技术的不足,本发明的目的是提供一种多功能靶向免疫小分子抗癌药枸橼酸Bestazomib(Bestazomib Citrate)。其对APN/CD13具有抑制活性,同时对肿瘤蛋白酶体也具有抑制活性。
为实现上述目的,本发明采用如下技术方案:
本发明的第一方面,提供一种式I所示的化合物,或其光学异构体、非对映异构体、消旋体或三者的混合物,或其药学上可接受的盐,或其溶剂合物;
本发明的第二方面,提供一种用于制备式I所示化合物的中间体,其结构如式II所示:
本发明的第三方面,提供上述式I所示化合物的制备方法,包括如下步骤:
以(2S,3R)-3-氨基-2-羟基-4-苯丁酸(AHPA)为原料,经Cbz保护伯胺基得中间体2;中间体2于无水DCM中在EDCI和HOBt催化下与(R)-1-氨基-3-甲基丁基硼酸蒎烷二醇酯三氟乙酸盐反应得到中间体3;中间体3在异丁基硼酸作用下脱保护基得到中间体4;中间体4在Pd/C和氢气下脱Cbz保护生成中间体5,最后与柠檬酸作用得到式I所示化合物。
其合成路线如下:
其中,Cbz-Cl为苄氧羰基氯,DCM为二氯甲烷,EDCI为1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐,HOBt为1-羟基苯并三唑,Pd/C为钯碳。
本发明的第三方面,提供上述式I所示的化合物,或其光学异构体、非对映异构体、消旋体或三者的混合物,或其药学上可接受的盐,或其溶剂合物在制备多功能靶向抑制剂中的应用;优选的,所述多功能靶向抑制剂对氨肽酶N和蛋白酶体均具有抑制活性。
本发明的第四方面,提供上述式I所示的化合物,或其光学异构体、非对映异构体、消旋体或三者的混合物,或其药学上可接受的盐,或其溶剂合物在制备预防或治疗肿瘤的药物中的应用。
优选的,所述肿瘤包括:骨髓瘤、白血病和实体瘤。
本发明的第五方面,提供一种药物组合物,所述药物组合物的活性成分为式I所示的化合物,或其光学异构体、非对映异构体、消旋体或三者的混合物,或其药学上可接受的盐,或其溶剂合物。
进一步的,所述药物组合物中还包括一种或多种药学上可接受的载体或赋形剂。
优选的,所述药物组合物为口服制剂或注射制剂。
上述药物组合物在制备治疗肿瘤疾病的药物制剂中的应用也是本发明的保护范围。优选的,所述肿瘤疾病包括:骨髓瘤、白血病和实体瘤。
本发明的第六方面,一种治疗肿瘤疾病的方法,该方法包括给予面临肿瘤疾病风险或经诊断患有肿瘤疾病的受试者治疗有效量的式I所示的化合物或其其药学上可接受的盐。
本文使用的术语“治疗有效量”表示,治疗、改善靶向的疾病或病症或者表现出可检测的治疗效果所需的治疗剂的量。
本发明的化合物在相当宽的剂量范围内是有效的。实际服用本发明式I所示的化合物的剂量可由医生根据有关的情况来决定。这些情况包括:受试者的身体状态、给药途径、年龄、体重、对药物的个体反应,症状的严重程度等。
在治疗过程中,上述式I化合物或其药学上可接受的盐可还以与至少一种其它药物合用。所涵盖的其它药物的原子组成或结构均异于式I的化合物。
本发明的有益效果:
(1)本发明的多功能靶向免疫小分子抗癌药枸橼酸Bestazomib不仅对APN/CD13具有抑制活性,同时对肿瘤蛋白酶体也具有抑制活性,可用于恶性肿瘤治疗药物的开发。
(2)以本发明的枸橼酸Bestazomib作为活性成分开发的抗癌药物,其具有多靶点和多功能性,无需与其他抗肿瘤药物联用也可实现对恶性肿瘤的治疗,避免了联合用药过程中由于药物相互作用所导致的危险,而且还降低了治疗成本。
附图说明
图1:各组肺结节数量。
图2:抑制肝癌H22向肺转移的抑制率测试结果。
图3:各组动物体重变化曲线。
图4:各组肺器官照片及肺部结节。
图5:各组动物生存期变化曲线。
图6:各组动物存活天数比较。
具体实施方式
应该指出,以下详细说明都是例示性的,旨在对本申请提供进一步的说明。除非另有指明,本文使用的所有技术和科学术语具有与本申请所属技术领域的普通技术人员通常理解的相同含义。
本文中所用的术语和定义含义如下:
“药学上可接受的盐”是指式I化合物具有疗效且无毒的盐形式。其可由任一碱性基团(如氨基)形成阳离子盐。本领域已知许多这样的盐,是在任何碱性基团(如氨基)上形成的阴离子盐。这些盐有许多是本领域已知的。还可通过使用相应的酸处理碱性形式的(I)方便地获得阴离子盐,这样的酸包括无机酸如盐酸、硫酸、硝酸、磷酸等;或有机酸如乙酸、三氟乙酸、丙酸、羟基乙酸、2-羟基丙酸、2-氧代丙酸、草酸、丙二酸、琥珀酸、马来酸、富马酸、苹果酸、酒石酸、2-羟基-1,2,3-丙三酸、甲磺酸、乙磺酸、苯甲磺酸、4-甲基苯磺酸、环己基亚磺酸、2-羟基苯甲酸、4-氨基-2-羟基苯甲酸等。这些盐是熟练技术人员熟知的,熟练的技术人员可制备本领域知识所提供的任何盐。此外,熟练技术人员可根据溶解度、稳定性、容易制剂等因素取某种盐而舍另一种盐。这些盐的测定和最优化在熟练技术人员的经验范围内。
正如背景技术部分所介绍的,现有的抗肿瘤药物其功能和靶点比较单一,通常需要联合用药。但联合用药会增加药物相互作用所导致的风险,还会增加治疗成本。基于此,本发明提供了一种多功能靶向免疫小分子抗癌药枸橼酸Bestazomib。
本发明的多功能靶向免疫小分子抗癌药枸橼酸Bestazomib具有如下结构:
枸橼酸Bestazomib的化学名为2,2'-(2-((R)-1-((2S,3R)-3-氨基-2-羟基-4-苯丁酰胺基)-3-甲基丁基)-5-氧-1,3,2-二氧硼戊环-4,4-二基)二乙酸。
本发明的多功能靶向免疫小分子抗癌药枸橼酸Bestazomib的设计构思为:本发明是以Bestain为基础进行结构设计,本发明首先通过对Bestain分子结构中的游离羧基进行修饰后,发现其仍能保持对APN/CD13的抑制活性,但体外抑制肿瘤细胞增殖的活性并未提高,而且对肿瘤蛋白酶体也无抑制活性。为实现化合物的多靶向和多功能性,本发明创新性的将Bestain分子结构中的羧基部分替换为硼酸,结果发现其对肿瘤细胞增殖的抑制活性明显提高。但是,将Bestain分子结构中的羧基部分替换为硼酸,硼酸容易形成三聚体结构,其稳定性欠佳,难以将其开发成口服抗癌药。为进一步的解决其稳定性的问题,本发明通过在化合物的分子结构中引入枸橼酸以稳定硼酸,增强化合物的稳定性。通过上述设计过程,本发明设计得到了式I所示的化合物枸橼酸Bestazomib(Bestazomib Citrate)。此化合物是一个前药分子,通过在体内代谢脱去枸橼酸部分进一步发挥细胞毒杀作用。
本发明设计的化合物Bestazomib Citrate与先导化合物相比,具有多靶向性和多功能性,不仅对APN/CD13的具有优异的抑制活性,同时对肿瘤蛋白酶体具有较好的抑制活性;细胞试验表明,本发明的化合物Bestazomib Citrate对多种肿瘤细胞的增殖也具有明显的抑制活性。
与先导化合物相比,本发明设计的化合物Bestazomib Citrate在药代动力学、生物利用度、安全性和物化性质等方面也都有了很大提高,其活性好、功能多、稳定性好,非常适合开发成多功能靶向免疫小分子的抗癌药。
本发明的多功能靶向免疫小分子抗癌药枸橼酸Bestazomib由如下方法制备而成:
以光学纯的(2S,3R)-3-氨基-2-羟基-4-苯丁酸(AHPA)为原料,经Cbz保护伯胺基得中间体2。于无水DCM中在EDCI和HOBt催化下与(R)-1-氨基-3-甲基丁基硼酸蒎烷二醇酯三氟乙酸盐反应得到3。中间体3在异丁基硼酸作用下脱保护基得到关键中间体4。中间体4在Pd/C和氢气下脱Cbz保护生成中间体5,最后与柠檬酸作用得到式I所示化合物6(Bestazomib Citrate)。反应式如下:
本领域技术人员可以对上述步骤进行变动以提高收率,他们可据本领域的基本知识确定合成的路线,如选择反应物,溶剂和温度,可以通过使用各种常规保护基以避免副反应的发生从而提高收率。这些常规的保护方法可参见例如T.Greene,Protecting Groupsin Organic Synthesis.
含有本发明化合物的药物组合物
本发明的部分衍生物可以游离形式或以盐形式存在。本领域技术人员已知许多化合物类型的药学上可接受的盐及其制备方法。药学上可接受的盐包括常规的无毒性的盐,包括这样的化合物碱与无机或有机酸形成的季铵盐。
本发明的化合物可形成水合物或溶剂合物。本领域熟练人员已知将化合物与水一起冻干时所形成的水合物或在溶液中与合适的有机溶剂浓缩时形成溶剂合物的方法。
本发明包含含有治疗量本发明化合物的药物,和一种或多种药学上可接受载体和/或赋形剂的药物组合物。载体包括如盐水,缓冲盐水,葡萄糖,水,甘油,乙醇和它们的结合物,下文更详细地论述。如果需要,该组合物还可以包含较小量的润湿剂或乳化剂,或pH缓冲剂。该组合物可以是液体,悬浮液,乳剂,片剂,丸剂,胶囊,持续释放制剂或粉末。该组合物可以用传统的黏合剂和载体如三酸甘油酯配制成栓剂。口服制剂可以包括标准载体如药物品级的甘露糖醇,乳糖,淀粉,硬脂酸镁,糖精钠,纤维素和碳酸镁等等。视需要制剂而定,配制可以设计混合,制粒和压缩或溶解成分。在另一个途径中,该组合物可以配制成纳米颗粒。
使用的药物载体可以为固体或者液体。
典型的固体载体包括乳糖,石膏粉,蔗糖,滑石,凝胶,琼脂,果胶,阿拉伯胶,硬脂酸镁,硬脂酸等等。固体载体可以包括一种或多种可能同时作为增香剂,润滑剂,增溶剂,悬浮剂,填料,助流剂,压缩助剂,粘合剂或片剂-崩解剂的物质;它还可以是包封材料。在粉末中,载体为精细粉碎的固体,它与精细粉碎的活性成分的混合。在片剂中活性成分与具有必要的压缩性质的载体以合适的比例混合,以需要的形状和大小压缩。粉末和片剂优选包含至多99%活性成分。合适的固体载体包括,例如,磷酸钙,硬脂酸镁,滑石,糖,乳糖,糊精,淀粉,凝胶,纤维素,甲基纤维素,羧甲基纤维素钠盐,聚乙烯吡咯烷酮烷酮,低熔点蜡和离子交换树脂。
典型的液体载体包括糖浆,花生油,橄榄油,水等等。液体载体用于制备溶液,悬浮液,乳剂,糖浆,酊剂和密封的组合物。活性成分可以溶解或悬浮于药学上可接受的液体载体如水,有机溶剂,二者的混合物或药学上可接受的油类或脂肪。液体载体可以包含其他合适的药物添加剂如增溶剂,乳化剂,缓冲剂,防腐剂,增甜剂,增香剂,悬浮剂,增稠剂,颜料,粘度调节剂,稳定形或渗透压-调节剂。用于口服和肠胃外给药的液体载体的合适的例子包括水(部分地包含如同上述的添加剂,例如纤维素衍生物,优选羧甲基纤维素钠盐溶液),醇(包括一元醇和多元醇,例如乙二醇)和它们的衍生物,和油类(例如分馏椰子油和花生油)。用于肠胃外给药的载体还可以为油脂如油酸乙酯和异丙基肉豆蔻酸盐。无菌的液体载体用于肠胃外给药的无菌的液态组合物。用于加压组合物的液体载体可以为卤代烃或其他药学上可接受的推进剂。无菌溶液或悬浮溶液液体药物组合物可以用来,例如,静脉内,肌内,腹膜内或皮下注射。注射时可单次推入或逐渐注入,入30分钟的经脉内灌注。该化合物还可以以液体或者固体组合物的形式口服给药。
载体或赋形剂可以包括本领域已知的时间延迟材料,如单硬脂酸甘油酯或二硬脂酸甘油酯,还可包括蜡,乙基纤维素,羟丙基甲基纤维素,异丁烯酸甲酯等等。当制剂用于口服时,公认PHOSALPG-50(磷脂(phospholipid)与1,2-丙二醇浓缩,A.Nattermann&Cie.GmbH)中的0.01%吐温80用于其他化合物的可接受的口服制剂的配制,可以适应于本发明各种化合物的配制。
给予本发明化合物时可以使用各式各样的药物形式。如果使用固体载体,制剂可以为片剂,被放入硬胶囊中的粉末或小药丸形式或锭剂或糖锭形式。固体载体的量在很大程度上变化,但是优选从约25mg到约1.0g。如果使用液体载体,制剂可以为糖浆,乳剂,软胶囊,在安瓿或小瓶或非水的液体悬浮液中的无菌注射溶液或悬浮液。
为了获得稳定的水溶性的剂型,可以将化合物或其药学上可接受的盐溶于有机或无机酸的水溶液,0.3M琥珀酸或柠檬酸溶液。选择性地,酸性的衍生物可以溶于合适的碱性溶液。如果得不到可溶形式,可将化合物溶于合适的共溶剂或它们的结合。这样的合适的共溶剂的例子包括,但是不局限于,浓度范围从0-60%总体积的乙醇,丙二醇,聚乙二醇300,聚山梨酸酯80,甘油,聚氧乙烯脂肪酸酯,脂肪醇或甘油羟脂肪酸酯等等。
各种释放系统是已知的并且可以用于化合物或其他各种制剂的给药,这些制剂包括片剂,胶囊,可注射的溶液,脂质体中的胶囊,微粒,微胶囊,等等。引入的方法包括但是不局限于皮肤的,皮内,肌内,腹膜内的,静脉内的,皮下的,鼻腔内的,肺的,硬膜外的,眼睛的和(通常优选的)口服途径。化合物可以通过任何方便的或者其它适当的途径给药,例如通过注入或快速浓注,通过上皮的或粘膜线路(例如,口腔粘膜,直肠和肠粘膜,等等)吸收或通过负载药物的支架以及可以于其他生物活性剂一起给药。可以全身或局部给药。
为了使得本领域技术人员能够更加清楚地了解本申请的技术方案,以下将结合具体的实施例详细说明本申请的技术方案。
本发明实施例中所用的未进行具体说明试验材料均为本领域常规的试验材料,均可通过商业渠道购买得到。
实施例1:(2S,3R)-3-((苄氧碳基)氨基)-2-羟基-4-苯丁酸(2)
将AHPA(1,1.95g,10.0mmol)溶于100mL四氢呋喃与1mol/L氢氧化钠的混合溶液,冰浴条件下滴加苄氧羰基氯(1.88g,11.0mmol)。室温反应6小时后,蒸除反应液中的四氢呋喃,水相用1mol/L盐酸调pH=1,乙酸乙酯萃取三次,合并有机相,无水硫酸镁干燥,蒸干溶剂得到白色固体2(2.11g,64%)。
实施例2:(R)-1-((2S,3R)-3-((苄氧羰基)氨基)-2-羟基-4-苯丁酰胺基)-3-甲基丁基硼酸蒎烷二醇酯(3)
化合物2(3.29g,10.0mmol)溶于50mL无水DCM中,冰浴条件下加入HOBt(1.49g,11mmol)和EDCI(2.10g,11.0mmol),0.5h后,加入(R)-1-氨基-3-甲基丁基硼酸蒎烷二醇酯三氟乙酸盐(4.07g,11.0mmol),三乙胺1.5mL。撤去冰浴,室温反应5h。反应完成后,有机层分别用水,1M柠檬酸,饱和碳酸氢钠,饱和氯化钠洗涤。无水硫酸镁干燥,过滤,蒸除溶剂,得白色固体3(3.05g,53%)。1H-NMR(400MHz DMSO-d6):0.86-0.88(d,3H),0.90-0.92(d,3H),1.03-1.06(s,3H),1.11-1.17(m,4H),1.38-1.53(m,8H),1.76-1.82(m,1H),2.05-2.10(m,1H),2.26-2.31(m,1H),2.78-2.82(m,1H),2.96-3.00(m,1H),3.42-3.45(t,1H),3.61-3.63(t,1H),4.25-4.26(d,1H),4.59-4.64(q,1H),4.74-4.78(s,1H),5.05-5.07(m,1H),5.51-5.54(d,1H),5.70-5.73(d,1H),6.55-6.59(s,1H),7.18-7.22(m,1H),7.26-7.35(m,9H).ESI-MS m/z:577.34(M+H)+。
实施例3:(R)-1-((2S,3R)-3-((苄氧羰基)氨基)-2-羟基-4-苯丁酰胺基)-3-甲基丁基硼酸(4)
化合物3(2.88g,5.0mmol)溶于50mL无水甲醇和正己烷1:1的混合溶剂中,并向其中加入异丁基硼酸(1.27g,12.5mmol)。冰浴条件下,加入1mol/L的盐酸溶液室温下继续搅拌6h。静置分液后下层加入2mol/L氢氧化钠溶清,二氯甲烷萃取三次。水相再用1N盐酸调pH=5,DCM萃取三次,合并DCM相,饱和食盐水洗涤,无水硫酸镁干燥,蒸干溶剂得白色固体4(0.77g,35%)。
实施例4:(R)-1-((2S,3R)-3-氨基-2-羟基-4-苯丁酰胺基)-3-甲基丁基硼酸(5)
化合物4(1.10g,2.5mmol)溶于溶于50mL无水甲醇中,加入10%钯碳0.1g,氢气下室温反应6h,过滤后蒸出溶剂得到白色固体5(1.26g,42%)。
实施例5:2,2'-(2-((R)-1-((2S,3R)-3-氨基-2-羟基-4-苯丁酰胺基)-3-甲基丁基)-5-氧-1,3,2-二氧硼戊环-4,4-二基)二乙酸(6)
化合物5(0.62g,2.0mmol)溶于20mL乙酸乙酯中,油浴65℃下加入柠檬酸(0.38g,2.0mmol)。反应0.5h后,降至室温继续搅拌2h。蒸除溶剂得到粗品,用乙酸乙酯重结晶得白色固体6(0.36g,40%)。1H-NMR(400MHz DMSO-d6):0.86-0.88(d,3H),0.91-0.93(d,3H),1.27-1.35(m,3H),1.46-1.48(t,2H),2.67-2.72(m,1H),2.92-2.97(m,1H),3.04-3.12(m,3H),3.61-3.67(m,3H),3.89-3.93(q,1H),4.34-4.36(m,1H),6.48-6.52(s,1H),7.16-7.30(m,5H).ESI-MS m/z:465.20(M+H)+;即为目标化合物6(Bestazomib Cirtate)。
实施例6:目标化合物体外抑制氨肽酶N的活性试验
氨肽酶N与其商品化底物L-亮氨酰对硝基苯胺(购自Sigma公司)相互作用,产生在405nm有吸收的对-硝基苯胺,并且对-硝基苯胺的浓度与酶活性的大小呈正相关。于405nm处测定吸收度,从而根据抑制剂组及对照组的吸收度计算抑制率,并求算IC50值。实验结果见表1。
表1:Bestazomib Citrate、Bestazomib和阳性对照Bestatin的体外抑酶试验结果
a表中数值为三次试验的平均值。
上述测试结果显示,化合物Bestazomib Citrate表现出对APN的抑制活性优于阳性对照药Bestatin,结果表明对Bestatin的羧基用硼酸进行替代后仍能保持对APN的抑制活性,可作为发现新型高效的氨肽酶N抑制剂的先导化合物,具有良好的开发前景。
实施例7:目标化合物体外抑制20S蛋白酶体的活性试验
采用20S蛋白酶体检测试剂盒(Calbiochems,EMD Millipore Co.,USA)进行体外蛋白酶体活性试验(Clinical Cancer Research,2011,17:5311-5321)。蛋白酶体与其底物相互作用产生荧光物质7-氨基-4甲基香豆素(7-AMC),并且7-AMC的浓度与蛋白酶体活性的大小呈正相关。于380/460nm处测定荧光强度,从而根据抑制剂组及对照组的吸收度计算抑制率,并求算IC50值。实验结果见表2。
表2:Bestazomib Citrate、Bestazomib和阳性对照Ixazomib的体外抑制20s蛋白酶体试验结果
a表中数值为三次试验的平均值。
上述测试结果显示,化合物Bestazomib Citrate亦表现出对蛋白酶体明显的抑制活性,抑制活性与阳性对照药Ixazomib相当,具有良好的开发前景。
实施例8:目标化合物体外抑制细胞增殖的活性试验
目标化合物体外抑制细胞增殖活性试验采用MTT法。取人白血病K562细胞株、人骨髓瘤U266细胞株、人肺癌A549细胞、人前列腺癌PC-3细胞株、人淋巴瘤U937细胞株及人肝癌PLC/PRF/5细胞株,均采用常规培养。实验时均用对数生长期细胞。取上述细胞的细胞悬液于倒置显微镜下计数细胞数目,加入培养基调整细胞数目至1×105/mL。取96孔细胞培养板进行细胞接种和药物实验,周边孔不用(充填无菌PBS),设立空白对照组、阴性对照组、阳性对照组和药物实验组,其中空白对照组只加入细胞培养液150μL/孔,阴性对照组接种细胞悬液100μL/孔并且加入细胞培养液50μL/孔,阳性对照组接种细胞悬液100μL/孔并且加入阳性对照药溶液50μL/孔,药物实验组接种细胞悬液100μL/孔并且加入待测化合物溶液50μL/孔,阳性对照组和药物实验组分别设立5个不同的药物终浓度:0.01、0.1、1、10、100μmol·L-1,每个药物浓度设3个平行复孔。药物加入完毕后,将96孔细胞培养板于37℃、5%CO2和饱和湿度条件下培养48h,每孔每孔加入10μL 0.5%的MTT染色液,继续孵育4h后,2500rpm,离心30min,然后抛弃板孔中培养基,每孔加入100μL的DMSO,在平板振荡器上振荡15min,使formazan结晶溶解完全。用酶标仪于波长570nm处测定各孔的OD值,细胞生长抑制率按下面公式计算:
表3:Bestazomib Citrate和阳性对照Bestatin对肿瘤细胞的增殖抑制活性结果(IC50,μM)
a表中数值为三次试验的平均值
上表测试数据表明,化合物Bestazomib Citrate对上述肿瘤细胞都有一定的增殖抑制作用,与阳性对照药Bestatin相比,Bestazomib Citrate对人淋巴瘤细胞U937、人白血病细胞K562和人骨髓瘤细胞U266的增殖抑制活性明显增强,对人前列腺癌细胞PC-3、人肺癌细胞A549和人肝癌细胞PLC/PRF/5也都有较明显的增殖抑制活性,具有良好的开发前景。
实施例9:目标化合物抑制肝癌H22肺转移实验
1、小鼠移植性肿瘤模型的建立
取生长良好的荷肝癌H22小鼠,抽取腹水,加无菌PBS溶液稀释至浓度为2.5*107个/mL,接种于昆明鼠右侧腋下,每只200μL。剔除体重过高或者过低的昆明鼠,随机分组,按照给药方案开始给药,以后每天给药一次,每给药5天停药2天,7天为一个周期,共两个周期,每周期开始和结束时记录每组昆明鼠体重,求均值。给药体积为每次每只200μL/20g;给药方式:灌胃给药,每天给药一次。
2、药效学试验
将接种H22肿瘤的昆明小鼠称重后随机分为以下6组,每组7只。(1)阴性对照:PBS;(2)Ixazomib高剂量组:4mg/kg/4d;(3)Ixazomib低剂量组:2mg/kg/4d;(4)BestazomibCitrate低剂量组:2.69mg/kg/4d;(5)Bestazomib Citrate中剂量组:3.59mg/kg/4d;(4)Bestazomib Citrate高剂量组:4.48mg/kg/d。Beatazomib Citrate按照每天给药一次,每给药5天停药2天,7天为一个周期,共两个周期(给药体积:每次每只200μL/20g,给药方式:灌胃给药),阳性对照Ixazomib按照每四天给药一次,每周期开始和结束时用游标卡尺测量肿瘤大小,用电子天平称量小鼠的体重,求均值。于接种后13天处死小鼠,剥取瘤块,称重。抑制率的计算公式如下:
3、试验结果:
各组肺结节数量见图1,抑制肝癌H22向肺转移的抑制率测试结果见图2,各组动物体重变化曲线见图3,各组肺器官照片及肺部结节见图4。
上述测试结果表明,Bestazomib Citrate作为多功能免疫小分子抗癌药具有较强的体内外抗肿瘤活性,具有一定的开发应用前景。
实施例10:碳粒廓清功能实验
1、实验原理
单核的巨噬细胞系统是一个非常重要的防御系统,它具有强大的吞噬廓清异种颗粒的能力。当一定浓度的碳粒经小鼠的尾静脉进入体内后,经血液的流动带到肝、脾等处,而这些器官的巨噬细胞能够对这些碳粒进行清除。在一定浓度范围内,巨噬细胞对碳粒的消除速率与其剂量是成指数函数关系,即吞噬的速度与血液中碳粒的浓度成正比。因此,以小鼠血液中碳粒浓度的对数值为纵坐标,时间为横坐标作图,那么其斜率K表示巨噬细胞的吞噬速度,但这是一个未经较正的吞噬指数。而实际上,其吞噬活性还与小鼠的肝、脾重量有关,重量不同则K值不同,因此,一般用校正后的吞噬指数α来表示,这样反应的是单位组织重量的吞噬活性。K和α的计算公式如下:
K=(logA1-logA2)/(t2-t1)
α=(k1/3×体质量)/(肝质量+脾质量)
2、实验材料和方法
材料:昆明小鼠(雌性,4-5周龄)、印度墨汁、生理盐水、Na2CO3溶液(0.1%g/v)、UV紫外可见光光度计。
将昆明小鼠,随机分组,给药2周。在末次给药后1h,给各鼠尾静脉注射经生理盐水5倍稀释后的印度墨汁0.1mL/10g,注入后立即开始计时,分别在2min(t1)、10min(t2)时间点分别从眼眶静脉丛准确取血20μL加入到2mL0.1%Na2CO3溶液中,混合均匀后,以0.1%Na2CO3溶液作为对照组,各给药组为实验组,用紫外分光光度计在600nm波长分别测定t1和t2两个时间点的吸光度,计为A1和A2。通过上面K值的计算公式计算出廓清指数。此外,取血完成后,将小鼠脱颈处死,分别摘取肝、脾称重。计算吞噬指数α。
表4:Bestazomib Cirtate和阳性对照Ixazomib在小鼠体内的巨噬细胞碳粒廓清指数(K)和吞噬指数(α)
a所呈现的结果表示为“平均值±标准偏差”。
上述测试结果显示,给予Bestazomib Citrate后的小鼠对巨噬细胞的吞噬能力明显的强于阳性对照Ixazomib,且具有一定的剂量依赖性。这一结果表明,BestazomibCitrate能够增强小鼠的巨噬细胞吞噬能力,从而增强小鼠的机体免疫功能。因此,Bestazomib Citrate作为多功能免疫小分子抗癌药具有较好的开发应用前景。
实施例11:昆明鼠生存期试验
取生长良好的荷肝癌H22小鼠,抽取腹水,加无菌PBS溶液稀释至浓度为2.5*107个/mL,接种于昆明鼠右侧腋下,每只200μL。5天后开始随机分组给药,接种当天为第1天,给药时记录动物体重。6天后随机称重分为以下6组,每组10只。(1)阴性对照:PBS;(2)Ixazomib高剂量组:4mg/kg/4d;(3)Ixazomib低剂量组:2mg/kg/4d;(4)BestazomibCitrate低剂量组:2.69mg/kg/4d;(5)Bestazomib Citrate中剂量组:3.59mg/kg/4d;(6)Bestazomib Citrate高剂量组:4.48mg/kg/d。按照预定给药剂量对小鼠进行给药,分别称重并记录。
用Origin7.5软件的单因素方差分析(One-Way ANOVA)功能求算出整体差异;用t检验分别对各组给药组与空白组进行两两比较,并以下面公式计算各组药物的生命延长率:
各组生存期变化曲线见图5,各组动物存活天数比较见图6。上述测试结果表明,在与阳性药Ixazomib等摩尔量的前提下,给予Bestazomib Citrate后的小鼠生存时间优于阳性药Ixazomib的延长时间。Bestazomib Citrate作为多功能免疫小分子抗癌药具有较好的开发应用前景。
以上所述仅为本申请的优选实施例而已,并不用于限制本申请,对于本领域的技术人员来说,本申请可以有各种更改和变化。凡在本申请的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本申请的保护范围之内。
Claims (10)
1.式I所示的化合物,或其光学异构体、非对映异构体、消旋体或三者的混合物,或其药学上可接受的盐,或其溶剂合物;
2.用于制备式I所示化合物的中间体,其结构如式II所示:
3.式I所示化合物的制备方法,其特征在于,包括如下步骤:
以(2S,3R)-3-氨基-2-羟基-4-苯丁酸为原料,经Cbz保护伯胺基得中间体2;中间体2于无水DCM中在EDCI和HOBt催化下与(R)-1-氨基-3-甲基丁基硼酸蒎烷二醇酯三氟乙酸盐反应得到中间体3;中间体3在异丁基硼酸作用下脱保护基得到中间体4;中间体4在Pd/C和氢气下脱Cbz保护生成中间体5,最后与柠檬酸作用得到式I所示化合物。
4.权利要求1所述的式I所示的化合物,或其光学异构体、非对映异构体、消旋体或三者的混合物,或其药学上可接受的盐,或其溶剂合物在制备多功能靶向抑制剂中的应用;
所述多功能靶向抑制剂对氨肽酶N和蛋白酶体均具有抑制活性。
5.权利要求1所述的式I所示的化合物,或其光学异构体、非对映异构体、消旋体或三者的混合物,或其药学上可接受的盐,或其溶剂合物在制备预防或治疗肿瘤的药物中的应用。
6.根据权利要求5所述的应用,其特征在于,所述肿瘤包括:骨髓瘤、白血病和实体瘤。
7.一种药物组合物,其特征在于,所述药物组合物的活性成分为式I所示的化合物,或其光学异构体、非对映异构体、消旋体或三者的混合物,或其药学上可接受的盐,或其溶剂合物。
8.根据权利要求7所述的药物组合物,其特征在于,所述药物组合物中还包括一种或多种药学上可接受的载体或赋形剂。
9.根据权利要求7或8所述的药物组合物,其特征在于,所述药物组合物为口服制剂或注射制剂。
10.权利要求7或8所述的药物组合物在制备治疗肿瘤疾病的药物制剂中的应用。
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EP19847870.3A EP3835305B1 (en) | 2018-08-09 | 2019-08-05 | Multifunctional immunity-targeted micromolecule anti-cancer medicine bestazomib (bestazomib) and preparation method and application thereof |
JP2021531165A JP7215774B2 (ja) | 2018-08-09 | 2019-08-05 | 多機能標的免疫小分子抗癌薬のクエン酸ベスタゾミブおよびその製造方法と使用 |
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WO2022089556A1 (zh) * | 2020-10-30 | 2022-05-05 | 苏州开拓药业股份有限公司 | 一种c-Myc蛋白抑制剂及其制备方法和用途 |
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