CN115093359B - 一种化合物、药物组合物及其在扩张血管或抗病毒领域的应用 - Google Patents
一种化合物、药物组合物及其在扩张血管或抗病毒领域的应用 Download PDFInfo
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Abstract
Description
技术领域
本发明属于血管舒张活性化合物技术领域,具体涉及一种化合物、包含所述化合物的药物组合物,及其在扩张 血管或抗病毒领域的应用。
背景技术
公开该背景技术部分的信息仅仅旨在增加对本发明的总体背景的理解,而不必然被视为承认或以任何形式暗示 该信息构成已经成为本领域一般技术人员所公知的现有技术。
高血压是指临床上未使用降压药物的情况下,非同日静息状态下测量3次血压,收缩压大于等于140mmHg和 (或)舒张压大于等于90mmHg。它是一种由遗传和环境危险因素引起的复杂疾病,是导致老年人群死亡和疾病高 发的最常见原因。高血压是心血管疾病(包括中风和心力衰竭)最重要的危险因素之一。全球有超过10亿人患有 高血压,相关的医疗费用每年都在增加。在我国,高血压患者已呈低龄化趋势,18岁及以上年龄人群高血压的患病率为27.9%,而老年高血压患者约占总患者人数的60~70%。
迄今为止,已经在哺乳动物中鉴定出18种HDAC亚型,根据其与酵母蛋白同源物的序列同源性,可将其分为 四类:I类(HDAC1、2、3、8)、IIa类(HDAC4、5、7、9)、IIb类(HDAC6、10)和IV类(HDAC11),这三类 均是采用精氨酸酶-去乙酰酶折叠方式的Zn2+依赖性酶;而III类HDACs(sirtuins 1–7)则是采用不相关折叠方式的 NAD+依赖性酶。研究证明,属于IIb类HDAC家族的组蛋白去乙酰化酶6(HDAC6)在高血压相关血管疾病的病 理生理学中发挥了一定的作用。与其他HDAC家族成员不同的是,HDAC6还介导细胞质中存在的非组蛋白底物如α-微管蛋白、热休克蛋白90(HSP90)和皮质蛋白的去乙酰化。研究人员通过研究其抑制剂和/或敲除基因使HDAC6 失活可以改善高血压并发挥心脏保护作用。因此,HDAC6被认为是心血管疾病药物开发的一个有前景的靶点。
此外,众所周知,高效抗病毒疗法虽然使HIV-1/AIDS病毒载量降低到很低的检测限水平,但仍无法彻底消除 HIV-1病毒,这很大程度上归因于潜伏状态的HIV-1病毒,即“潜伏病毒库”的存在,从而成为治愈HIV-1的主要瓶 颈。这些潜伏病毒不会在细胞表面表达病毒蛋白因此不会被宿主免疫系统识别,因而抗病毒药物或者免疫系统对其 无效。目前广泛接受并使用的“激活并杀灭”策略,使用安全有效的潜伏病毒激活剂是关键。研究证实,HDAC6是 开发HIV潜伏病毒激活剂的潜在靶标,目前进入临床阶段研究的HIV潜伏病毒激活剂均为HDAC抑制剂(HDACi)。
HDAC抑制剂的典型特征包括一个与酶表面区域相互作用的帽子基团(Cap)、一个与催化口袋中的锌离子相互 作用的锌离子结合基团(ZBG)以及作为帽子基团和锌离子结合基团之间起桥梁作用的连接基团(Linker)。目前, 已有包括Vorinostat(SAHA)、Romidepsin、Belinostat和Panobinostat在内的四种HDAC抑制剂被美国食品药品监 督管理局(FDA)批准上市。Vorinostat(SAHA,商品名:)是一种线型结构的异羟肟酸类广谱HDAC抑 制剂,于2006年10月被FDA批准用于治疗皮肤T细胞淋巴瘤(CTCL)。在醋酸去氧皮质酮(DOCA)-盐型高血 压大鼠中,SAHA能显著降低收缩压,并明显减轻由高血压引起的胶原沉积、舒张僵硬和促炎标志物的增加。因此, 开发具有血管舒张活性的HDAC6特异性抑制剂具有重要意义。
发明内容
针对现有技术的需求,本发明目的是提供系列具有血管舒张和HIV潜伏病毒激活活性的化合物,所述化合物不 仅具有显著的血管舒张作用和HIV潜伏病毒激活效果,还具有较强的HDAC6抑制活性,具有较好的临床应用前景。
具体的,本发明提供如下技术方案:
本发明第一方面,提供一种化合物,所述化合物具有式I、式II或式III所示的结构或其药用盐、溶剂化物和水 合物;
其中,R选自异羟肟酸基、亚甲基异羟肟酸基团;X,Y,Z选自氮或碳,R1选自氢、甲基或羟甲基;R2选自 -OH、-NH-OH、-NH-NH2。
优选的,所述R选自3-CONHOH、4-CONHOH、3-CH2CONHOH、4-CH2CONHOH。
优选的,所述化合物的药用盐,旨在改善化合物理化性质所进行基团修饰后的衍生物,通常为所述化合物 与无机盐如盐酸、硫酸、硝酸或氢溴酸等所形成的盐,以及与有机酸,例如甲磺酸、甲苯磺酸、柠檬酸或三氟 乙酸等所形成的盐。
进一步的,式I所示化合物具体如下:
3-(2-(1H-吲哚-3-基)乙酰氨基)-N-羟基苯甲酰(代号XCY-A1);
4-(2-(1H-吲哚-3-基)乙酰氨基)-N-羟基苯甲酰(代号XCY-A2);
2-(3-(2-(1H-吲哚-3-基)乙酰氨基)苯基)-N-羟基乙酰胺(代号XCY-A3);
2-(4-(2-(1H-吲哚-3-基)乙酰氨基)苯基)-N-羟基乙酰胺(代号XCY-A4)。
进一步的,式I所示化合物的合成路线如下:
具体的合成步骤如下:
将含有R4取代基的氨基苯衍生物与氯化亚砜回流反应,采用乙酸乙酯对产物进行萃取,得到化合物2;将化合 物2与2-(1H-吲哚-3-基)乙酸在EDCI及DMAP条件下室温反应一段时间,对产物进行纯化得到式I所示化合物; 其中,R4选自3-COOH,4-COOH,3-CH2COOH,4-CH2COOH。
优选的,式II所示化合物具体如下:
N-羟基-3-(2-(萘-2-基)乙酰氨基)苯甲酰胺(代号XCY-C1);
N-羟基-4-(2-(萘-2-基)乙酰氨基)苯甲酰胺(代号XCY-C2);
N-羟基-2-(3-(2-(萘-2-基)乙酰胺基)苯基)乙酰胺(代号XCY-C3);
N-羟基-2-(4-(2-(萘-2-基)乙酰胺基)苯基)乙酰(代号XCY-C4);
进一步的,式II所示化合物合成路线如下:
具体合成步骤如下:
将含有R4取代基的氨基苯衍生物与氯化亚砜回流反应,采用乙酸乙酯对产物进行萃取,得到化合物2;将化合 物2与2-萘乙酸在EDCI及DMAP条件下室温反应一段时间,对产物进行纯化后得到化合物4,将化合物4与盐酸 羟胺在惰性气体保护下室温反应一段时间得到式II所示化合物;其中,R4选自3-COOH,4-COOH,3-CH2COOH, 4-CH2COOH。
优选的,式III所示化合物具体如下:
4-(3-(3’-甲氧基-[1,1’-联苯]-4-基)脲基)苯甲酸甲酯(代号XCY-D1);
4-(3-(3’-甲氧基-[1,1’-联苯]-4-基)脲基)苯甲酸(代号XCY-D2);
4-(3-(3’-甲氧基-[1,1’-联苯]-4-基)脲基)-N-甲基苯甲酰胺(代号XCY-D3);
1-(4-(肼羰基)苯基)-3-(3’-甲氧基-[1,1’-联苯基]-4-基)脲(代号XCY-D4);
N-羟基-4-(2-(3’-甲氧基-[1,1’-联苯]-4-基)乙酰胺基)苯甲酰胺(代号XCY-D5);
N-羟基-4-(2-((3’-甲氧基-[1,1’-联苯]-4-基))氨基)-2-氧代乙基)苯甲酰胺(代号XCY-D6);
N1-羟基-N4-(3’-甲氧基-[1,1’-联苯]-4-基)对苯二甲酰胺(代号XCY-D7);
N-羟基-4-((1-(4-羟基丁基)-3-(3’-甲氧基-[1,1’-联苯]-4-基)脲基)甲基)苯甲酰胺(代号XCY-D8);
4-((1-(4-羟基丁基)-3-(3’-甲氧基-[1,1’-联苯]-4-基)脲基)甲基)苯甲酸(代号XCY-D9);
1-(4-(肼羰基)苄基)-1-(4-羟基丁基)-3-(3'-甲氧基-[1,1’-联苯]-4-基)脲(代号XCY-D10);
4-((1-丁基-3-(3'-甲氧基-[1,1’-联苯]-4-基)脲基)甲基)-N-羟基苯甲酰胺(代号XCY-D11);
4-((1-丁基-3-(3'-甲氧基-[1,1’-联苯]-4-基)脲基)甲基)苯甲酸(代号XCY-D12);
1-丁基-1-(4-(肼羰基)苄基)-3-(3’-甲氧基-[1,1’-联苯]-4-基)脲(代号XCY-D13)。
进一步,式III所示化合物的合成路线如下:
根据上述合成路线,上述化合物XCY-D5的具体合成方式如下:
将3-甲氧基苯硼酸(化合物9)、4-溴苯基乙酸、Ph(PPh3)4和K2CO3溶于二氧六环的水溶液中,在惰性气体保 护条件下回流反应一段时间得到化合物12,将化合物12溶于无水二氯甲烷中,依次加入DCC、4-氨基苯甲酸甲酯 和DMAP,室温下搅拌反应得到化合物13,将化合物13溶于二氯甲烷和甲醇的混合溶液中,加入盐酸羟胺和KOH, 惰性气体保护下,室温下搅拌反应一段时间得到所述化合物XCY-D5。
上述化合物XCY-D1的具体合成方式如下:
将3-甲氧基苯硼酸(化合物9)、1-溴-4-硝基苯、Ph(PPh3)4和K2CO3溶于二氧六环水溶液中,在惰性气体保护 条件下回流反应一段时间得到化合物10。将化合物10与锌粉和氯化铵溶于四氢呋喃、乙醇的水溶液中,惰性气体 保护条件下回流反应得到化合物11,将化合物11与三乙胺溶于二氯甲烷中,再加入化合物6室温反应一段时间得 到。
上述化合物XCY-D2~D4的具体合成方式如下:
将化合物XCY-D1加入不同R取代基的醇或胺溶液中回流反应一段时间制得。
上述化合物XCY-D6的具体合成方式如下:
将2-萘乙酸、化合物2a在EDCI、DMAP条件下室温反应一段时间得到化合物14a;将化合物14a溶于二氯甲 烷和甲醇的混合溶液中,加入盐酸羟胺和KOH,惰性气体保护条件下反应一段时间制得。
上述化合物XCY-D7的具体合成方式如下:
将化合物11溶于无水二氯甲烷溶液中,依次加入DCC、对苯二甲酸单甲酯和DMAP,室温下搅拌反应一段时 间得到化合物14b。将化合物14b溶于二氯甲烷和甲醇的混合溶液中,加入盐酸羟胺和KOH,惰性气体保护下室温 反应一段时间制得。
上述化合物XCY-D8、化合物XCY-D11的具体合成方式如下:
冰浴条件下,将三光气溶于乙酸乙酯中,再缓慢滴加化合物11和三乙胺的乙酸乙酯溶液,室温反应得到化合 物15;将化合物8和三乙胺溶于二氯甲烷中,再缓慢滴加化合物15的二氯甲烷溶液,室温反应一段时间得到化合 物16;将化合物16溶于二氯甲烷和甲醇的混合溶液中,加入盐酸羟胺和KOH,氮气保护下,室温下搅拌反应制得。
上述化合物XCY-D9、化合物XCY-D12的具体合成方式如下:
将化合物16溶于甲醇中,加入KOH反应制得。
上述化合物XCY-D10、化合物XCY-D13的具体合成方式如下:
将化合物16溶于乙醇中,加入水合肼,惰性气体保护条件下回流反应制得。
上述化合物合成方式中,所述化合物6、化合物7及化合物8可以采用下述方式进行合成:
本发明第二方面,提供一种药物组合物,所述药物组合物中包括第一方面所述化合物及必要的药物载体。
上述药物组合物施用于受试者,用于实现预防、改善或治疗疾病的目的,上述化合物应当是增效有效剂量的, 所述剂量可依据受试者及用药目的基于本领域常规技术手段进行确认;优选的方案中,所述受试者为哺乳动物,如 人、猴、兔、狗或鼠;进一步优选的,所述受试者为人。
优选的,所述药物组合物中,还包括药学上所必须的药物载体;所述药物载体包括但不限于离子交换剂,氧化 铝,硬脂酸铝,卵磷脂,血清蛋白,缓冲物质(如磷酸盐),甘油,山梨酯,山梨酸钾,饱和植物脂肪酸的部分甘油酯混合物,水,盐或电解质(如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐),胶态氧化硅,三硅酸 镁,聚乙烯吡咯烷酮,纤维素物质,聚乙二醇,羧甲基纤维素钠,聚丙烯酸酯,蜂蜡,羊毛酯等;所述药物载体在 药物组合物中的含量可以是1重量%-98重量%,通常大约占到80重量%。
优选的,所述药物组合物可以通过以下方式施与:口服、喷雾吸入、直肠给药、鼻腔给药、阴道给药、局部给 药、非肠道给药如皮下、静脉、肌内、腹膜内、鞘内、心室内、胸骨内或颅内注射或输入,或借助一种外植的储器 用药,其中更为优选口服、肌注、腹膜内或静脉内用药方式。
优选的,所述药物组合物的剂型可以是液体剂型、固体剂型;其中,液体剂型可以是真溶液类、胶体类、微粒 剂型、乳剂剂型、混悬剂型;所述固体剂型包括片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、乳剂、颗粒剂、栓剂、 冻干粉针剂、包合物、填埋剂、贴剂、擦剂等。
本发明第三方面,提供第一方面所述化合物、第二方面所述药物组合物作为HDAC抑制剂的应用。
优选的,所述作为HDAC抑制的应用包括但不限于以下任意一种方式:
(1)用于制备HDAC抑制模型的模型药剂;
(2)用于预防、改善或治疗与HDAC相关疾病;
(3)用于制备与HDAC相关疾病的治疗药物。
上述(1)方面,所述模型药剂用于制备疾病模型,可以为细胞、组织或动物模型。
上述(2)、(3)方面中,所述HDAC相关疾病表示以HDAC作为治疗靶点的疾病,或在疾病表征中出现了HDAC 的异常高表达;具体的实例如淋巴瘤、三阴乳腺癌、非小细胞肺癌、骨髓瘤、结肠癌、前列腺癌、艾滋病、高血压 等。
本发明第四方面,提供一种舒张血管的药物,所述药物中包括第一方面所述化合物和/或第二方面所述药物组合 物。
本发明第五方面,提供一种降血压的药物,所述药物中包括第一方面所述化合物和/或第二方面所述药物组合物。
本发明第六方面,提供一种舒张血管的方法,包括向有需要的个体施用第一方面所述化合物和/或第二方面所述 药物组合物。
本发明第七方面,提供第一方面所述化合物、第二方面所述药物组合物作为HIV潜伏病毒激活剂的应用。
本发明验证的一种实施方式中,第一方面所述化合物进一步的为化合物XCY-D6,该优选的实施方式中,上述 第七方面所述应用为化合物XCY-D6、包含化合物XCY-D6的药物组合物作为HIV潜伏病毒激活剂的应用。
优选的,上述作为HIV潜伏病毒激活剂的应用包括但不限于以下任意一种方式:
(1)用于激活潜伏的HIV病毒发生转录;
(2)用于改善或治疗HIV病毒相关疾病;
(3)用于制备抗AIDS的药物。
经本发明验证,化合物XCY-D6能够有效激活潜伏的HIV病毒使之发生转录,通过与高效抗逆转录病毒疗法 (highly active antiretroviral therapy,HAART)联合使用,并结合细胞的自身免疫系统,从而实现清除HIV-1潜伏病 毒库的目的;上述(1)方面的一种实施方式中,所述化合物、药物组合物用于激活疾病模型中潜伏的HIV病毒表 达,激活目的可以是筛选有效抗HIV病毒药物。
本发明第八方面,提供一种用于治疗AIDS的药物,所述药物中,化合物XCY-D6作为活性成分。
上述治疗AIDS的药物中,除包含化合物XCY-D6外,包括其他活性成分,所述其他活性成分为抗病毒药物或 免疫激活药物;其中,所述抗病毒药物为核苷类反转录酶抑制剂,例如拉米夫定、齐多夫定、替诺福韦或恩曲他滨; 所述免疫激活药物的具体实例如卡介苗、白细胞介素-2、转移因子、胸腺肽、左旋咪唑等。
附图说明
构成本发明的一部分说明书附图用来提供对本发明的进一步理解,本发明的示意性实施例及其说明用于解释本 发明,并不构成对本发明的不当限定。
图1示意了本发明示例化合物在小鼠主动脉段暴露于1×10-6mol/L苯肾上腺素(Phe)以诱导收缩的血管舒张 活性结果。
图2示意了本发明示例化合物在小鼠主动脉段暴露于60mM KCl以诱导收缩的血管舒张活性结果。
图3示意了采用不同浓度XCY-D6(1000IU/ml)处理后,GFP阳性的J-Lat细胞中GFP的表达情况。
图4示意了本发明示例化合物XCY-A2与HDAC6的作用模式图;
其中,左图为化合物XCY-A2与靶标HDAC6关键氨基酸的作用模式图;
右图为化合物XCY-A2伸入靶标HDAC6活性结合腔的模式图。
具体实施方式
应该指出,以下详细说明都是示例性的,旨在对本发明提供进一步的说明。除非另有指明,本文使用的所有技 术和科学术语具有与本发明所属技术领域的普通技术人员通常理解的相同含义。
需要注意的是,这里所使用的术语仅是为了描述具体实施方式,而非意图限制根据本发明的示例性实施方式。 如在这里所使用的,除非上下文另外明确指出,否则单数形式也意图包括复数形式,此外,还应当理解的是,当在 本说明书中使用术语“包含”和/或“包括”时,其指明存在特征、步骤、操作、器件、组件和/或它们的组合。
为了使得本领域技术人员能够更加清楚地了解本发明的技术方案,以下将结合具体的实施例详细说明本发明的 技术方案。
实施例1化合物的制备
本发明所述的式I化合物可通过如下反应路线制备得到:
上述制备流程中所用的试剂分别为:a:氯化亚砜;甲醇;75℃;12h;b:2-(1H-吲哚-3-基)乙酸;EDCI;DMAP; 二氯甲烷;室温;c:盐酸羟胺;KOH;二氯甲烷/甲醇;室温;3h。
具体地,本发明在实施例中给出了部分示意化合物的制备过程以及效果验证数据。
(1)中间体3-氨基苯甲酸甲酯(2a)的制备
冰浴条件下,将3-氨基苯甲酸1a(1.00g,7.29mmol)溶于20mL甲醇中,再缓慢滴加氯化亚砜(2.17g,18.23 mmol)。滴加完毕后,回流搅拌反应12h。将反应液浓缩后,加入饱和碳酸氢钠溶液(50mL),用乙酸乙酯萃取三 次(3×50mL)。将有机相合并,用无水MgSO4干燥。过滤,真空浓缩,得黄色油状物0.99g,收率90%。
(2)中间体4-氨基苯甲酸甲酯(2b)的制备
冰浴条件下,将4-氨基苯甲酸1b(1.00g,7.29mmol)溶于20mL甲醇中,再缓慢滴加氯化亚砜(2.17g,18.23 mmol)。滴加完毕后,回流搅拌反应12h。将反应液浓缩后,加入饱和碳酸氢钠溶液(50mL),用乙酸乙酯萃取三 次(3×50mL)。将有机相合并,用无水MgSO4干燥。过滤,真空浓缩,得淡粉色固体0.98g,收率89%。熔点: 109~111℃。MS(ESI)m/z:calcd.for C8H9NO2[2M+Na]+:325.15,found:325.33。
(3)中间体3-氨基苯基乙酸甲酯(2c)的制备
冰浴条件下,将3-氨基苯基乙酸1c(1.00g,6.62mmol)溶于20mL甲醇中,再缓慢滴加氯化亚砜(1.97g, 16.54mmol)。滴加完毕后,回流搅拌反应12h。将反应液浓缩后,加入饱和碳酸氢钠溶液(50mL),用乙酸乙酯 萃取三次(3×50mL)。将有机相合并,用无水MgSO4干燥。过滤,真空浓缩,得黄色油状物0.87g,收率87%。
(4)中间体2-(4-氨基苯基)乙酸甲酯(2d)的制备
冰浴条件下,将4-氨基苯基乙酸1d(1.00g,6.62mmol)溶于20mL甲醇中,再缓慢滴加氯化亚砜(1.97g, 16.54mmol)。滴加完毕后,回流搅拌反应12h。将反应液浓缩后,加入饱和碳酸氢钠溶液(50mL),用乙酸乙酯 萃取三次(3×50mL)。将有机相合并,用无水MgSO4干燥。过滤,真空浓缩,得黄色油状物0.85g,收率85%。
(5)中间体3-(2-(1H-吲哚-3-基)乙酰氨基)苯甲酸甲酯(3a)的制备
将2-(1H-吲哚-3-基)乙酸(0.50g,2.85mmol)溶于50mL无水二氯甲烷溶液中,加入EDCI(0.60g,3.14mmol), 室温下搅拌反应1h。加入中间体2a(0.47g,3.14mmol)和DMAP(0.04g,0.29mmol),室温下搅拌反应3h。 反应结束后,加入2M盐酸(50mL),室温下强烈搅拌10min。将反应液浓缩后,用二氯甲烷萃取三次(3×50mL)。 将有机相合并,用无水Na2SO4干燥。过滤,真空浓缩,硅胶柱层析(二氯甲烷:甲醇=200:1)得黄色油状物0.60 g,收率71%。MS(ESI)m/z:calcd.for C18H16N2O3[M+H]+:309.12,found:309.18。
(6)中间体4-(2-(1H-吲哚-3-基)乙酰氨基)苯甲酸甲酯(3b)的制备
将2-(1H-吲哚-3-基)乙酸(0.50g,2.85mmol)溶于50mL无水二氯甲烷溶液中,加入EDCI(0.60g,3.14mmol), 室温下搅拌反应1h。加入中间体2b(0.47g,3.14mmol)和DMAP(0.04g,0.29mmol),室温下搅拌反应3h。 反应结束后,加入2M盐酸(50mL),室温下强烈搅拌10min。将反应液浓缩后,用二氯甲烷萃取三次(3×50mL)。 将有机相合并,用无水Na2SO4干燥。过滤,真空浓缩,硅胶柱层析(二氯甲烷:甲醇=200:1)得黄色固体0.61 g,收率69%。熔点:94~96℃。MS(ESI)m/z:calcd.for C18H16N2O3[M-H]-:307.12,found:307.36。
(7)中间体2-(3-(2-(1H-吲哚-3-基)乙酰氨基)苯乙酸甲酯(3c)的制备
将2-(1H-吲哚-3-基)乙酸(0.50g,2.85mmol)溶于50mL无水二氯甲烷溶液中,加入EDCI(0.60g,3.14mmol), 室温下搅拌反应1h。加入中间体2c(0.52g,3.14mmol)和DMAP(0.04g,0.29mmol),室温下搅拌反应3h。 反应结束后,加入2M盐酸(50mL),室温下强烈搅拌10min。将反应液浓缩后,用二氯甲烷萃取三次(3×50mL)。 将有机相合并,用无水Na2SO4干燥。过滤,真空浓缩,硅胶柱层析(二氯甲烷:甲醇=200:1)得黄色固体0.60 g,收率66%。熔点:139–141℃。MS(ESI)m/z:calcd.for C19H18N2O3[M+Cl]-:357.58,found:358.06。
(8)中间体2-(4-(2-(1H-吲哚-3-基)乙酰氨基)苯乙酸甲酯(3d)的制备
将2-(1H-吲哚-3-基)乙酸(0.50g,2.85mmol)溶于50mL无水二氯甲烷溶液中,加入EDCI(0.60g,3.14mmol), 室温下搅拌反应1h。加入中间体2d(0.52g,3.14mmol)和DMAP(0.04g,0.29mmol),室温下搅拌反应3h。 反应结束后,加入2M盐酸(50mL),室温下强烈搅拌10min。将反应液浓缩后,用二氯甲烷萃取三次(3×50mL)。 将有机相合并,用无水Na2SO4干燥。过滤,真空浓缩,硅胶柱层析(二氯甲烷:甲醇=200:1)得黄色固体0.46 g,收率50%。熔点:136–138℃。MS(ESI)m/z:calcd.for C19H18N2O3[M+Cl]-:357.58,found:358.02。
(9)3-(2-(1H-吲哚-3-基)乙酰氨基)-N-羟基苯甲酰(XCY-A1)的制备
将中间体3a(0.20g,0.65mmol)溶于10mL二氯甲烷和10mL甲醇的混合溶液中,加入盐酸羟胺(1.35g, 19.46mmol)和KOH(1.13g,20.15mmol),氮气保护下,室温下搅拌反应3h。将反应液浓缩后,用乙酸乙酯萃 取三次(3×50mL)。将有机相合并,用饱和食盐水洗涤,无水Na2SO4干燥。过滤,真空浓缩,硅胶柱层析(二氯 甲烷:甲醇=40:1)得白色固体0.12g,收率59%。熔点:195–197℃。1H NMR(400MHz,DMSO-d6):δ11.17(s,1H, NH),10.92(s,1H,OH),10.24(s,1H,ArH),9.01(s,1H,ArH),8.01(s,1H,ArH),7.79(d,J=7.1Hz,1H,NH),7.60(dd,J =23.5,7.7Hz,1H,NH),7.34(dd,J=22.6,13.3Hz,4H,ArH),7.04(dt,J=34.2,7.2Hz,2H,ArH),3.76(s,2H,CH2);13C NMR(100MHz,DMSO-d6):δ170.39,164.80,140.00,136.61,133.99,129.15,127.75,124.40,122.06,121.58,121.48, 119.15,118.90,118.63,111.85,108.91,34.31;MS(ESI)m/z:calcd.for C17H15N3O3[2M+H]+:619.22,found:618.78。
(10)4-(2-(1H-吲哚-3-基)乙酰氨基)-N-羟基苯甲酰(XCY-A2)的制备
将中间体3b(0.20g,0.65mmol)溶于10mL二氯甲烷和10mL甲醇的混合溶液中,加入盐酸羟胺(1.35g, 19.46mmol)和KOH(1.13g,20.15mmol),氮气保护下,室温下搅拌反应3h。将反应液浓缩后,用乙酸乙酯萃 取三次(3×50mL)。将有机相合并,用饱和食盐水洗涤,无水Na2SO4干燥。过滤,真空浓缩,硅胶柱层析(二氯 甲烷:甲醇=40:1)得白色固体0.11g,收率56%。熔点:251–253℃。1H NMR(400MHz,DMSO-d6):δ11.09(s,1H, NH),10.92(s,1H,OH),10.31(s,1H,ArH),8.92(s,1H,ArH),7.76–7.65(m,4H,ArH),7.61(d,J=7.8Hz,1H,NH),7.37 (d,J=8.1Hz,1H,ArH),7.28(s,1H,ArH),7.08(t,J=7.4Hz,1H,ArH),6.99(t,J=7.4Hz,1H,NH),3.77(s,2H,CH2);13C NMR(100MHz,DMSO-d6):δ170.56,164.41,142.39,136.60,128.15,127.68,127.56(2C),124.40,121.49(2C), 119.11,118.90,118.82,111.86,108.79,34.33;MS(ESI)m/z:calcd.for C17H15N3O3[M-H]-:308.11,found:308.12。
(11)2-(3-(2-(1H-吲哚-3-基)乙酰氨基)苯基)-N-羟基乙酰胺(XCY-A3)的制备
将中间体3c(0.20g,0.62mmol)溶于10mL二氯甲烷和10mL甲醇的混合溶液中,加入盐酸羟胺(1.29g, 18.61mmol)和KOH(1.08g,19.22mmol),氮气保护下,室温下搅拌反应3h。将反应液浓缩后,用乙酸乙酯萃 取三次(3×50mL)。将有机相合并,用饱和食盐水洗涤,无水Na2SO4干燥。过滤,真空浓缩,硅胶柱层析(二氯 甲烷:甲醇=40:1)得白色固体0.10g,收率53%。熔点:159–161℃。1H NMR(400MHz,DMSO-d6):δ10.92(s,1H, NH),10.67(s,1H,OH),10.10(s,1H,ArH),8.84(s,1H,ArH),7.63(d,J=7.8Hz,1H,ArH),7.56–7.48(m,2H,ArH),7.37(d,J=8.1Hz,1H,NH),7.27(d,J=1.7Hz,1H,ArH),7.21(t,J=7.8Hz,1H,ArH),7.09(t,J=7.4Hz,1H,ArH),7.00(t,J=7.4Hz,1H,ArH),6.94(d,J=7.5Hz,1H,NH),3.74(s,2H,CH2),3.25(s,2H,CH2);13C NMR(150MHz, DMSO-d6):δ170.22,167.45,139.73,136.95,136.62,128.92,127.71,124.32(2C),121.49,120.23,119.17,118.90,117.90, 111.85,109.10,69.11,34.28;MS(ESI)m/z:calcd.for C18H17N3O3[2M+H]+:647.26,found:646.80。
(12)2-(4-(2-(1H-吲哚-3-基)乙酰氨基)苯基)-N-羟基乙酰胺(XCY-A4)的制备
将中间体3d(0.20g,0.62mmol)溶于10mL二氯甲烷和10mL甲醇的混合溶液中,加入盐酸羟胺(1.29g, 18.61mmol)和KOH(1.08g,19.22mmol),氮气保护下,室温下搅拌反应3h。将反应液浓缩后,用乙酸乙酯萃 取三次(3×50mL)。将有机相合并,用饱和食盐水洗涤,无水Na2SO4干燥。过滤,真空浓缩,硅胶柱层析(纯乙 酸乙酯)得白色固体0.10g,收率50%。熔点:183–185℃。1H NMR(400MHz,DMSO-d6):δ10.91(s,1H,NH),10.63 (s,1H,OH),10.10(s,1H,ArH),8.80(s,1H,ArH),7.61(d,J=7.8Hz,1H,ArH),7.54(d,J=7.9Hz,2H,ArH),7.36(d,J =8.0Hz,1H,NH),7.26(s,1H,ArH),7.17(d,J=8.2Hz,2H,ArH),7.07(t,J=7.4Hz,1H,ArH),6.98(t,J=7.4Hz,1H, NH),3.73(s,2H,CH2),3.29–3.18(m,2H,CH2);13C NMR(150MHz,DMSO-d6):δ170.06,167.63,138.32,136.63, 131.13,129.56(2C),127.74,124.30(2C),121.43,119.54,119.15,118.84,111.83,109.11,39.27,34.24;MS(ESI)m/z:calcd. for C18H17N3O3[2M+Na]+:669.26,found:668.19。
本发明所述的式II化合物可通过如下反应路线制备得到:
上述制备流程中所用的试剂分别为:a:氯化亚砜;甲醇;75℃;12h;b:2-(1H-吲哚-3-基)乙酸;EDCI;DMAP; 二氯甲烷;室温;c:盐酸羟胺;KOH;二氯甲烷/甲醇;室温;3h。
具体地,本发明在实施例中给出了部分示意化合物的制备过程以及效果验证数据。
(1)中间体3-(2-(萘-2-基)乙酰氨基)苯甲酸甲酯(4a)的制备
将2-萘乙酸(0.50g,2.69mmol)溶于50mL无水二氯甲烷溶液中,加入EDCI(0.57g,2.95mmol),室温下 搅拌反应1h。加入中间体2a(0.45g,2.95mmol)和DMAP(0.03g,0.27mmol),室温下搅拌反应3h。反应结 束后,加入2M盐酸(50mL),室温下强烈搅拌10min。将反应液浓缩后,用二氯甲烷萃取三次(3×50mL)。将 有机相合并,用无水Na2SO4干燥。过滤,真空浓缩,得黄色固体0.53g,收率62%。熔点:142–144℃。MS(ESI)m/z: calcd.forC20H17NO3[M+Cl]-:354.57,found:354.89。
(2)中间体4-(2-(萘-2-基)乙酰氨基)苯甲酸甲酯(4b)的制备
将2-萘乙酸(0.50g,2.69mmol)溶于50mL无水二氯甲烷溶液中,加入EDCI(0.57g,2.95mmol),室温下 搅拌反应1h。加入中间体2b(0.45g,2.95mmol)和DMAP(0.03g,0.27mmol),室温下搅拌反应3h。反应结 束后,加入2M盐酸(50mL),室温下强烈搅拌10min。将反应液浓缩后,用二氯甲烷萃取三次(3×50mL)。将 有机相合并,用无水Na2SO4干燥。过滤,真空浓缩,得白色固体0.47g,收率55%。熔点:155–157℃。MS(ESI)m/z: calcd.forC20H17NO3[M+Cl]-:354.57,found:354.89。
(3)中间体2-(3-(2-(萘-2-基)乙酰氨基)苯基)乙酸甲酯(4c)的制备
将2-萘乙酸(0.50g,2.69mmol)溶于50mL无水二氯甲烷溶液中,加入EDCI(0.57g,2.95mmol),室温下 搅拌反应1h。加入中间体2c(0.49g,2.95mmol)和DMAP(0.03g,0.27mmol),室温下搅拌反应3h。反应结 束后,加入2M盐酸(50mL),室温下强烈搅拌10min。将反应液浓缩后,用二氯甲烷萃取三次(3×50mL)。将 有机相合并,用无水Na2SO4干燥。过滤,真空浓缩,得黄色固体0.53g,收率59%。熔点:135–137℃。MS(ESI)m/z: calcd.forC21H19NO3[M+Cl]-:368.59,found:368.95。
(4)中间体2-(4-(2-(萘-2-基)乙酰氨基)苯基)乙酸甲酯(4d)的制备
将2-萘乙酸(0.50g,2.69mmol)溶于50mL无水二氯甲烷溶液中,加入EDCI(0.57g,2.95mmol),室温下 搅拌反应1h。加入中间体2d(0.49g,2.95mmol)和DMAP(0.03g,0.27mmol),室温下搅拌反应3h。反应结 束后,加入2M盐酸(50mL),室温下强烈搅拌10min。将反应液浓缩后,用二氯甲烷萃取三次(3×50mL)。将 有机相合并,用无水Na2SO4干燥。过滤,真空浓缩,得白色固体0.54g,收率61%。熔点:124–126℃。MS(ESI)m/z: calcd.forC21H19NO3[M+Cl]-:368.59,found:368.99。
(5)N-羟基-3-(2-(萘-2-基)乙酰氨基)苯甲酰胺(XCY-C1)的制备
将中间体4a(0.20g,0.63mmol)溶于10mL二氯甲烷和10mL甲醇的混合溶液中,加入盐酸羟胺(1.31g, 18.79mmol)和KOH(1.09g,19.53mmol),氮气保护下,室温下搅拌反应3h。将反应液浓缩后,用乙酸乙酯萃 取三次(3×50mL)。将有机相合并,用饱和食盐水洗涤,无水Na2SO4干燥。过滤,真空浓缩,硅胶柱层析(二氯 甲烷:甲醇=40:1)得白色固体0.10g,收率52%。熔点:189–191℃。1H NMR(400MHz,DMSO-d6):δ11.19(s,1H, OH),10.41(s,1H,ArH),9.03(s,1H,ArH),8.02(s,1H,NH),7.91–7.83(m,4H,ArH),7.79(d,J=7.4Hz,1H,NH),7.57–7.44(m,3H,ArH),7.45–7.31(m,2H,ArH),3.85(s,2H,CH2);13C NMR(150MHz,DMSO-d6):δ170.11,164.60, 142.13,133.79,133.46,132.35,128.25,128.19,128.06,127.96,127.94(2C),127.88(2C),127.71,126.67,126.17,119.08,43.87;MS(ESI)m/z:calcd.forC19H16N2O3[M+Cl]-:355.57,found:354.92。
(6)N-羟基-4-(2-(萘-2-基)乙酰氨基)苯甲酰胺(XCY-C2)的制备
将中间体4b(0.20g,0.63mmol)溶于10mL二氯甲烷和10mL甲醇的混合溶液中,加入盐酸羟胺(1.31g, 18.79mmol)和KOH(1.09g,19.53mmol),氮气保护下,室温下搅拌反应3h。将反应液浓缩后,用乙酸乙酯萃 取三次(3×50mL)。将有机相合并,用饱和食盐水洗涤,无水Na2SO4干燥。过滤,真空浓缩,硅胶柱层析(二氯 甲烷:甲醇=40:1)得白色固体0.12g,收率60%。熔点:241–243℃。1H NMR(400MHz,DMSO-d6):δ11.11(s,1H, OH),10.47(s,1H,ArH),8.95(s,1H,NH),7.89(d,J=8.0Hz,3H,ArH),7.84(s,1H,NH),7.71(q,J=8.8Hz,4H,ArH),7.49(ddd,J=8.5,7.4,4.8Hz,3H,ArH),3.86(s,2H,CH2);13C NMR(150MHz,DMSO-d6):δ169.79,164.77,139.75, 133.97,133.48,132.35,129.24,128.22,128.09,127.96,127.92(2C),127.89(2C),126.63,126.12,122.23,121.86,43.90; MS(ESI)m/z:calcd.forC19H16N2O3[M+Cl]-:355.57,found:354.90。
(7)N-羟基-2-(3-(2-(萘-2-基)乙酰胺基)苯基)乙酰胺(XCY-C3)的制备
将中间体4c(0.12g,0.36mmol)溶于8mL二氯甲烷和8mL甲醇的混合溶液中,加入盐酸羟胺(0.75g,10.80 mmol)和KOH(0.62g,11.16mmol),氮气保护下,室温下搅拌反应3h。将反应液浓缩后,用乙酸乙酯萃取三次 (3×50mL)。将有机相合并,用饱和食盐水洗涤,无水Na2SO4干燥。过滤,真空浓缩,硅胶柱层析(二氯甲烷: 甲醇=40:1)得白色固体0.06g,收率49%。熔点:189–191℃。1H NMR(400MHz,DMSO-d6):δ10.65(s,1H,OH), 10.24(s,1H,ArH),7.89(dd,J=8.6,2.7Hz,3H,ArH),7.84(s,1H,NH),7.49(ddd,J=9.9,8.5,7.0Hz,6H,ArH),7.22(t, J=7.8Hz,1H,ArH),6.95(d,J=7.5Hz,1H,NH),3.82(s,2H,CH2),3.25(s,2H,CH2);13C NMR(150MHz,DMSO-d6): δ169.55,167.42,139.52,137.01,134.16,133.48,132.33,128.98,128.19,128.09,127.96,127.88,127.86,126.61,126.09,124.53,120.31,117.97,43.90,39.52;MS(ESI)m/z:calcd.for C20H18N2O3[M+Cl]-:369.58,found:368.95。
(8)N-羟基-2-(4-(2-(萘-2-基)乙酰胺基)苯基)乙酰胺(XCY-C4)的制备
将中间体4d(0.15g,0.45mmol)溶于10mL二氯甲烷和10mL甲醇的混合溶液中,加入盐酸羟胺(0.94g, 13.50mmol)和KOH(0.78g,13.95mmol),氮气保护下,室温下搅拌反应3h。将反应液浓缩后,用乙酸乙酯萃 取三次(3×50mL)。将有机相合并,用饱和食盐水洗涤,无水Na2SO4干燥。过滤,真空浓缩,硅胶柱层析(二氯 甲烷:甲醇=40:1)得白色固体0.08g,收率51%。熔点:193–195℃。1H NMR(400MHz,DMSO-d6):δ10.64(s,1H, OH),10.22(s,1H,ArH),8.83(s,1H,ArH),7.88(s,3H,ArH),7.52(s,6H,ArH),7.19(s,2H,NH),3.82(s,2H,CH2),3.24 (s,2H,CH2);13C NMR(100MHz,DMSO-d6):δ169.42,167.63,138.11,134.17,133.47,132.32,131.35,129.65(2C), 128.18,128.15,127.96(2C),127.89,126.61,126.08,119.59(2C),43.86,39.25;MS(ESI)m/z:calcd.for C20H18N2O3[M+Cl]-:369.58,found:368.95。
本发明所述的式III化合物可通过如下反应路线制备得到:
上述制备流程中所用的试剂分别为:a:三光气;三乙胺;乙酸乙酯;室温;5h;b:ⅰ:4-氨基-1-丁醇/正丁胺; 无水乙醇;95℃;5h;ⅱ:硼氢化钠;甲醇;0℃;2h;c:1-溴-4-硝基苯;四(三苯基膦)钯;碳酸钾;1,4-二氧 六环/水;95℃,12h;d:锌;氯化铵;四氢呋喃/乙醇/水;75℃;4h;e:三乙胺;二氯甲烷;室温;3h;f:ⅰ: 氢氧化钾;甲醇;80℃;6h;ⅱ:甲胺水溶液;60℃;2h;ⅲ:水合肼;90℃;7h;g:对溴苯乙酸;四(三苯基 膦)钯;碳酸钾;1,4-二氧六环/水;95℃,12h;h:DCC;DMAP;二氯甲烷;室温;3h;i:盐酸羟胺;KOH;二氯甲烷/甲醇;室温;3h;j:2-(4-甲氧羰基苯基)乙酸/对苯二甲酸单甲酯;DCC;DMAP;二氯甲烷;室温;3h; k:盐酸羟胺;KOH;二氯甲烷/甲醇;室温;3h;l:三光气;三乙胺;乙酸乙酯;室温;5h;m:三乙胺;二氯甲烷;室温;3h;n:盐酸羟胺;KOH;二氯甲烷/甲醇;室温;3h。
具体地,本发明在实施例中给出了部分示意化合物的制备过程以及效果验证数据。
(1)中间体4-异氰酸苯甲酸甲酯(6)的制备
冰浴条件下,将三光气(0.20g,0.66mmol)溶于10mL乙酸乙酯中,再缓慢滴加4-氨基苯甲酸甲酯5(0.20g, 1.32mmol)和三乙胺(0.13g,1.32mmol)的乙酸乙酯溶液10mL。滴加完毕后,室温下搅拌反应5h。过滤,将 反应液浓缩得黄色油状物,直接投入下一步。
(2)中间体4-(((4-羟基丁基)氨基)甲基)苯甲酸甲酯(8a)的制备
将4-氨基-1-丁醇(0.28mL,6.10mmol)和4-甲酰基苯甲酸甲酯7(0.50g,3.05mmol)溶于25mL无水乙醇 中,回流搅拌反应2h。将反应液冷却至室温,真空浓缩,粗产物直接用于下一步。冰浴条件下,将粗产物溶于50mL 甲醇中,在10min内分批加入NaBH4(0.12g,3.10mmol),室温下搅拌反应2h。用水淬灭反应,将反应液浓缩后, 用乙酸乙酯萃取三次(3×50mL)。将有机相合并,用饱和食盐水洗涤,无水Na2SO4干燥。过滤,真空浓缩,得无 色油状物0.63g,两步收率87%。MS(ESI)m/z:calcd.for C13H19NO3[M+H]+:238.14,found:238.20。
(3)中间体4-((丁基氨基)甲基)苯甲酸甲酯(8b)的制备
将正丁胺(0.45g,6.10mmol)和4-甲酰基苯甲酸甲酯7(0.50g,3.05mmol)溶于25mL无水乙醇中,回流 搅拌反应2h。将反应液冷却至室温,真空浓缩,粗产物直接用于下一步。冰浴条件下,将粗产物溶于50mL甲醇 中,在10min内分批加入NaBH4(0.12g,3.10mmol),室温下搅拌反应2h。用水淬灭反应,将反应液浓缩后,用 乙酸乙酯萃取三次(3×50mL)。将有机相合并,用饱和食盐水洗涤,无水Na2SO4干燥。过滤,真空浓缩,得无色 油状物0.54g,两步收率80%。
(4)中间体3-甲氧基-4'-硝基-1,1'-联苯(10)的制备
将3-甲氧基苯硼酸9(0.90g,5.94mmol)、1-溴-4-硝基苯(1.00g,4.95mmol)、Ph(PPh3)4(0.29g,0.25mmol) 和K2CO3(2.05g,14.85mmol)溶于40mL二氧六环和8mL水的混合溶液中,氮气保护下,回流搅拌反应12h。 将反应液冷却,加适量水,用乙酸乙酯萃取三次(3×50mL)。将有机相合并,用硅藻土过滤,无水Na2SO4干燥。 过滤,真空浓缩,得棕红色油状物1.85g,直接投下一步。
(5)中间体3'-甲氧基-[1,1'-联苯]-4-胺(11)的制备
将中间体10(1.85g,8.08mmol)、锌粉(2.64g,40.38mmol)和氯化铵(4.32g,80.75mmol)溶于20mL 四氢呋喃、20mL乙醇和6mL水的混合溶液中,氮气保护下,回流搅拌反应4h。将反应液冷却,用硅藻土过滤, 加适量水,乙酸乙酯萃取三次(3×50mL)。将有机相合并,用无水Na2SO4干燥。过滤,真空浓缩,硅胶柱层析(石 油醚:乙酸乙酯=50:1)得黄色固体1.05g,收率65%。熔点:109–111℃。1H NMR(400MHz,DMSO-d6):δ7.36 (d,J=8.4Hz,2H,ArH),7.27(t,J=7.9Hz,1H,ArH),7.09(t,J=7.5Hz,1H,ArH),7.05(s,1H,ArH),6.78(dd,J=8.1, 1.9Hz,1H,ArH),6.64(d,J=8.4Hz,2H,ArH),5.25(s,2H,NH2),3.79(s,3H,CH3);MS(ESI)m/z:calcd.for C13H13NO [M+H]+:200.10,found:200.07。
(6)中间体2-(3'-甲氧基-[1,1'-联苯]-4-基)乙酸(12)的制备
将3-甲氧基苯硼酸9(0.85g,5.58mmol)、4-溴苯基乙酸(1.00g,4.65mmol)、Ph(PPh3)4(0.27g,0.23mmol) 和K2CO3(1.93g,13.95mmol)溶于40mL二氧六环和8mL水的混合溶液中,氮气保护下,回流搅拌反应12h。 将反应液冷却,用硅藻土过滤,加适量水,乙酸乙酯萃取三次(3×50mL)。将有机相合并,用无水Na2SO4干燥。 过滤,真空浓缩,硅胶柱层析(石油醚:乙酸乙酯=3:1)得黄色油状物0.82g,收率73%。1H NMR(400MHz,DMSO-d6): δ12.39(s,1H,OH),7.61(d,J=7.9Hz,2H,ArH),7.36(dd,J=13.7,7.8Hz,3H,ArH),7.26–7.15(m,2H,ArH),6.93(d,J=7.1Hz,1H,ArH),3.82(s,3H,CH3),3.62(s,2H,CH2)。
(7)中间体4-(2-(3'-甲氧基-[1,1'-联苯]-4-基)乙酰氨基)苯甲酸甲酯(13)的制备
将中间体12(0.50g,2.06mmol)溶于20mL无水二氯甲烷溶液中,依次加入DCC(0.56g,2.68mmol)、4- 氨基苯甲酸甲酯(0.34g,2.27mmol)和DMAP(0.02g,0.21mmol),室温下搅拌反应3h。反应结束后,加适量 水,用二氯甲烷萃取三次(3×50mL)。将有机相合并,用无水Na2SO4干燥。过滤,真空浓缩,硅胶柱层析(石油 醚:乙酸乙酯=9:1)得白色固体0.50g,收率65%。熔点:129–131℃。1H NMR(400MHz,DMSO-d6):δ7.92(d, J=8.5Hz,2H,ArH),7.75(d,J=8.6Hz,2H,ArH),7.63(d,J=7.9Hz,2H,ArH),7.50–7.31(m,3H,ArH),7.29–7.09(m,2H,ArH),6.93(d,J=6.7Hz,1H,ArH),5.58(d,J=6.8Hz,1H,NH),3.82(s,6H,CH3CH3),3.73(s,2H,CH2);MS(ESI) m/z:calcd.for C23H21NO4[2M+Cl]-:785.75,found:784.63。
(8)中间体3-(2-(萘-2-基)乙酰氨基)苯甲酸甲酯(14a)的制备
将2-萘乙酸(0.50g,2.69mmol)溶于50mL无水二氯甲烷溶液中,加入EDCI(0.57g,2.95mmol),室温下 搅拌反应1h。加入中间体2a(0.45g,2.95mmol)和DMAP(0.03g,0.27mmol),室温下搅拌反应3h。反应结 束后,加入2M盐酸(50mL),室温下强烈搅拌10min。将反应液浓缩后,用二氯甲烷萃取三次(3×50mL)。将 有机相合并,用无水Na2SO4干燥。过滤,真空浓缩,得黄色固体0.53g,收率62%。熔点:142–144℃。MS(ESI)m/z: calcd.forC20H17NO3[M+Cl]-:354.57,found:354.89。
(9)中间体4-((3'-甲氧基-[1,1'-联苯]-4-基)氨基甲酰基)苯甲酸甲酯(14b)的制备
将中间体11(0.12g,0.61mmol)溶于20mL无水二氯甲烷溶液中,依次加入DCC(0.15g,0.73mmol)、对 苯二甲酸单甲酯(0.10g,0.56mmol)和DMAP(0.01g,0.06mmol),室温下搅拌反应3h。反应结束后,加适量 水,用二氯甲烷萃取三次(3×50mL)。将有机相合并,用无水Na2SO4干燥。过滤,真空浓缩,硅胶柱层析(石油 醚:乙酸乙酯=9:1)得白色固体0.17g,收率85%。熔点:147–149℃。MS(ESI)m/z:calcd.for C22H19NO4[M-H]-: 360.13,found:360.20。
(10)中间体4'-异氰酸根-3-甲氧基-1,1'-联苯(15)的制备
冰浴条件下,将三光气(0.15g,0.50mmol)溶于10mL乙酸乙酯中,再缓慢滴加中间体11(0.20g,1.00mmol) 和三乙胺(0.15g,1.50mmol)的乙酸乙酯溶液10mL。滴加完毕后,室温下搅拌反应5h。过滤,将反应液浓缩得 黄色油状物,直接投入下一步。
(11)中间体4-((1-(4-羟基丁基)-3-(3'-甲氧基-[1,1'-联苯]-4-基)脲基)甲基)苯甲酸甲酯(16a)的制备
冰浴条件下,将中间体8a(0.24g,1.00mmol)和三乙胺(0.31g,3.00mmol)溶于15mL二氯甲烷中,再缓 慢滴加中间体15(0.45g,2.00mmol)的二氯甲烷溶液15mL。滴加完毕后,室温下搅拌反应3h。反应结束后, 加适量水,用乙酸乙酯萃取三次(3×50mL)。将有机相合并,用无水Na2SO4干燥。过滤,真空浓缩,硅胶柱层析 (二氯甲烷:甲醇=200:1)得黄色油状物0.40g,收率64%。MS(ESI)m/z:calcd.for C27H30N2O5[M-H]-:461.22,found: 461.19。
(12)中间体4-((1-丁基-3-(3'-甲氧基-[1,1'-联苯]-4-基)脲基)甲基)苯甲酸甲酯(16b)的制备
冰浴条件下,将中间体8b(0.22g,1.00mmol)和三乙胺(0.31g,3.00mmol)溶于15mL二氯甲烷中,再缓 慢滴加中间体15(0.45g,2.00mmol)的二氯甲烷溶液15mL。滴加完毕后,室温下搅拌反应3h。反应结束后, 加适量水,用乙酸乙酯萃取三次(3×50mL)。将有机相合并,用无水Na2SO4干燥。过滤,真空浓缩,硅胶柱层析 (二氯甲烷:甲醇=200:1)得黄色油状物0.31g,收率69%。MS(ESI)m/z:calcd.for C27H30N2O4[M-H]-:445.22,found:445.12。
(13)4-(3-(3'-甲氧基-[1,1'-联苯]-4-基)脲基)苯甲酸甲酯(XCY-D1)的制备
冰浴条件下,将中间体11(0.18g,0.88mmol)和三乙胺(0.27g,2.65mmol)溶于10mL二氯甲烷中,再缓 慢滴加中间体6(0.23g,1.32mmol)的二氯甲烷溶液5mL。滴加完毕后,室温下搅拌反应3h。将反应液浓缩后, 加适量水,用乙酸乙酯萃取三次(3×50mL)。将有机相合并,用无水Na2SO4干燥。过滤,真空浓缩,硅胶柱层析 (二氯甲烷:甲醇=200:1)得白色固体0.30g,收率60%。熔点:173–175℃。1H NMR(400MHz,DMSO-d6):δ9.13 (s,1H,NH),8.93(s,1H,NH),7.91(d,J=8.7Hz,2H,ArH),7.61(dt,J=19.3,7.6Hz,6H,ArH),7.35(t,J=7.9Hz,1H, ArH),7.25–7.14(m,2H,ArH),6.90(dd,J=8.1,1.9Hz,1H,ArH),3.83(s,6H,CH3CH3);13C NMR(150MHz,DMSO-d6): δ166.43,160.25,152.61,144.79,141.78,139.37,134.35,130.88(2C),130.39,127.61(2C),123.03,119.23(2C),119.00,117.87(2C),112.96,112.16,55.57,52.23;MS(ESI)m/z:calcd.for C22H20N2O4[M+Cl]-:411.59,found:410.90。
(14)4-(3-(3'-甲氧基-[1,1'-联苯]-4-基)脲基)苯甲酸(XCY-D2)的制备
将目标化合物XCY-D1(0.10g,0.27mmol)溶于10mL甲醇中,加入KOH(0.15g,2.67mmol),回流搅拌 反应6h。将反应液浓缩后,加适量水,用乙酸乙酯萃取三次(3×50mL)。将有机相合并,用无水Na2SO4干燥。过 滤,真空浓缩,硅胶柱层析(二氯甲烷:甲醇=100:1)得白色固体0.07g,收率67%。熔点:255–257℃。1H NMR (400MHz,DMSO-d6):δ9.35(s,1H,OH),9.18(s,1H,NH),7.90(d,J=8.6Hz,2H,ArH),7.61(q,J=8.6Hz,6H,ArH), 7.41–7.27(m,1H,NH),7.24–7.09(m,2H,ArH),6.89(dd,J=8.1,1.7Hz,1H,ArH),3.81(d,J=9.3Hz,3H,CH3);13C NMR(150MHz,DMSO-d6):δ167.91,160.24,152.77,144.32,141.81,139.56,134.20,130.97(2C),130.38,127.59(2C), 124.75,119.17(2C),119.00,117.73(2C),112.92,112.14,55.56;MS(ESI)m/z:calcd.for C21H18N2O4[M-H]-:361.13,found:361.36。
(15)4-(3-(3'-甲氧基-[1,1'-联苯]-4-基)脲基)-N-甲基苯甲酰胺(XCY-D3)的制备
将目标化合物XCY-D1(0.15g,0.40mmol)溶于5mL甲胺水溶液中,氮气保护下,回流搅拌反应2h。将反 应液浓缩后,加适量水,用乙酸乙酯萃取三次(3×50mL)。将有机相合并,用饱和食盐水洗涤,无水Na2SO4干燥。 过滤,真空浓缩,硅胶柱层析(二氯甲烷:甲醇=100:1)得白色固体0.07g,收率46%。熔点:239–241℃。1H NMR (600MHz,DMSO-d6):δ8.95(s,1H,NH),8.87(s,1H,NH),8.28(q,J=4.3Hz,1H,NH),7.80(d,J=8.7Hz,2H,ArH), 7.65–7.59(m,2H,ArH),7.55(dd,J=12.3,8.8Hz,4H,ArH),7.35(t,J=7.9Hz,1H,ArH),7.23–7.20(m,1H,ArH), 7.18–7.16(m,1H,ArH),6.92–6.87(m,1H,ArH),3.82(s,3H,CH3),2.78(d,J=4.5Hz,3H,CH3);13C NMR(150MHz, DMSO-d6):δ166.76,160.25,152.77,142.71,141.81,139.55,134.18,130.39,128.49(2C),128.23,127.60(2C),119.13 (2C),118.99,117.73(2C),112.93,112.15,55.57,26.65;MS(ESI)m/z:calcd.for C22H21N3O3[M+Cl]-:410.61,found: 411.07。
(16)1-(4-(肼羰基)苯基)-3-(3'-甲氧基-[1,1'-联苯基]-4-基)脲(XCY-D4)的制备
将目标化合物XCY-D1(0.12g,0.32mmol)溶于10mL乙醇中,加入水合肼(0.10g,1.60mmol),氮气保护 下,回流搅拌反应7h。将反应液浓缩后,加适量水,用乙酸乙酯萃取三次(3×50mL)。将有机相合并,用饱和食 盐水洗涤,无水Na2SO4干燥。过滤,真空浓缩,硅胶柱层析(二氯甲烷:甲醇=100:1)得白色固体0.07g,收 率46%。熔点:251–253℃。1H NMR(600MHz,DMSO-d6):δ9.62(s,1H,NH),8.96(s,1H,NH),8.89(s,1H,NH),7.79 (d,J=8.6Hz,2H,ArH),7.62(d,J=8.7Hz,2H,ArH),7.55(dd,J=15.0,8.6Hz,4H,ArH),7.35(t,J=7.9Hz,1H,ArH), 7.21(d,J=7.9Hz,1H,ArH),7.19–7.11(m,1H,ArH),6.90(dd,J=8.2,2.3Hz,1H,ArH),4.47(s,2H,NH2),3.82(s,3H, CH3);13C NMR(150MHz,DMSO-d6):δ166.20,160.24,152.77,142.79,141.80,139.54,134.19,130.39,128.39(2C), 127.60(2C),126.90,119.15(2C),118.99,117.80(2C),112.93,112.14,55.57;MS(ESI)m/z:calcd.forC21H20N4O3[2M+H]+:753.30,found:752.56。
(17)N-羟基-4-(2-(3'-甲氧基-[1,1'-联苯]-4-基)乙酰胺基)苯甲酰胺(XCY-D5)的制备
将中间体13(0.20g,0.53mmol)溶于10mL二氯甲烷和10mL甲醇的混合溶液中,加入盐酸羟胺(1.11g, 15.98mmol)和KOH(0.94g,16.74mmol),氮气保护下,室温下搅拌反应2h。将反应液浓缩后,用乙酸乙酯萃 取三次(3×50mL)。将有机相合并,用饱和食盐水洗涤,无水Na2SO4干燥。过滤,真空浓缩,硅胶柱层析(二氯 甲烷:甲醇=100:1)得白色固体0.05g,收率23%。熔点:179–181℃。1H NMR(400MHz,DMSO-d6):δ11.16(d, J=38.9Hz,1H,OH),10.38(d,J=35.3Hz,1H,NH),8.95(s,1H,ArH),7.79–7.59(m,6H,ArH),7.49–7.30(m,3H,ArH),7.25–7.13(m,2H,ArH),6.93(d,J=7.0Hz,1H,NH),3.82(s,3H,CH3),3.68(d,J=34.0Hz,2H,CH2);13C NMR(150 MHz,DMSO-d6):δ169.93,164.45,160.23,142.17,141.95,138.95,135.60,130.45(2C),130.13(2C),128.18,127.76, 127.22(2C),119.39(2C),118.94,113.38,112.60,55.59,43.44;MS(ESI)m/z:calcd.for C22H20N2O4[M+Cl]-:410.59, found:409.96。
(18)N-羟基-4-(2-((3'-甲氧基-[1,1'-联苯]-4-基)氨基)-2-氧代乙基)苯甲酰胺(XCY-D6)的制备 将中间体14a(0.25g,0.67mmol)溶于10mL二氯甲烷和10mL甲醇的混合溶液中,加入盐酸羟胺(1.39g, 19.98mmol)和KOH(1.16g,20.77mmol),氮气保护下,室温下搅拌反应2h。将反应液浓缩后,用乙酸乙酯萃取三次(3×50mL)。将有机相合并,用饱和食盐水洗涤,无水Na2SO4干燥。过滤,真空浓缩,硅胶柱层析(二氯 甲烷:甲醇=100:1)得白色固体0.08g,收率32%。熔点:191–193℃。1H NMR(400MHz,DMSO-d6):δ11.19(s, 1H,OH),10.31(s,1H,NH),9.02(s,1H,ArH),7.71(dd,J=14.7,8.2Hz,4H,ArH),7.63(d,J=8.5Hz,2H,ArH),7.43(d, J=7.9Hz,2H,ArH),7.35(t,J=7.9Hz,1H,ArH),7.21(d,J=7.7Hz,1H,ArH),7.17(s,1H,ArH),6.90(d,J=6.6Hz,1H,NH),3.82(s,3H,CH3),3.74(s,2H,CH2);13CNMR(150MHz,DMSO-d6):δ169.22,164.72,160.24,141.64,139.65, 139.13,135.35,131.61,130.41,129.62(2C),127.49(2C),127.40,119.98(2C),119.08(2C),113.13,112.21,55.58,43.56; MS(ESI)m/z:calcd.for C22H20N2O4[M+Cl]-:410.59,found:410.92。
(19)N1-羟基-N4-(3'-甲氧基-[1,1'-联苯]-4-基)对苯二甲酰胺(XCY-D7)的制备
将中间体14b(0.16g,0.43mmol)溶于10mL二氯甲烷和10mL甲醇的混合溶液中,加入盐酸羟胺(0.90g, 12.95mmol)和KOH(0.75g,13.33mmol),氮气保护下,室温下搅拌反应2h。将反应液浓缩后,用乙酸乙酯萃 取三次(3×50mL)。将有机相合并,用饱和食盐水洗涤,无水Na2SO4干燥。过滤,真空浓缩,硅胶柱层析(二氯 甲烷:甲醇=100:1)得白色固体0.06g,收率40%。熔点:267–269℃。1H NMR(600MHz,DMSO-d6):δ11.33(s, 1H,OH),10.38(s,1H,NH),9.11(s,1H,ArH),7.98(d,J=7.9Hz,2H,ArH),7.83(t,J=8.7Hz,4H,ArH),7.63(d,J=8.4 Hz,2H,ArH),7.30(t,J=7.8Hz,1H,NH),7.21–7.10(m,2H,ArH),6.85(dd,J=8.0,1.7Hz,1H,ArH),3.76(s,3H,CH3);13C NMR(150MHz,DMSO-d6):δ165.39,163.94,160.27,141.66,139.06,137.59,135.86,130.43,128.24(2C),127.40 (4C),121.16(3C),119.15,113.22,112.30,55.61;MS(ESI)m/z:calcd.for C21H18N2O4[M-H]-:361.13,found:361.20。
(20)N-羟基-4-((1-(4-羟基丁基)-3-(3'-甲氧基-[1,1'-联苯]-4-基)脲基)甲基)苯甲酰胺(XCY-D8)的制备
将中间体16a(0.16g,0.43mmol)溶于10mL二氯甲烷和10mL甲醇的混合溶液中,加入盐酸羟胺(1.74g, 24.95mmol)和KOH(1.46g,26.04mmol),氮气保护下,室温下搅拌反应2h。将反应液浓缩后,用乙酸乙酯萃 取三次(3×50mL)。将有机相合并,用饱和食盐水洗涤,无水Na2SO4干燥。过滤,真空浓缩,硅胶柱层析(二氯 甲烷:甲醇=40:1)得白色固体0.18g,收率48%。熔点:113–115℃。1H NMR(600MHz,DMSO-d6):δ11.18(s,1H, OH),9.01(s,1H,NH),8.52(s,1H,NH),7.74(d,J=7.4Hz,2H,ArH),7.58(s,4H,ArH),7.35(d,J=7.6Hz,3H,ArH),7.24–7.11(m,2H,ArH),6.88(d,J=7.2Hz,1H,ArH),4.64(s,2H,CH2),4.51(s,1H,OH),3.82(s,3H,CH3),3.49–3.36 (m,4H,CH2,CH2),1.57(s,2H,CH2),1.43(s,2H,CH2);13C NMR(100MHz,DMSO-d6):δ164.59,160.22,155.66, 142.77,141.94,140.68,133.81,131.93,130.34,127.52(2C),127.48(2C),127.05(2C),120.53(2C),118.95,112.81, 112.07,61.12,55.55,49.46,46.78,29.77,25.11;MS(ESI)m/z:calcd.for C26H29N3O5[M+Cl]-:498.66,found:497.75。
(21)4-((1-(4-羟基丁基)-3-(3'-甲氧基-[1,1'-联苯]-4-基)脲基)甲基)苯甲酸(XCY-D9)的制备
将中间体16a(0.22g,0.48mmol)溶于20mL甲醇中,加入KOH(0.27g,4.80mmol),回流搅拌反应6h。 将反应液浓缩后,加适量水,用乙酸乙酯萃取三次(3×50mL)。将有机相合并,用无水Na2SO4干燥。过滤,真空 浓缩,硅胶柱层析(二氯甲烷:甲醇=100:1)得白色固体0.09g,收率42%。熔点:67–69℃。1H NMR(400MHz, DMSO-d6):δ12.86(s,1H,OH),8.54(s,1H,NH),7.94(d,J=8.0Hz,2H,ArH),7.63–7.54(m,4H,ArH),7.40(d,J=8.0 Hz,2H,ArH),7.34(t,J=7.9Hz,1H,ArH),7.20(d,J=7.7Hz,1H,ArH),7.16(s,1H,ArH),6.88(d,J=8.0Hz,1H,ArH), 4.68(s,2H,CH2),4.52(s,1H,OH),3.82(s,3H,CH3),3.39(d,J=17.3Hz,4H,CH2CH2),1.56(dd,J=13.9,7.1Hz,2H, CH2),1.43(dd,J=13.7,6.6Hz,2H,CH2);13C NMR(100MHz,DMSO-d6):δ167.66,160.20,155.65,144.75,141.92, 140.65,133.82,130.33,129.99(2C),129.89,127.63(2C),127.04(2C),120.54(2C),118.94,112.81,112.05,61.12,55.54,49.56,46.85,29.86,25.11;MS(ESI)m/z:calcd.for C26H28N2O5[2M-H]-:895.40,found:894.73。
(22)1-(4-(肼羰基)苄基)-1-(4-羟基丁基)-3-(3'-甲氧基-[1,1'-联苯]-4-基)脲(XCY-D10)的制备
将中间体16a(0.16g,0.35mmol)溶于15mL乙醇中,加入水合肼(0.09g,1.73mmol),氮气保护下,回流 搅拌反应7h。将反应液浓缩后,加适量水,用乙酸乙酯萃取三次(3×50mL)。将有机相合并,用饱和食盐水洗涤, 无水Na2SO4干燥。过滤,真空浓缩,硅胶柱层析(二氯甲烷:甲醇=100:1)得白色固体0.07g,收率43%。熔 点:165–167℃。1H NMR(600MHz,DMSO-d6):δ9.01(s,1H,NH),8.52(s,1H,NH),7.74(d,J=7.4Hz,2H,ArH),7.58 (s,4H,ArH),7.35(d,J=7.6Hz,3H,ArH),7.24–7.11(m,2H,ArH),6.88(d,J=7.2Hz,1H,ArH),4.64(s,4H,CH2,NH2), 4.51(s,1H,OH),3.82(s,3H,CH3),3.49–3.36(m,4H,CH2CH2),1.57(s,2H,CH2),1.43(s,2H,CH2);13C NMR(100 MHz,DMSO-d6):δ167.20,161.10,155.10,144.75,141.92,140.65,133.82,130.33,129.99(2C),129.89,127.63(2C), 127.04(2C),120.54(2C),118.94,112.81,112.05,61.12,55.54,49.56,46.85,29.86,25.11;MS(ESI)m/z:calcd.for C26H30N4O4[M-H]-:461.23,found:461.12。
(23)4-((1-丁基-3-(3'-甲氧基-[1,1'-联苯]-4-基)脲基)甲基)-N-羟基苯甲酰胺(XCY-D11)的制备
将中间体16b(0.31g,0.69mmol)溶于10mL二氯甲烷和10mL甲醇的混合溶液中,加入盐酸羟胺(1.44g, 20.68mmol)和KOH(1.20g,21.39mmol),氮气保护下,室温下搅拌反应2h。将反应液浓缩后,用乙酸乙酯萃 取三次(3×50mL)。将有机相合并,用饱和食盐水洗涤,无水Na2SO4干燥。过滤,真空浓缩,硅胶柱层析(二氯 甲烷:甲醇=40:1)得淡红色固体0.16g,收率52%。熔点:101–103℃。1H NMR(400MHz,DMSO-d6):δ11.19(s, 1H,OH),9.01(s,1H,NH),8.49(s,1H,NH),7.74(d,J=7.9Hz,2H,ArH),7.59(d,J=9.3Hz,4H,ArH),7.34(t,J=7.4 Hz,3H,ArH),7.20(d,J=7.7Hz,1H,ArH),7.15(s,1H,ArH),6.88(d,J=8.0Hz,1H,ArH),4.65(s,2H,CH2),3.82(s, 3H,CH3),3.32(d,J=7.3Hz,2H,CH2),1.51(dd,J=14.2,7.2Hz,2H,CH2),1.30–1.24(m,2H,CH2),0.87(t,J=7.3Hz, 3H,CH3);13C NMR(100MHz,DMSO-d6):δ164.57,160.22,155.66,142.76,141.94,140.68,133.81,131.95,130.34, 127.53(2C),127.48(2C),127.03(2C),120.58(2C),118.95,112.81,112.06,55.55,49.55,46.65,30.45,19.94,14.27;MS (ESI)m/z:calcd.for C26H29N3O4[M+Cl]-:482.67,found:481.68。
(24)4-((1-丁基-3-(3'-甲氧基-[1,1'-联苯]-4-基)脲基)甲基)苯甲酸(XCY-D12)的制备
将中间体16b(0.20g,0.45mmol)溶于20mL甲醇中,加入KOH(0.25g,4.50mmol),回流搅拌反应6h。 将反应液浓缩后,加适量水,用乙酸乙酯萃取三次(3×50mL)。将有机相合并,用无水Na2SO4干燥。过滤,真空 浓缩,硅胶柱层析(二氯甲烷:甲醇=100:1)得白色固体0.08g,收率40%。熔点:125–127℃。1H NMR(400MHz, DMSO-d6):δ12.87(s,1H,OH),8.51(s,1H,NH),7.94(d,J=8.1Hz,2H,ArH),7.58(s,4H,ArH),7.40(d,J=8.0Hz,2H, ArH),7.34(t,J=7.9Hz,1H,ArH),7.20(d,J=7.6Hz,1H,ArH),7.15(s,1H,ArH),6.94–6.81(m,1H,ArH),4.68(s,2H,CH2),3.82(s,3H,CH3),3.26(s,2H,CH2),1.49(dd,J=14.3,7.5Hz,2H,CH2),1.25(dd,J=14.1,6.7Hz,2H,CH2),0.87 (t,J=7.3Hz,3H,CH3);13C NMR(150MHz,DMSO-d6):δ167.62,160.25,155.69,144.72,141.98,140.67,133.88, 130.31,129.96(2C),127.65(2C),127.01(2C),120.62(2C),120.52,118.97,112.84,112.12,55.58,49.71,46.75,30.45,19.92,14.22;MS(ESI)m/z:calcd.for C26H28N2O4[M+H]+:433.20,found:433.12。
(25)1-丁基-1-(4-(肼羰基)苄基)-3-(3'-甲氧基-[1,1'-联苯]-4-基)脲(XCY-D13)的制备
将中间体16b(0.20g,0.45mmol)溶于15mL乙醇中,加入水合肼(0.11g,2.25mmol),氮气保护下,回流 搅拌反应7h。将反应液浓缩后,加适量水,用乙酸乙酯萃取三次(3×50mL)。将有机相合并,用饱和食盐水洗涤, 无水Na2SO4干燥。过滤,真空浓缩,硅胶柱层析(二氯甲烷:甲醇=100:1)得白色固体0.09g,收率45%。熔 点:145–147℃。1H NMR(400MHz,DMSO-d6):δ9.01(s,1H,NH),8.49(s,1H,NH),7.74(d,J=7.9Hz,2H,ArH),7.59 (d,J=9.3Hz,4H,ArH),7.34(t,J=7.4Hz,3H,ArH),7.20(d,J=7.7Hz,1H,ArH),7.15(s,2H,ArH),6.88(d,J=8.0Hz,2H,NH2),4.65(s,2H,CH2),3.82(s,3H,CH3),3.32(d,J=7.3Hz,2H,CH2),1.51(dd,J=14.2,7.2Hz,2H,CH2), 1.30–1.24(m,2H,CH2),0.87(t,J=7.3Hz,3H,CH3);13CNMR(150MHz,DMSO-d6):δ166.71,160.25,157.80,147.56, 142.00,140.13,133.47,130.29,129.46(2C),128.45(2C),127.34(2C),118.91(2C),118.89,112.76,112.09,55.55,53.15,52.39,48.89,32.16,20.42,14.35;MS(ESI)m/z:calcd.for C26H30N4O3[M+Cl]-:481.68,found:481.68。
实施例2化合物对HDAC6的抑制活性检测
使用7-氨基-4-甲基香豆素(AMC)荧光分析法对实施例1中所述化合物进行HDAC6抑制活性检测。与传统 的紫外分析法相比,该方法灵敏度更高、误差更小。其检测原理主要分为两步:第一步,利用一种特殊的肽链荧光 底物(Boc-Lys(acetyl)-AMC),其包含一个乙酰赖氨酸残基和一个荧光团7-氨基-4-甲基香豆素(AMC),该荧光底物在HDAC6酶和待测化合物的作用下脱去乙酰基,底物脱去乙酰基后被激活,释放出胰酶水解底物 Boc-Lys-AMC。第二步,Boc-Lys-AMC在胰酶的作用下水解,释放出荧光团7-氨基-4-甲基香豆素(AMC),在发 射波长/激发波长355nm/460nm处测定AMC的荧光强度。由于化合物抑制效果不同,产生不同数量的荧光团,因 而有不同的吸光度,根据吸光度可求得化合物对HDAC6酶的抑制率。
(1)缓冲液(Buffer)的配制:配制1×缓冲液(含15mM Tris-HCl(pH 8.0),250μMEDTA,250mM NaCl, 10%甘油)。
(2)HDAC6酶溶液的配制:用1×缓冲液对酶溶液进行适当的稀释。
(3)待测化合物溶液的配制:取2.0mg左右的目标化合物和阳性对照药SAHA溶解在不同体积的100%DMSO 中,再用1×缓冲液稀释,DMSO的最终比例为1%。
(4)荧光底物溶液的配制:用DMSO溶解配成30mM的储液,用1×缓冲液稀释至300μM。
(5)胰酶(Trypsin)溶液:胰酶溶液含10mg/mL胰酶,50mM Tris-HCl(pH 8.0),100mM NaCl,2μM TSA。
(6)吸取50μL待测化合物溶液加入384孔板中,每个浓度设置3个复孔,阴性对照组和空白组各加入50μL 缓冲液,再吸取10μL配制好的HDAC6酶溶液,分别加入实验组和阴性对照组,空白组补加10μL缓冲液,加完 后在37℃恒温摇床摇5min,让化合物与HDAC6充分结合。
(7)吸取40μL配置好的荧光底物溶液加入各孔,在37℃恒温摇床孵育30min,让底物与HDAC6充分反应。
(8)吸取100μL配制好的含胰酶的TSA终止液加入各孔,在37℃恒温摇床摇20min。
(9)反应结束后,在激发波长355nm下,测定460nm波长处的发射光强度。
(10)实验数据处理:抑制率=(阴性对照组荧光值-实验组荧光值)/(阴性对照组荧光值-空白组荧光值)×100%。
实施例1中所述化合物对HDAC6酶的抑制率结果如下表1所示:
表1
实验结果:根据表1的结果显示,1μM浓度下,上述化合物中,XCY-A1、XCY-A2、XCY-A4、XCY-C1、XCY-C4、 XCY-D5、XCY-D6、XCY-D7、XCY-D8、XCY-D11对HDAC6酶的抑制率均超过了70%,表明上述化合物具有良 好的酶抑制活性;进一步的,化合物XCY-A2、XCY-A4、XCY-C2、XCY-C4、XCY-D5、XCY-D6、XCY-D8、XCY-D11 的抑制率超过了95%,与阳性药物SAHA相当。
实施例3血管舒张活性实验
实验原理:离体血管环实验是研究血管舒缩功能的一种实验,利用该实验来检测化合物对血管的舒张活性。随 着实验装置的不断推陈出新,目前使用较广泛的是620M型多通道离体血管张力测定系统(DMT公司,丹麦)。其 检测原理为:首先分离血管,迅速清除其周围的结缔组织和脂肪组织,切成2–3mm长的血管环,再用金属丝或钨 丝穿过血管环并悬挂于张力浴槽内,连接张力换能器和计算机,测定并记录离体血管的舒缩活动,常用于研究大鼠肠系膜动脉、大鼠脑基底动脉、小鼠肠系膜动脉、小鼠主动脉、髂动脉、颈动脉、肾动脉等微小血管的功能。
实验材料与仪器:4–6周的雄性C57BL/6小鼠,苯肾上腺素(Phe,Sigma-Aldrich),KCl,左旋硝基精氨酸甲 酯(L-NAME,Sigma-Aldrich),亚甲蓝(Sigma-Aldrich),二甲基亚砜(DMSO,Sigma-Aldrich),乙酰胆碱(Ach), 待测化合物,动物解剖台,手术解剖显微镜,620M型多通道离体血管张力测定仪,氧气瓶,微型真空泵,培养皿, 水浴锅,常用动物手术器械等。
实验方法:
(1)取4–6周大的雄性C57BL/6小鼠,采用颈椎脱臼法处死后,迅速打开胸腔,取胸主动脉,在充入100%O2饱和4℃预冷的Krebs-Henseleit(K-H)液(pH=7.4)中浸泡以维持血管活性,洗净血污。显微操作去除血管周围 结缔组织及脂肪组织。K-H液成分为(mmol/L):NaCl 119.0,NaHCO3 25.0,MgCl2 1.0,KCl 4.7,KH2PO4 1.2,CaCl22.5,D-glucose 11.0。
(2)每条胸主动脉可切成4条2mm的血管环,将血管环标本通过两根细钢丝与DMT血管张力测量系统相连, 水平悬挂于5mL含K-H液的恒温浴槽内,使用Power Lab数据采集分析系统记录血管张力的变化。调节基础张力 至3mN,平衡60min,期间每隔20min换一次K-H液,并使张力维持在3mN。在实验全程,浴槽内的K-H液持 续通以100%O2,温度控制在37±0.5℃。
(3)血管张力稳定后,将浴槽内的K-H液置换为60mM KCl的K-H液(NaCl 63.7,NaHCO3 25.0,MgCl2 1.0, KCl 60.0,KH2PO4 1.2,CaCl2 2.5,D-glucose 11.0),检测血管的反应性。高钾使胸主动脉产生收缩反应,维持10min 后,充分冲洗(3次,每次间隔10min)至基线,30min后,重复上述实验。
(4)前后两次高钾刺激后,血管收缩的幅度差值<10%,说明血管活性良好。
(5)重新平衡血管环30min,用血管收缩剂Phe(1×10-6M)引起血管持续性收缩,再加入血管舒张剂Ach(1×10-5M),检测血管内皮的完整情况。若血管的舒张幅度>60%,视为内皮完整,可用于后续实验。
(6)分别用受体依赖性收缩剂Phe(1×10-6M)或非受体依赖性收缩剂KCl(60mM)预收缩内皮完整的血管 环,待血管张力达到稳定平台后,加入累积浓度的溶于DMSO的待测化合物,计算血管舒张率。根据加入待测化 合物的时间,加入等体积的DMSO作为对照。
(7)血管舒张率(%)=(Phe或60mM KCl诱发的血管环最大收缩张力-给予化合物后血管环张力)/(Phe 或60mM KCl诱发的血管环最大收缩张力-血管环基础张力)×100%。
实验结果:图1给出的是部分化合物在小鼠主动脉段暴露于1×10-6mol/L的α-肾上腺素能受体激动剂苯肾上腺 素(Phe)以诱导收缩的血管舒张活性结果。其中,XCY-A3、XCY-C1、XCY-D7、XCY-D8、XCY-D10在3μM~300μM 浓度范围内能够有效舒张由Phe诱导的血管收缩。XCY-A3最大舒张率为39.7%,XCY-C1最大舒张率为11.2%, XCY-D7最大舒张率为23.6%,XCY-D8最大舒张率为21.61%,XCY-D10最大舒张率为36.83%。
图2给出的是部分化合物在小鼠主动脉段暴露于60mM KCl以诱导收缩的血管舒张活性结果。其中,XCY-A3、 XCY-A4、XCY-C1、XCY-C2、XCY-C4、XCY-D10、XCY-D13在3μM~300μM浓度范围内均能有效舒张由60mM KCl诱导的血管收缩。XCY-A3最大舒张率为13.96%,XCY-A4最大舒张率为16.01%,XCY-C1最大舒张率为23.49%, XCY-C2最大舒张率为22.35%,XCY-C4最大舒张率为21.93%,XCY-D10最大舒张率为72.49%,XCY-D13最大舒 张率为60.26%。
实施例4化合物XCY-D6的HIV潜伏病毒激活活性结果
实验原理:本实施例建立了用于高通量筛选的J-Lat细胞模型来初步评价化合物激活HIV潜伏病毒的效果。 J-Lat10.6细胞是使用HIV-1假病毒感染Jurkat细胞后,筛选出的GFP阴性的细胞,该部分细胞在潜伏激活剂处理 后GFP的表达会迅速升高。本实施例使用不同的化合物处理细胞48小时后,在荧光显微镜下观察GFP的表达情况。 GFP的表达越强荧光强度越高,表明该化合物是潜伏激活剂。
实验结果:结果表明采用XCY-D6(1000IU/ml)处理后,GFP阳性的J-Lat细胞中GFP的表达都有不同程度 的上调,尤其是在12μM浓度下GFP的表达最强,表明该化合物是潜在的潜伏病毒激活剂(图3)。
实施例5化合物与HDAC6的对接研究
实验原理:SYBYL是美国Tripos公司开发的计算机分子模拟软件,其中Surflex-Dock分子对接模块采用独特 的经验打分函数和拥有专利的搜索引擎(基于分子相似性的搜索引擎)将配体分子对接到蛋白的结合位点,属于柔性对接技术,同时支持考虑生物大分子蛋白残基柔性的对接,是化合物虚拟活性筛选的主要考量因素,可为发现新 型HDAC6靶点先导化合物及其结构改造和修饰提供理论支撑和技术指导。
实验步骤:1)从蛋白质数据库中下载HDAC6复合物晶体结构6CW8。2)配体优化:在对接软件中画出配体 分子,进一步优化处理在SYBYL配体准备模块(ligand structurepreparation)进行。首先,对配体分子进行加氢处理;然后,进行能量优化,参数设置如下:力场设定为Tripos力场,能量优化计算方法为Powell,梯度为最大迭代次数为10000次。3)受体优化:在SYBYL Surflex-Dock蛋白准备模块(prepare proteinstructure)对6CW8 进行优化处理。首先将复合物晶体结构中的配体抽提出来,对蛋白进行加氢处理。然后,以复合物晶体结构中配体 分子的坐标为中心生成原型分子即对接口袋,保存当前生成的文件用于下一步分子对接操作。4)配体分子与HDAC6 蛋白分子对接:为了检验分子对接软件的对接效果,并进一步确定HDAC6抑制剂与蛋白对接的合适参数,在SYBYL Surflex-Dock模块,将配体分子对接回蛋白活性口袋。选择Surflex-Dock对接模式,导入处理后的受体分子和配体 分子,对接参数设置如下:每个片段的最大生成构象(Maxconformations per Fragment)为20,每个配体分子最大输 出构象(Maximum Number ofPoses per Ligand)为20,最终保留对接构象间的RMSD值(Minimum RMSD Between FinalPoses)为/>为了比较对接构象与结晶构象之间的差异,设定6CW8中。
结果分析:如图4所示,化合物XCY-A2的ZBG区域与水合的催化金属Zn2+螯合,ZBG区中的OH与氨基酸 残基H574形成氢键相互作用,Linker区酰胺基中的NH与关键氨基酸残基S531形成氢键相互作用,Cap区占据表 面识别区,形成稳定的疏水相互作用,这一定程度上解释了该化合物优异的HDAC6抑制活性。
以上所述仅为本发明的优选实施例而已,并不用于限制本发明,对于本领域的技术人员来说,本发明可以有各 种更改和变化。凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范 围之内。
Claims (14)
2.如权利要求1所述化合物,其特征在于,所述化合物的药用盐,为所述化合物与无机酸或有机酸形成的盐;所述无机酸为盐酸、硫酸、硝酸或氢溴酸,所述有机酸为甲磺酸、甲苯磺酸或三氟乙酸。
3.如权利要求1所述化合物,其特征在于,式I所示化合物具体如下:
3-(2-(1H-吲哚-3-基)乙酰氨基)-N-羟基苯甲酰;
4-(2-(1H-吲哚-3-基)乙酰氨基)-N-羟基苯甲酰;
2-(3-(2-(1H-吲哚-3-基)乙酰氨基)苯基)-N-羟基乙酰胺;
2-(4-(2-(1H-吲哚-3-基)乙酰氨基)苯基)-N-羟基乙酰胺。
5.如权利要求1所述化合物,其特征在于,式II所示化合物具体如下:
N-羟基-3-(2-(萘-2-基)乙酰氨基)苯甲酰胺;
N-羟基-4-(2-(萘-2-基)乙酰氨基)苯甲酰胺;
N-羟基-2-(3-(2-(萘-2-基)乙酰胺基)苯基)乙酰胺;
N-羟基-2-(4-(2-(萘-2-基)乙酰胺基)苯基)乙酰。
7.一种药物组合物,其特征在于,所述药物组合物中包括权利要求1-6任一项所述化合物及药物载体,所述药物组合物施用于受试者,用于实现预防、改善或治疗疾病的目的。
8.如权利要求7所述药物组合物,其特征在于,所述受试者为哺乳动物,所述哺乳动物为人、猴、兔、狗或鼠。
9.如权利要求8所述药物组合物,其特征在于,所述受试者为人。
10.如权利要求7所述药物组合物,其特征在于,所述药物组合物的剂型为液体剂型、固体剂型;其中,液体剂型选自真溶液类、胶体类、微粒剂型、乳剂剂型、混悬剂型;所述固体剂型选自片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、乳剂、颗粒剂、栓剂、冻干粉针剂、包合物、填埋剂、贴剂、擦剂。
11.权利要求1-6任一项所述化合物、权利要求7-10所述药物组合物作为HDAC抑制剂的应用。
12.如权利要求11所述化合物、药物组合物作为HDAC抑制剂的应用,其特征在于,所述作为HDAC抑制的应用为以下任意一种方式:
(1)用于制备HDAC抑制模型的模型药剂;
(2)用于预防、改善或治疗与HDAC相关疾病;
(3)用于制备与HDAC相关疾病的治疗药物;
上述(1)方面,所述模型药剂用于制备疾病模型,包括细胞、组织或动物模型;
上述(2)、(3)方面中,所述HDAC相关疾病表示以HDAC作为治疗靶点的疾病,或在疾病表征中出现了HDAC的异常高表达。
13.如权利要求12所述化合物、药物组合物作为HDAC抑制剂的应用,其特征在于,所述HDAC相关疾病为淋巴瘤、三阴乳腺癌、非小细胞肺癌、骨髓瘤、结肠癌、前列腺癌、艾滋病或高血压。
14.一种舒张血管或降血压的药物,其特征在于,所述药物中包括权利要求1-6任一项所述化合物、权利要求7-10所述药物组合物。
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