CN116120335B - 作为Wnt信号通路激动剂的莪术醇衍生物及其制法和应用 - Google Patents
作为Wnt信号通路激动剂的莪术醇衍生物及其制法和应用 Download PDFInfo
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- CN116120335B CN116120335B CN202310063390.6A CN202310063390A CN116120335B CN 116120335 B CN116120335 B CN 116120335B CN 202310063390 A CN202310063390 A CN 202310063390A CN 116120335 B CN116120335 B CN 116120335B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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Abstract
本发明提供了作为Wnt信号通路激动剂的莪术醇衍生物及其制法和应用。具体地,本发明提供了式I化合物,或其药学上可接受的盐或酯。本发明的莪术醇及其衍生物可用于:(a)制备调节经典Wnt信号通路的药物;(b)预防和治疗由经典Wnt信号通路异常失活引起的疾病或失调;和/或(c)维持干细胞生长和增殖。
Description
技术领域
本发明涉及生物医药领域,具体地涉及作为Wnt信号通路激动剂的莪术醇衍生物及其制法和应用。
背景技术
Wnt信号通路在生物进化中高度保守,并在胚胎发育、组织稳态维持、受损组织再生等众多生物学过程中扮演着重要角色。Wnt信号通过调节下游因子的转录激活,调控细胞的增值、分化、迁移和凋亡等。Wnt信号通路缺陷严重影响一系列组织器官的表型,包括脑、骨、肠、皮肤、牙齿等。Wnt信号通路组分的异变也和癌症发生相关。
Wnt信号通路可分为依赖于β-catenin/TCF转录复合物的经典Wnt信号通路和不依赖于β-catenin/TCF的非经典Wnt信号通路,包括Wnt/PCP和Wnt/Ca2+信号通路等。
经典Wnt/β-catenin信号通路包含以下一系列典型的事件:当没有Wnt信号的时候,APC、Axin、GSK3和CKI组成降解复合物以降解β-catenin核心信号分子,其中Axin和APC结合锚定β-catenin,而GSK3和CKI激酶磷酸化β-catenin;磷酸化的β-catenin被识别并降解。经典Wnt信号通路的激活依赖于Wnt1类配体,Wnt1类配体中研究最多的即是Wnt3a蛋白。Wnt蛋白结合细胞膜表面的受体(七次跨膜受体FZD(Frizzled))和它的共受体LRP5/6(low-density lipoproteub receptor-related protein 5/6),进而通过FZD在细胞膜内的区域招募支架蛋白DVL(Dishevelled),这促进了LRP5/6的磷酸化。磷酸化的LRP5/6在细胞膜内招募β-catenin降解复合物的重要组分Axin,从而抑制了β-catenin降解复合物的形成;β-catenin的降解作用被抑制后,积累的β-catenin入核结合TCF/LEF转录因子,并激活其转录活性,促进下游基因的表达,包括AXIN2、c-MYC和Dkk1等。
Wnt信号通路在促进细胞生长和增殖方面具有重要作用,开发激动剂激活Wnt信号通路来促进组织再生,在治疗损伤或病变的组织、促进组织稳态维持、抗衰老等方面有巨大的前景。Wnt信号通路可以促进肠隐窝内细胞的增殖。激活Wnt信号通路能保护骨髓移植患者排异反应造成的肠道干细胞损伤,而且Wnt/β-catenin信号通路能通过增加成骨细胞数量来增加骨密度,因此Wnt激动剂可以用来治疗骨质疏松以及相关骨疾病。Wnt信号通路也能通过促进基质细胞的增殖来促进毛发生长。这显示出Wnt激动剂在防治脱发方面的潜在作用,比如治疗由化疗造成的脱发等。Wnt激动剂也是干细胞培养液中的重要组成部分,可防止干细胞分化。阿尔兹海默病的病变过程常伴随着Wnt信号通路的异常失活,因此利用Wnt激动剂调节Wnt信号通路有望为阿尔兹海默病的治疗提供新的途径。
Wnt信号通路激动剂主要包括以下三大类:Wnt蛋白及其类似物,比如UM206和Norrin蛋白;Wnt信号通路抑制物的抑制剂,比如DKK蛋白抗体和R-spondin蛋白;β-catenin降解复合物的抑制剂,比如GSK3和CKI激酶的抑制剂。然而,多数Wnt激动剂仍处于早期开发阶段,包括蛋白和抗体在内的大分子药物,需要解决递药系统、稳定性、剂量依赖效应等问题;而小分子药物,比如常见的GSK3和CKI激酶的抑制剂,又因为GSK3和CKI参与了包括Wnt信号通路在内的多种通路,因此特异性较差。
综上所述,本领域亟需开发一种具有高稳定性和特异性的Wnt信号通路激动剂。
发明内容
本发明的目的是提供一种作为Wnt信号通路激动剂的莪术醇衍生物及其制备方法。
本发明的另一目的是提供莪术醇及其衍生物的应用。
在本发明的第一方面,提供了一种具有式I所示结构的化合物、或其药学上可接受的盐或酯,
在本发明的第二方面,提供了一种制备本发明第一方面所述的式I化合物的方法,包括步骤:
(C)在第三惰性溶剂中,使式II化合物(EZC-17)与酰化剂发生酯化反应,从而得到式I化合物:
在另一优选例中,所述的酰化剂选自下组:酸、酰氯、酸酐、或其组合。
在另一优选例中,所述的酰化剂包括对硝基苯甲酸、对硝基苯甲酰氯、对硝基苯甲酸酐、或其组合。
在另一优选例中,在步骤(C)中,所述反应在催化剂和/或脱水剂存在下进行。
在另一优选例中,所述的催化剂包括有机碱、无机碱或其组合。
在另一优选例中,所述的有机碱(催化剂)选自下组:吡啶、4-二甲氨基吡啶、或其组合。
在另一优选例中,所述的催化剂为4-二甲氨基吡啶(DMAP)。
在另一优选例中,所述的无机碱选自下组:碳酸钠、碳酸钾、氢化钠、或其组合。
在另一优选例中,在步骤(C)中,所述第三惰性溶剂选自下组:二氯甲烷、苯、甲苯、或其组合。
在另一优选例中,所述的第三惰性溶剂包括二氯甲烷。
在另一优选例中,在步骤(C)中,式II化合物与酰化剂的摩尔比为1:1~2;较佳地1:1.1~1.5。
在另一优选例中,在步骤(C)中,所述的脱水剂为二环己基碳二亚胺(DCC)、分子筛、或其组合;较佳地,所述的脱水剂为二环己基碳二亚胺。
在另一优选例中,在步骤(C)中,所述的脱水剂与式II化合物的摩尔比为1:1~5;较佳地1:2~4。
在另一优选例中,在步骤(C)中,所述反应在第三惰性溶剂的熔点(或0℃)至第三惰性溶剂的回流温度下进行,较佳地在室温或4-25℃下进行。
在另一优选例中,所述方法还包括:通过步骤(B)制备所述的式II化合物:
(B)在第二惰性溶剂中,在碱存在下,式III化合物发生开环反应,从而得到式II化合物:
在另一优选例中,在步骤(B)中,所述的碱为氢氧化钠、氢氧化钾、或其组合;较佳地,所述的碱为氢氧化钠。
在另一优选例中,在步骤(B)中,所述的第二惰性溶剂为C1-C6烷基醇或其组合;较佳地,所述的第二惰性溶剂为丙醇,更佳地为异丙醇(IPA)。
在另一优选例中,在步骤(B)中,式III化合物与碱的摩尔比为1:1-6;较佳地1:2-1:4。
在另一优选例中,在步骤(B)中,所述反应在40-90℃,较佳地50-80℃,更佳地在第二惰性溶剂的回流温度下进行。
在另一优选例中,所述方法还包括:通过步骤(A)制备所述的式III化合物:
(A)在第一惰性溶剂中,莪术醇(EZC)与间氯过氧苯甲酸(m-CPBA)发生氧化反应(或成环反应),从而得到式III化合物;
在另一优选例中,在步骤(A)中,所述的第一惰性溶剂选自下组:二氯甲烷(DCM)、甲苯、苯、或其组合;较佳地,所述的第一惰性溶剂为二氯甲烷。
在另一优选例中,在步骤(A)中,莪术醇与间氯过氧苯甲酸的摩尔比为1:1~1:4;较佳地1:1.2~1:2,更佳地1:1.3-1:1.8。
在另一优选例中,在步骤(A)中,所述反应在第一惰性溶剂的熔点(或0℃)至第一惰性溶剂的回流温度下进行,较佳地在室温或4-25℃下进行。
在另一优选例中,所述的第一惰性溶剂、第二惰性溶剂和/或第三惰性溶剂为无水溶剂(或水含量≤1wt%,较佳地≤0.2wt%,更佳地≤0.1wt%)。
在本发明的第三方面,提供了一种药物组合物,所述药物组合物包括:
(a)本发明第一方面所述的式I化合物或其可药学上可接受的盐或酯;和
(b)药学上可接受的载体;
在另一优选例中,所述的药物组合物包括固体制剂、液态剂型、或凝胶制剂。
在另一优选例中,所述的药物组合物的剂型为口服给药或非口服给药剂型。
在另一优选例中,所述的口服给药剂型选自下组片剂、胶囊剂、粉剂(散剂)、颗粒剂,口服液(乳剂或糖浆剂)。
在另一优选例中,所述的非口服给药剂型是注射剂或针剂。
在另一优选例中,所述的药物组合物为冻干制剂或酊剂。
在本发明的第四方面,提供了一种制备本发明第三方面所述的药物组合物的方法,包括步骤:将(i)本发明第一方面所述的式I化合物、或其药学上可接受的盐或酯与(ii)药学上可接受的载体进行混合,从而形成本发明第三方面所述的药物组合物。
在另一优选例中,所述的药物组合物用于调节经典Wnt信号通路。
在本发明的第五方面,提供了一种活性成分的用途,所述活性成分用于制备组合物或制剂,所述组合物或制剂用于:
(a)制备调节经典Wnt信号通路的药物;
(b)预防和治疗由经典Wnt信号通路异常失活引起的疾病或失调;和/或
(c)维持干细胞生长和增殖,
其中,所述的活性成分选自下组:
(Z1)莪术醇或其药学上可接受的盐或酯;或
(Z2)本发明第一方面所述的式I化合物、或其药学上可接受的盐或酯;
(Z3)Z1和Z2的组合。
在另一优选例中,所述的经典Wnt信号通路异常失活引起的疾病或失调选自下组:风湿性关节炎、骨质疏松症、脱发、阿尔兹海默症、或其组合。
在另一优选例中,所述式I化合物或其药学上可接受的盐或酯为化学合成的。
在另一优选例中,所述组合物包括药物组合物、食品组合物或保健品组合物。
在另一优选例中,所述的药物组合物含有(i)式I所示的化合物或其药学上可接受的盐或酯;以及(ii)药学上可接受的载体。
在另一优选例中,所述组分(i)占所述药物组合物总重量的0.001-99.9wt%,较佳地0.01-99wt%,更佳地0.1%-90wt%。
在另一优选例中,所述的组合物或制剂包括:口服制剂和非口服制剂。
在另一优选例中,所述组合物为口服制剂。
在另一优选例中,所述的药物组合物包括固体制剂、液态剂型、或凝胶制剂。
在另一优选例中,所述的口服剂型选自下组:片剂、胶囊剂、粉剂(散剂)、颗粒剂,口服液(乳剂或糖浆剂)。
在另一优选例中,所述的非口服给药剂型是注射剂或针剂。
在另一优选例中,所述的药物组合物为冻干制剂或酊剂。
在另一优选例中,所述的组合物或制剂通过以下方式施用于哺乳动物:口服、静脉注射、皮下注射、或局部给药(如涂抹在皮肤上)。
在另一优选例中,所述哺乳动物包括人或非人哺乳动物。
在另一优选例中,所述非人哺乳动物包括啮齿动物,如小鼠、大鼠。
在本发明的第六方面,提供了一种体外激活经典Wnt信号通路的方法,在含有Wnt3a蛋白的条件培养基和活性成分的存在下,培养细胞,从而激活所述细胞中的经典Wnt信号通路,
其中,所述的活性成分选自下组:
(Z1)莪术醇或其药学上可接受的盐或酯;或
(Z2)本发明第一方面所述的式I化合物、或其药学上可接受的盐或酯;
(Z3)Z1和Z2的组合。
在另一优选例中,所述方法还进一步调控(如上调或下调)所述经典Wnt信号通路的报告基因或下游靶基因的表达和/或活性。
在另一优选例中,所述的细胞为体细胞,更佳地为人和非人哺乳动物的体细胞。
在另一优选例中,所述的细胞为胚肾细胞,较佳地HEK293T细胞。
在另一优选例中,所述方法是非诊断和非治疗的。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
附图说明
图1显示了莪术醇对经典Wnt信号通路报告基因Topflash活性的影响结果。
图2显示了莪术醇对经典Wnt信号通路靶基因DKK1的mRNA水平的影响结果。
图3显示了莪术醇对β-catenin蛋白水平的影响结果。
图4显示了化合物I对经典Wnt信号通路报告基因Topflash活性的影响结果。
图5显示了化合物I对经典Wnt信号通路吧基因DKK1的mRNA水平的影响结果。
图6显示了化合物I对β-catenin蛋白水平的影响结果。
具体实施方式
经过广泛而深入的研究,通过筛选大量的化合物,本发明人首次意外地发现莪术醇可以激活Wnt信号通路。在此基础上,又进一步制备了活性更高的莪术醇衍生物(如式I化合物)。实验结果表明,本发明的莪术醇及其衍生物能够以一种依赖于Wnt3a蛋白的形式,激活经典Wnt信号通路报告基因Topflash的活性以及信号通路靶基因的mRNA水平,并促进细胞内β-catenin的积累。在此基础上完成了本发明。
术语
除非另有定义,否则本文中所用的全部技术术语和科学术语均具有如本发明所属领域普通技术人员通常理解的相同含义。
式I化合物
在本发明中,式I化合物的结构如下所示。
如本文所用,“本发明化合物”指式I所示的化合物,并且还包括式I化合物的药学上可接受的盐或酯。此外,本发明化合物还包括莪术醇、或其药学上可接受的盐或酯。
如本文所用,“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于:盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸,甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯甲磺酸,苯磺酸等有机酸;以及天冬氨酸、谷氨酸等酸性氨基酸。一类优选的盐是本发明化合物与碱形成的盐。适合形成盐的碱包括但并不限于:氢氧化钠、氢氧化钾、碳酸钠、碳酸氢钠、磷酸钠等无机碱,氨水、三乙胺、二乙胺、哌嗪等有机碱。
本发明化合物可以是无定形的、晶型或其混合物。
活性成分
本发明提供了一种本发明活性成分的用途,用于:(a)制备调节经典Wnt信号通路的药物;(b)预防和治疗由经典Wnt信号通路异常失活引起的疾病或失调;和/或(c)维持干细胞生长和增殖。
本文所用,术语“本发明的活性成分”、“本发明的莪术醇及其衍生物”可互换使用。
本发明的活性成分选自下组:
(Z1)莪术醇或其药学上可接受的盐或酯;
(Z2)式I所示结构的化合物或其药学上可接受的盐或酯;或
(Z3)Z1和Z2的组合。
药物组合物和施用方法
本发明化合物或活性成分可以制备成药物组合物,诸如片剂、胶囊、粉剂、微粒剂、溶液剂、锭剂、胶冻、乳膏制剂、醑剂、悬液、酊、泥敷剂、搽剂、洗剂、和气雾剂之类的剂型。药物能够由通常已知的制备技术来制备,并且合适的药物添加剂能够被添加到该药物中。
药物添加剂的例子包括赋形剂、粘结剂、分解剂、润滑剂、流动助剂、悬浮剂、乳化剂、稳定剂、保温(润湿)剂、防腐剂、溶剂、增溶剂、防腐剂、调味剂、增甜剂、染料、香料、推进剂等,这些药物添加剂可以进行选择并以在不影响本发明的效果的范围内的合适量添加。
“药学上可接受的载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和式I化合物相互掺和,而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明的药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,本发明化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性成分外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。本发明化合物在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂,或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药,或者与其他药学上可接受的用于治疗皮肤疾病的化合物联合给药。
Wnt信号通路以及相关疾病
本发明化合物或活性成分可用于调节(上调)经典Wnt信号通路,可用于预防和治疗由经典Wnt信号通路异常失活引起的疾病或失调。
在本发明中,代表性的经典Wnt信号通路异常失活引起的疾病或失调包括(但不限于):风湿性关节炎、骨质疏松症、脱发、阿尔兹海默症、或其组合。
制备方法
下面更具体地描述本发明式I结构化合物的制备方法,但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得,这样的组合可由本发明所属领域的技术人员容易地进行。
通常,在制备流程中,各反应通常在惰性溶剂中,在室温至回流温度(如0℃~80℃,优选0℃~50℃)下进行。反应时间通常为0.1小时-60小时,较佳地为0.5-48小时。
在本发明的一个优选例中,式I化合物的制备方法包括步骤:
(A)使莪术醇与间氯过氧苯甲酸(m-CPBA)发生氧化反应,得到式III化合物;
(B)式III化合物与碱发生开环反应,得到式II化合物;
(C)式II化合物与对硝基苯甲酸发生酯化反应得到式I化合物。
典型地,本发明式I化合物的制备方法包括:
步骤(A):在第一惰性溶剂中,莪术醇(EZC)与间氯过氧苯甲酸(m-CPBA)发生氧化反应,得到式III化合物;
步骤(B):在第二惰性溶剂中,式III化合物与碱发生开环反应,得到式II化合物:
步骤(C):在第三惰性溶剂中,在任选的催化剂的作用下,式II化合物(EZC-17)与酰化剂(如对硝基苯甲酸)发生酯化反应,得到式I化合物:
本发明的主要优点包括:
1.本发明首次发现能够显著激活Wnt信号通路的莪术醇及其衍生物。
2.本发明的莪术醇及其衍生物能够以一种依赖于Wnt3a蛋白的形式去激活经典Wnt信号通路。
3.本发明的莪术醇及其衍生物能够以一种依赖于Wnt3a蛋白的形式去激活经典Wnt信号通路的下游靶基因的转录和表达。
4.本发明的莪术醇及其衍生物能够以一种依赖于Wnt3a蛋白的形式促进细胞内β-catenin的积累。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。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。除非另外说明,否则百分比和份数是重量百分比和重量份数。
实施例1化合物I的合成
1.以莪术醇(EZC)为起始原料制备中间体I(EZC-16):
将莪术醇(3g,1当量)溶解于二氯甲烷中,加入间氯过氧苯甲酸(m-CPBA)(3.28g,1.5当量),室温下搅拌,TLC(5%硫酸乙醇显色)跟踪至反应完全,依次用饱和亚硫酸氢钠、饱和碳酸氢钠、饱和食盐水洗,无水硫酸钠干燥后减压浓缩,得油状液体中间体I(EZC-16)2.595g,收率81.1%。
NMR分析确认产物:1H-NMR(CDCl3,400MHz)δ:2.77(2H,m,H-7),2.27(2H,m,H-4),1.01(6H,overlap,H-12,H-13),0.94(3H,d,J=6.0Hz,H-11)。13C-NMR(CDCl3,100MHz)δ:104.5(C-6),87.0(C-3a),58.8(C-9),56.9(C-8),55.8(C-5),51.9(C-8a),39.8(C-3),37.4(C-7),34.6(C-4),30.2(C-2),30.0(C-10),24.3(C-1),23.2(C-11),21.2(C-12),12.1(C-13);
ESI-MS m/z:275.1[M+Na]+。
2.从中间体I(EZC-16)出发制备中间体II(EZC-17):
将油状液体中间体I(EZC-16)2.595g溶于异丙醇(IPA)中,加入氢氧化钠(1.525g,3当量),70℃下反应,TLC(5%的硫酸乙醇显色)跟踪至反应完全,依次用饱和酒石酸,饱和食盐水洗,无水硫酸钠干燥后减压浓缩,经柱色谱(石油醚∶乙酸乙酯=3∶1)分离得2.242g白色固体中间体II(EZC-17),收率70%。
NMR、MS分析确认产物:1H-NMR(CD3OD,400MHz)δ:5.77(1H,s,H-7),3.99(2H,s,H-9),2.18(2H,m,H-4),0.99(3H,d,J=6.4Hz,H-12),0.98(3H,d,J=6.4Hz,H-13),0.88(3H,d,J=6.8Hz,H-11)。13C-NMR(CD3OD,100MHz)δ:144.9(C-8),124.6(C-7),104.7(C-6),87.9(C-3a),64.4(C-9),59.6(C-5),50.6(C-8a),41.3(C-3),37.5(C-4),32.2(C-2),32.0(C-10),28.5(C-1),23.1(C-11),21.8(C-12),12.1(C-13);
ESI-MS m/z:275.2[M+Na]+。
3.从中间体II(EZC-17)出发制备化合物I(HCL-13):
将中间体II(EZC-17;50mg,1当量)溶解于二氯甲烷(DCM)中,再依次加入对硝基苯甲酸(40mg,1.2当量)、二环己基碳二亚胺(DCC)(123mg,3当量)及催化剂4-二甲氨基吡啶(DMAP),室温下搅拌,TLC(5%硫酸乙醇显色)跟踪至反应完全,依次用饱和碳酸氢钠、饱和酒石酸、饱和食盐水洗,无水硫酸钠干燥后减压浓缩,经柱色谱(石油醚∶乙酸乙酯=10∶1)分离得53mg无色透明油状液体(HCL-13),收率67%。
NMR、MS分析确认产物:1H NMR(600MHz,Acetone-d6)δ8.38-8.40(2H,dt,J=8.8,1.9Hz,H-4′,6′),8.29-8.31(2H,dt,J=8.8,1.9Hz,H-3′,H-7′),6.00(1H,s,H-7),5.35(1H,s,OH),4.83-4.91(2H,m,H-9),1.00-1.01(3H,d,J=6.6Hz,H-11),0.97-1.01(3H,d,J=6.6Hz,H-12),0.86-0.88(3H,d,J=6.6Hz,H-13);13CNMR(150MHz,Acetone-d6)δ:164.1(C-1′),150.8(C-5′),137.7(C-8),135.6(C-2′),130.7(C-3′,7′),128.9(C-7),123.7(C-4′,6′),103.0(C-6),85.9(C-3α),66.8(C-9),59.1(C-5),49.6(C-8α),40.1(C-3),36.2(C-4),31.3(C-2),30.8(C-10),27.5(C-1),22.3(C-11),21.0(C-12),11.2(C-13);
ESI-MS m/z:424.1[M+Na]+.
实施例2莪术醇和化合物I激活Wnt信号通路活性
1.细胞培养
HEK293T细胞(人肾上皮细胞)在含10%胎牛血清的DMEM(invitrogen)培养液中培养,37℃,5% CO2。
2.Wnt3a对照培养基(CM)的制备
稳定分泌小鼠Wnt3a的L细胞株(CRL-2647,为小鼠成纤维细胞)及对照L细胞株(CRL-2648)购自美国ATCC细胞库。用含有G418和10%胎牛血清的DMEM培养液培养细胞48小时后,对其进行换液(不含G418),此时细胞密度应为70%左右。培养三天后,收集培养液上清并离心去沉淀,此培养液上清即为含Wnt3a蛋白的条件培养基。
3.报告基因检测基因活性
将报告基因质粒用Lipofectamine3000(Invitrogen)试剂转染至HEK293T细胞中(24孔板每孔10ng Topflash报告质粒(Millipore),10ng GFP质粒(Millipore)和230ngLacZ质粒),18小时后,加入Wnt3a条件培养基或对照培养基刺激细胞。6小时后,弃尽培养液,加入裂解液(Boehringer Mannheim Luci-ferase检测试剂盒;200μl/孔)在水平摇床上裂解细胞15分钟。将50μl上清裂液转移至96孔细胞板中,使用Synergy 2Multi-ModeMicroplate Reader(Bio-Tek生物公司)依次检测细胞裂解液中背景读值和GFP荧光数值。再加入荧光素酶底物(10μl/孔),混匀后,检测荧光素酶的化学发光数值。GFP的表达不受Wnt信号通路调控,其荧光数值用于对荧光素酶的化学发光数值进行归一化处理。最终,经扣除背景和归一化后,计算得到相对的报告基因活性。
4.蛋白质免疫印迹(Western Blot)
向细胞中加入SDS-PAGE加样缓冲液混合,95℃加热5min后混匀并离心,制成蛋白质样品。配制合适浓度的SDS-PAGE胶,加入蛋白样品并进行电泳分离。湿法电转将蛋白质转到硝酸纤维膜上后,用5%脱脂牛奶中封闭1小时。用TBST缓冲液洗涤3次,每次5分钟,再将膜放入一抗孵育液(β-catenin(610154)抗体购自BD Biosciences公司;TUBULIN抗体(T5168)购自Sigma Aldrich公司;抗体1:1000稀释到TBST中)中4℃孵育过夜。一抗孵育过的膜用TBST洗涤3次,每次5分钟。加入针对一抗种属的HRP二抗,室温孵育1小时。用TBST洗涤膜3次,每次5分钟。加入显影底物(Thermo Scientific公司)后用Tanon 5200仪器进行成像。
5.RNA反转录和荧光定量PCR
利用TRIzol试剂(Invitrogen)裂解细胞后,加入氯仿并混匀,静置5分钟后13200转4℃离心,待匀浆分离成上层水层和下层有机层。吸取水层并加入异丙醇,静置10分钟使RNA沉淀析出。13200转4℃离心后吸弃上清,用70%乙醇洗涤两次,每次13200转4℃离心。室温干燥15分钟,加入DEPC水溶解RNA。将提取的RNA利用SuperscriptTM III第一链合成系统试剂盒(Invitrogen公司)反转录获得cDNA后,借助ABI7500快速实时PCR(AppliedBiosystems公司)用SYBR premix Ex Taq试剂盒(Takara公司)进行实时定量PCR,引物序列参见表1。
表1引物序列
6.HEK293T细胞中转染Topflash报告基因质粒,18小时后分别加入特定浓度的莪术醇或者溶剂对照组DMSO的对照培养基或Wnt3a条件培养基。6小时后收集细胞检测报告基因活性。
结果如图1所示,在Topflash报告基因质粒中,荧光素酶报告基因的上游存在TCF转录因子的结合位点。Wnt3a蛋白结合到细胞膜上的受体激活Wnt信号通路。Wnt信号通路的激活促进TCF转录因子的转录活性,进而促进报告基因的表达。相比使用对照培养基,加入含Wnt3a蛋白的条件培养基6小时后,报告基因活性有了显著提高,而天然化合物莪术醇能进一步增强报告基因活性。但在使用对照培养基的情况下,莪术醇并不能激活报告基因活性。
因此天然化合物莪术醇能够以一种依赖于Wnt3a蛋白的形式去激活经典Wnt信号通路报告基因Topflash的活性。
7.DKK1为经典Wnt信号通路下游靶基因。HEK293T细胞加入特定浓度的莪术醇或者溶剂对照DMSO的对照培养基或Wnt3a条件培养基。6小时后收集细胞用实时定量PCR的方法检测DKK1的mRNA水平。
结果如图2所示,相比使用对照培养基,加入含Wnt3a蛋白的条件培养基6小时后,DKK1基因的mRNA水平有了显著提高,而莪术醇能进一步增加DKK1的mRNA水平。但在使用对照培养基的情况下,莪术醇并不能增加DKK1的mRNA水平。
因此莪术醇能够以一种依赖于Wnt3a蛋白的形式去激活经典Wnt信号通路靶基因的mRNA水平。
8.β-catenin是经典Wnt信号通路的核心信号分子,Wnt信号通路的激活能抑制β-catenin的降解并促进其积累。HEK293T细胞加入特定浓度的莪术醇或者溶剂对照DMSO的对照培养基或Wnt3a条件培养基。3小时后收集细胞检测β-catenin的蛋白水平。
结果如图3所示,相比使用对照培养基,加入含Wnt3a蛋白的条件培养基3小时后,细胞内的β-catenin蛋白水平有了显著的上升,而莪术醇能进一步增加β-catenin的蛋白水平。但在使用对照培养基的情况下,莪术醇并不能增加β-catenin的蛋白水平。
9.HEK293T细胞中转染TOFlash报告基因,18小时后分别加入特定浓度的化合物I或者溶剂对照组DMSO的对照培养基或Wnt3a条件培养基。6小时后收集细胞检测报告基因活性。
结果如图4所示,化合物I能够以一种依赖于Wnt3a的形式去激活经典Wnt信号通路报告基因Topflash的活性。同时相比于莪术醇,化合物I达到相同激活效果所需的浓度大幅降低。
10.HEK293T细胞加入特定浓度的化合物I和溶剂对照DMSO的Wnt条件培养基或对照培养基。6小时后收集细胞用实时定量PCR的方法检测DKK1的mRNA水平。
结果如图5所示,化合物I能够以一种依赖于Wnt3a的形式去激活经典Wnt信号通路靶基因的mRNA水平。
HEK293T细胞加入特定浓度的化合物I或者溶剂对照DMSO的对照培养基或Wnt3a条件培养基。3小时后收集细胞检测β-catenin的蛋白水平。
结果如图6所示,化合物I能够以一种依赖于Wnt3a的形式促进细胞内β-catenin的积累。
讨论
激活经典Wnt信号通路的化合物可用于治疗由Wnt信号通路异常失活引起的疾病或失调,比如风湿性关节炎、骨质疏松症、脱发、阿尔兹海默症等。目前已知的经典Wnt信号通路的激动剂多有弊端:一部分激动剂如LiCl、BIO(6-bromoindirubin-3'-oxime)等GSK3或CKI激酶的抑制剂存在特异性较差的问题,导致在治疗过程中出现不同程度的副作用;而另一部分激动剂,包括Wnt蛋白类似物以及Wnt信号通路抑制物的抗体抑制剂等大分子药物,虽然具有高特异性,但是存在使用成本高,制备和递药系统复杂以及稳定性和剂量依赖效应差等问题。本发明提供的小分子化合物为解决这些目前已知的经典Wnt信号通路激动剂所面临的问题以及为潜在的临床应用提供了新的可能,具有重要意义。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (10)
1.一种活性成分在制备经典Wnt信号通路激动剂中的用途;
其中,所述活性成分为式I化合物、或其药学上可接受的盐;
2.一种活性成分在制备预防和治疗由经典Wnt信号通路异常失活引起的疾病或失调的药物组合物或制剂中的用途;
其中所述活性成分为式I化合物、或其药学上可接受的盐;
且所述的经典Wnt信号通路异常失活引起的疾病或失调选自下组:骨质疏松症、脱发、阿尔兹海默症、或其组合。
3.如权利要求2所述的用途,其特征在于,所述的药物组合物含有(i)式I所示的化合物或其药学上可接受的盐;以及(ii)药学上可接受的载体。
4.如权利要求2所述的用途,其特征在于,所述的药物组合物包括固体制剂、液态剂型、或凝胶制剂。
5.如权利要求3所述的用途,其特征在于,所述的药物组合物或制剂为口服制剂或注射剂。
6.如权利要求5所述的用途,其特征在于,所述的口服剂型选自下组:片剂、胶囊剂、粉剂、颗粒剂和口服液。
7.一种非诊断和非治疗的激活体外培养的细胞中的经典Wnt信号通路的方法,其特征在于,在含有Wnt3a蛋白的条件培养基和活性成分的存在下,培养细胞,从而激活所述细胞中的经典Wnt信号通路,
其中,所述的活性成分为式I化合物、或其药学上可接受的盐,
8.如权利要求7所述的方法,其特征在于,所述的细胞为人或非人哺乳动物的体细胞。
9.如权利要求7所述的方法,其特征在于,所述的细胞为胚肾细胞。
10.如权利要求7所述的方法,其特征在于,所述的细胞为HEK293T细胞。
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