CN116425733A - 靶向泛素化降解Pin1蛋白的化合物及其药用组合物和应用 - Google Patents
靶向泛素化降解Pin1蛋白的化合物及其药用组合物和应用 Download PDFInfo
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Abstract
本发明公开了一种靶向泛素化降解Pin1蛋白的化合物及其药用组合物和应用。其结构如式I所示，具有抑制Pin1蛋白活性与降解Pin1蛋白活性，可有效抑制白血病MV‑4‑11细胞恶性增殖。因此本发明可用于与Pin1蛋白异常表达的相关疾病，如各种癌症。
Description
技术领域
本发明涉及药物化学领域，具体涉及一类靶向泛素化降解Pin1蛋白的化合物及其药用组合物和应用。
背景技术
白血病是一类造血干细胞的恶性克隆性疾病，是血液肿瘤。除了有普通肿瘤生长快，不易死，会转移到其他器官的特点外，与肝癌，胃癌这种实体肿瘤不同的是，白血病是没法用手术切除治疗的，而且化疗，放疗的治疗效果也无法保证，因此治疗难度更大。由于胰腺是位于胃和脊柱之间，深藏于腹部深处的腺体，患者早期症状不典型，起病隐匿；多数患者确诊时已处于疾病晚期，丧失手术机会，导致胰腺癌预后差，多数患者确诊后生存期仅为1年左右。诊断困难，治疗效果差是胰腺癌被称为“癌王”的主要原因。
Pin1蛋白功能的异常活化或过表达通常(1)脯氨酸异构酶Pin1调节多种癌症相关通路。在多种肿瘤中，Pin1异常激活可直接或间接引起60种原癌蛋白被激活，以及超过30种抑制因子被抑制，从而促进肿瘤生成，其中包括血液肿瘤和胰腺癌。Pin1基因敲除鼠发育正常，且肿瘤生成受到显著抑制。因此，Pin1是一个极具潜力的抗肿瘤靶点。
泛素介导的蛋白降解是细胞内蛋白质最主要的负向调节方式。泛素-蛋白酶体系统(UPS)负责清理细胞中误用或者有害的蛋白，是细胞内的“清洁工”，维持了细胞内蛋白质的平衡。蛋白水解靶向嵌合体(PROTACs)是一类异双功能分子，能够同时结合兴趣蛋白和E3泛素连接酶，泛素化和降解兴趣蛋白。具有催化降解的特点，给药量低。
因此，通过设计合成对Pin1蛋白具有更强活性的反向激动剂，并将蛋白水解靶向嵌合体(PROTACs)技术应用于Pin1蛋白。可为Pin1作为药物开发靶点，白血病的治疗以及PROTAC技术的开发应用可行性提供重要的参考。
发明内容
针对上述问题，本发明的其中一个目的在于提供一种新型靶向泛素化降解Pin1蛋白的化合物或其药学可接受的盐、水合物或者溶剂化物。
基于上述目的，本发明提供了以下技术方案；
本发明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、水合物或溶剂化物：
其中：
R1选自
R2为(-CH2-)n，n选自1-4的整数；即R2可以是(-CH2-)1、(-CH2-)2、(-CH2-)3、(-CH2-)4；
L选自C4-18烷基、烷氧基或-R3-C(＝O)NH-R4-组成的组；L选自C4-18烷基时，其包括但不限于C4烷基、C5烷基、C6烷基、C7烷基、C8烷基、C9烷基、C10烷基、C11烷基、C12烷基、C13烷基、C14烷基、C15烷基、C16烷基、C17烷基、C18烷基。
R3选自C1-6烷基，具体可以是C1烷基、C2烷基、C3烷基、C4烷基、C5烷基、C6烷基；
R4选自C3-14烷基或-CH2-(-CH2-O-CH2-)m-CH2-，m选自1-4的整数；R4具体可以是C3烷基、C4烷基、C5烷基、C6烷基、C7烷基、C8烷基、C9烷基、C10烷基、C11烷基、C12烷基、C13烷基、C14烷基、-CH2-(-CH2-O-CH2-)1-CH2-、-CH2-(-CH2-O-CH2-)2-CH2-、-CH2-(-CH2-O-CH2-)3-CH2-、-CH2-(-CH2-O-CH2-)4-CH2-；R4优选C12烷基或-CH2-(-CH2-O-CH2-)3-CH2-；
X为-CH2-、-NH-或-O-；
A任选以下的组：
此外，通常而言，L不具有方向性，可以通过左侧与酰胺连接、右侧与A相连，也可以左侧与A相连、右侧与酰胺相连。但在某些优选情况下，当L为-R3-C(＝O)NH-R4-时，优选R3侧与酰胺相连，R4侧与X相连。
作为优选，所述的化合物或其药学上可接受的盐、水合物或溶剂化物具有式II所示结构：
L选自C4-18烷基、烷氧基或-R3-C(＝O)NH-R4-组成的组；
R3选自C1-6烷基；
R4选自C3-14烷基或-CH2-(-CH2-O-CH2-)m-CH2-，m选自1-4的整数，m优选3；
X为-CH2-、-NH-或-O-；
A任选以下的组：
作为优选，X为-NH-。
作为优选，所述的化合物或其药学上可接受的盐、水合物或溶剂化物具有式III所示结构：
X为-CH2-、-NH-或-O-；
n选自1-4的整数；
A任选以下的组：
作为优选，所述的化合物或其药学上可接受的盐、水合物或溶剂化物具有式IV所示结构：
n选自1-4的整数；
L选自C4-18烷基、烷氧基或-R3-C(＝O)NH-R4-组成的组；
R3选自C1-6烷基；
R4选自C3-14烷基或-CH2-(-CH2-O-CH2-)m-CH2-，m选自1-4的整数；
X为-CH2-、-NH-或-O-。
作为优选，化合物或其药学上可接受的盐、水合物或溶剂化物具有式V所示结构：
L选自C4-18烷基、烷氧基或-R3-C(＝O)NH-R4-组成的组；
R3选自C1-6烷基；
R4选自C3-14烷基或-CH2-(-CH2-O-CH2-)m-CH2-，m选自1-4的整数；
X为-CH2-、-NH-或-O-。
进一步优选，X为-NH-。
更进一步优选，L为-CH2CH2CONH(-CH2-)12-。
作为优选，所述化合物或其药学上可接受的盐、水合物或溶剂化物选自：
本发明另一方面还提供了一种上述化合物或其药学上可接受的盐、水合物或溶剂化物在制备预防或治疗与Pin1蛋白活性异常表达相关的疾病的药物中的应用。
作为优选，所述与Pin1蛋白活性异常表达相关的疾病包括：肿瘤、高血糖、糖尿病、肥胖、高血脂症、高胆固醇血症、高脂蛋白血症、高甘油三酯血症、高血压、高胰岛素血症、高尿酸血症、帕金森病、阿兹海默病。
本发明另一方面还提供了一种上述化合物或其药学上可接受的盐、水合物或溶剂化物在制备预防治疗或预防与肿瘤或防止肿瘤术后复发的药物中的应用。
作为优选，所述肿瘤为：非小细胞肺癌、恶性黑色素瘤、前列腺癌、肾癌、膀胱癌、卵巢癌、结肠癌、直肠癌、乳腺癌、宫颈癌、肺癌、喉癌、鼻咽癌、胰腺癌或多发性骨髓瘤、B淋巴瘤、白血病中的一种或几种。
本发明另一方面还提供了一种组合物，含有上述任一项所述的化合物或其药学上可接受的盐、水合物或溶剂化物。
基于上述方案，本发明具有以下有益的效果：
本发明提供的化合物，具有抑制Pin1蛋白活性与降解Pin1蛋白活性，可有效抑制白血病MV-4-11细胞恶性增殖。因此本发明可用于与Pin1蛋白异常表达的相关疾病，如各种癌症。
该化合物可以有效抑制Pin1蛋白，并具有Pin1靶蛋白降解功能。其蛋白降解机理是通过该分子同时结合Pin1蛋白和E3泛素连接酶，随后泛素化和降解靶蛋白。该化合物能够明显抑制肿瘤细胞的增殖，可为Pin1作为药物开发靶点的研究与开发。白血病的治疗以及PROTAC技术的开发应用可行性提供了重要的参考。
附图说明
图1为片段S1-S6的化学结构。
图2为Sulfopin与化合物1对多种急性髓细胞性白血病细胞的增殖抑制作用。
具体实施方式
以下将通过实施例来详细说明本申请的实施方式，借此对本申请如何应用技术手段来解决技术问题并达成技术功效的实现过程能充分理解并据以实施。
本申请中所用原料、设备，若无特别说明，均为本领域的常用原料、设备，均来自市售产品。本申请中所用方法，若无特别说明，均为本领域的常规方法。
本申请还存在其它多种可实施的技术方案，在此不做一一列举，本申请权利要求中要求保护的技术方案都是可以实施的。
“包含”或“包括”旨在表示组合物(例如介质)和方法包括所列举的要素，但不排除其他要素。当用于定义组合物和方法时，“基本上由……组成”意味着排除对于所述目的的组合具有任何重要意义的其他要素。因此，基本上由本文定义的元素组成的组合物不排除不会实质上影响要求保护的本申请的基本和新颖特征的其他材料或步骤。“由……组成”是指排除其他组成部分的微量元素和实质性的方法步骤。由这些过渡术语中的每一个定义的实施方案都在本申请的范围内。
下面结合附图对本发明做进一步说明。
实施例1：合成M6
步骤1：合成M2
将化合物M1(1.03g,10mmol)、琥珀酸单叔丁酯(1.74g,10mmol)溶于N,N-二甲基甲酰胺(10ml)中，加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(3.8g,10mmol)、N,N-二异丙基乙胺(2.6ml,15mmol)，室温搅拌2小时。监测反应完成后，加入水和乙酸乙酯萃取，合并有机相，水洗，饱和食盐水洗，无水硫酸钠干燥，旋干溶剂，柱层析纯化，得到白色固体M2，(2.07g,80％yield).1HNMR(500MHz,Chloroform-d)δ6.40–6.28(m,1H),4.02–3.90(m,1H),3.11(d,J＝5.9Hz,2H),3.06(d,J＝6.8Hz,2H),2.57(t,J＝6.6Hz,2H),2.44(t,J＝6.6Hz,2H),1.42(s,9H),0.85(s,6H).13C NMR(126MHz,Chloroform-d)δ173.69,172.32,81.00,67.95,46.43,36.83,31.21,30.96,28.04,22.61.UPLC-MS(ESI)for[M+H]+260.18.
步骤2:合成M3
将中间体M2(1.55g,6mmol)溶于二氯甲烷中(10mL)，随后缓慢加入戴斯马丁氧化试剂(2.5g,6mmol，溶解于20mL二氯甲烷中).混合溶液室温搅拌5小时。反应完全后，加入硫代硫酸钠溶液(20mL,0.5M)直至体系澄清，随后水洗(20mL)，饱和食盐水洗(20mL)，浓缩后柱层析纯化，得到化合物M3，白色固体(1.33g,86％yield).1H NMR(500MHz,Chloroform-d)δ9.42(s,1H),3.34(d,J＝6.5Hz,2H),2.53(t,J＝6.7Hz,2H),2.38(t,J＝6.8Hz,2H),1.42(s,9H),1.07(s,6H).13CNMR(126MHz,Chloroform-d)δ205.30,172.24,171.96,80.80,47.50,44.15,31.25,30.82,28.04,19.61.UPLC-MS(ESI)for[M+H]+258.18.
步骤3:合成M4
将化合物M3(1.29g,5mmol)溶于1,2-二氯乙烷(8mL)，随后加入3-氨基环丁砜盐酸盐(CAS:51642-03-6,858mg,5mmol)，三乙酰氧基硼氢化钠(3.18g,15mmol)，混合溶液室温搅拌1天。反应完全后，加入饱和碳酸氢钠溶液淬灭，乙酸乙酯(3×10mL)萃取，合并有机相，分别用水和饱和食盐水洗。旋干溶剂，柱层析纯化得化合物M4，白色固体(2.8g,67％yield).1H NMR(500MHz,Chloroform-d)δ6.53(s,1H),3.55–3.47(m,1H),3.36–3.30(m,1H),3.23–3.14(m,2H),3.09–2.98(m,3H),2.60–2.53(m,2H),2.44–2.37(m,3H),2.36–2.31(m,2H),2.20–2.08(m,1H),1.43(s,9H),0.90(s,6H).13C NMR(126MHz,Chloroform-d)δ172.50,172.28,80.73,56.84,56.14,55.80,50.39,47.58,35.26,31.36,30.96,29.79,28.11,24.33,24.20.UPLC-MS(ESI)for[M+H]+377.21.
步骤4:合成M5
将中间体M4(1.88g,5mmol)溶于二氯甲烷(10mL)，冰浴条件下缓慢加入乙酰氯(355μL,5mmol)和三乙胺(837μL,6mmol)。混合溶液室温下搅拌1小时。反应完全后，加水淬灭，二氯甲烷(3×10mL)萃取，合并有机相，并用水(10mL)和饱和食盐水(10mL)洗涤。有机相旋干，柱层析纯化，得化合物M5，白色固体(2.08g,92％yield).1HNMR(500MHz,Chloroform-d)δ6.26–6.13(m,1H),4.17–4.06(m,2H),3.97–3.86(m,1H),3.74–3.62(m,2H),3.34(d,J＝15.8Hz,1H),3.22(d,J＝15.7Hz,1H),3.17–3.09(m,3H),3.06–2.98(m,1H),2.62–2.57(m,2H),2.54–2.46(m,2H),2.45–2.38(m,2H),1.42(s,9H),0.98(s,6H).13C NMR(126MHz,Chloroform-d)δ172.77,172.59,167.95,81.10,58.48,57.66,50.40,49.10,48.20,42.29,38.04,31.30,30.63,28.07,26.58,23.87,23.80.UPLC-MS(ESI)for[M+H]+453.18.
步骤5:合成M6
将中间体M5(452mg,1mmol)溶于二氯甲烷(10ml)中，加入三氟乙酸(3ml),室温搅拌2小时。监测反应完全后，停止反应，旋干溶剂得到粘稠状中间体M6，直接用于下一步，无需纯化,UPLC-MS(ESI)for[M+H]+397.22。
实施例2：化合物1的合成
将中间体M6(1mmol)与片段S1(S1-S6的化学结构见图1)(1mmol)溶于N,N-二甲基甲酰胺(4ml)中，加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(1mmol)，N,N-二异丙基乙胺(1.5mmol)，室温反应2小时。反应完成后，加入水(10ml)，用乙酸乙酯萃取(3×10ml)萃取，合并有机相，分别用水、饱和食盐水洗涤，无水硫酸钠干燥，旋去溶剂，柱层析纯化分离，得化合物1，黄色固体，收率84％。1H NMR(500MHz,Methanol-d4)δ7.55(d,J＝8.4Hz,1H),6.97(d,J＝2.2Hz,1H),6.82(dd,J＝8.4,2.2Hz,1H),5.03(dd,J＝12.7,5.5Hz,1H),4.32–4.21(m,2H),4.15–3.98(m,1H),3.68–3.49(m,2H),3.40–3.32(m,2H),3.23–3.17(m,2H),3.16–3.04(m,5H),2.90–2.80(m,1H),2.78–2.65(m,2H),2.57–2.51(m,2H),2.49(s,4H),2.13–2.06(m,1H),1.71–1.59(m,2H),1.52–1.40(m,4H),1.37–1.26(m,16H),0.98(s,6H).13C NMR(126MHz,Methanol-d4)δ173.90,173.30,172.99,170.37,168.97,168.29,167.93,154.79,134.55,124.83,116.54,115.19,105.34,57.90,57.82,50.52,49.17,48.90,42.78,42.08,39.10,37.50,30.81,30.59,29.21,29.02,28.99,28.42,26.68,26.57,26.12,22.66,22.46.HPLC>95％；HRMS(ESI-TOF)m/z:[M+H]+calcd forC40H60ClN6O9S+,835.3826；found,835.3832.
实施例3：化合物2的合成
将中间体M6(1mmol)与片段S2(1mmol)溶于N,N-二甲基甲酰胺(4ml)中，加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(1mmol)，N,N-二异丙基乙胺(1.5mmol)，室温反应2小时。反应完成后，加入水(10ml)，用乙酸乙酯萃取(3×10ml)萃取，合并有机相，分别用水、饱和食盐水洗涤，无水硫酸钠干燥，旋去溶剂，柱层析纯化分离，得化合物2，黄色固体，收率87％。1H NMR(500MHz,Methanol-d4)δ7.54(t,J＝7.8Hz,1H),7.03(d,J＝7.3Hz,2H),5.05(dd,J＝12.4,5.5Hz,1H),4.32–4.22(m,2H),4.12–4.01(m,1H),3.67–3.50(m,2H),3.37(d,J＝15.9Hz,1H),3.33(d,J＝4.7Hz,3H),3.17–3.02(m,5H),2.91–2.80(m,1H),2.79–2.66(m,2H),2.58–2.47(m,6H),2.15–2.06(m,1H),1.69–1.61(m,2H),1.51–1.40(m,4H),1.39–1.26(m,16H),0.98(s,6H).13C NMR(126MHz,Methanol-d4)δ173.90,173.26,172.99,170.27,169.40,168.96,167.94,146.91,135.83,132.51,116.60,110.33,109.56,57.91,57.82,50.53,49.18,48.79,42.09,42.02,39.11,37.51,30.83,30.60,29.22,29.18,29.04,29.00,28.98,28.88,26.58,26.52,26.12,22.66,22.41.HPLC>95％；HRMS(ESI-TOF)m/z:[M+H]+calcd for C40H60ClN6O9S+,835.3826；found,835.3826.
实施例4：化合物3的合成
将中间体M6(1mmol)与片段S3(1mmol)溶于N,N-二甲基甲酰胺(4ml)中，加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(1mmol)，N,N-二异丙基乙胺(1.5mmol)，室温反应2小时。反应完成后，加入水(10ml)，用乙酸乙酯萃取(3×10ml)萃取，合并有机相，分别用水、饱和食盐水洗涤，无水硫酸钠干燥，旋去溶剂，柱层析纯化分离，得化合物3，黄色固体，收率69％。1H NMR(500MHz,Chloroform-d)δ9.24(s,1H),7.57(d,J＝8.3Hz,1H),7.07–6.98(m,2H),6.91(t,J＝5.2Hz,1H),6.76(dd,J＝8.3,2.2Hz,1H),4.99–4.89(m,1H),4.18–4.06(m,2H),3.96–3.88(m,1H),3.86–3.78(m,2H),3.75–3.71(m,2H),3.68–3.60(m,9H),3.56–3.51(m,2H),3.44–3.36(m,4H),3.34–3.19(m,2H),3.18–2.96(m,4H),2.89–2.80(m,1H),2.78–2.69(m,2H),2.59–2.42(m,6H),2.19–2.06(m,1H),0.95(s,6H).13C NMR(126MHz,Chloroform-d)δ173.53,172.87,171.80,169.35,168.19,168.05,167.46,153.99,134.39,125.62,117.94,115.78,107.08,70.38,70.18,70.06,69.55,68.89,58.14,57.57,50.50,49.09,48.08,43.02,42.41,39.45,37.73,31.66,31.46,31.23,26.55,23.83,22.80.HPLC>95％；HRMS(ESI-TOF)m/z:[M+H]+calcd forC36H52ClN6O12S+,827.3047；found,827.3047.
实施例5：化合物4的合成：
将中间体M6(1mmol)与片段S4(1mmol)溶于N,N-二甲基甲酰胺(4ml)中，加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(1mmol)，N,N-二异丙基乙胺(1.5mmol)，室温反应2小时。反应完成后，加入水(10ml)，用乙酸乙酯萃取(3×10ml)萃取，合并有机相，分别用水、饱和食盐水洗涤，无水硫酸钠干燥，旋去溶剂，柱层析纯化分离，得化合物4，黄色固体，收率73％。1H NMR(500MHz,Methanol-d4)δ7.55(d,J＝8.4Hz,1H),6.96(d,J＝2.1Hz,1H),6.82(dd,J＝8.4,2.1Hz,1H),5.04(dd,J＝12.6,5.5Hz,1H),4.32–4.22(m,2H),4.12–4.03(m,1H),3.68–3.49(m,2H),3.41–3.33(m,2H),3.22–3.17(m,2H),3.16–3.03(m,5H),2.90–2.81(m,1H),2.78–2.65(m,2H),2.58–2.47(m,6H),2.13–2.05(m,1H),1.69–1.61(m,2H),1.50–1.41(m,4H),1.39–1.23(m,14H),0.98(s,6H).13C NMR(126MHz,Methanol-d4)δ173.45,172.86,172.53,169.94,168.51,167.83,167.46,154.32,134.10,124.38,116.07,114.75,104.89,57.43,57.36,50.07,48.71,48.44,42.32,41.65,38.64,37.06,30.36,30.12,28.75,28.70,28.58,28.53,27.96,26.23,26.11,25.67,22.20,22.00.HPLC>95％；HRMS(ESI-TOF)m/z:[M+H]+calcd for C39H58ClN6O9S+,821.3669；found,821.3667.
实施例6：化合物5的合成
将中间体M6(1mmol)与片段S5(1mmol)溶于N,N-二甲基甲酰胺(4ml)中，加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(1mmol)，N,N-二异丙基乙胺(1.5mmol)，室温反应2小时。反应完成后，加入水(10ml)，用乙酸乙酯萃取(3×10ml)萃取，合并有机相，分别用水、饱和食盐水洗涤，无水硫酸钠干燥，旋去溶剂，柱层析纯化分离，得化合物5，黄色固体，收率85％。1H NMR(500MHz,Methanol-d4)δ7.55(d,J＝8.4Hz,1H),6.97(d,J＝2.2Hz,1H),6.82(dd,J＝8.4,2.2Hz,1H),5.03(dd,J＝12.6,5.5Hz,1H),4.34–4.22(m,2H),4.12–4.04(m,1H),3.62–3.58(m,1H),3.58–3.49(m,1H),3.40–3.32(m,2H),3.22–3.17(m,2H),3.15–3.04(m,5H),2.88–2.79(m,1H),2.76–2.66(m,2H),2.56–2.50(m,2H),2.49(s,4H),2.12–2.05(m,1H),1.69–1.61(m,2H),1.50–1.40(m,4H),1.37–1.29(m,12H),0.99(s,6H).13C NMR(126MHz,Methanol-d4)δ173.89,173.28,172.97,170.37,168.96,168.28,167.92,154.83,134.57,124.81,116.51,115.16,105.29,57.89,57.82,50.51,49.17,48.90,42.74,42.07,39.07,37.50,30.81,30.58,29.13,29.11,29.02,28.99,28.94,28.42,26.66,26.54,26.12,22.65,22.45.HPLC>95％；HRMS(ESI-TOF)m/z:[M+H]+calcd for C38H56ClN6O9S+,807.3513；found,807.3519.
实施例7：化合物6的合成
将中间体M6(1mmol)与片段S6(1mmol)溶于N,N-二甲基甲酰胺(4ml)中，加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(1mmol)，N,N-二异丙基乙胺(1.5mmol)，室温反应2小时。反应完成后，加入水(10ml)，用乙酸乙酯萃取(3×10ml)萃取，合并有机相，分别用水、饱和食盐水洗涤，无水硫酸钠干燥，旋去溶剂，柱层析纯化分离，得化合物6，黄色固体，收率89％。1H NMR(500MHz,Methanol-d4)δ7.55(d,J＝8.4Hz,1H),6.97(d,J＝2.2Hz,1H),6.82(dd,J＝8.4,2.2Hz,1H),5.03(dd,J＝12.6,5.4Hz,1H),4.32–4.22(m,2H),4.11–4.02(m,1H),3.69–3.49(m,2H),3.40–3.32(m,2H),3.20(t,J＝7.1Hz,2H),3.16–3.04(m,5H),2.90–2.80(m,1H),2.77–2.64(m,2H),2.58–2.46(m,6H),2.13–2.05(m,1H),1.69–1.61(m,2H),1.51–1.41(m,4H),1.40–1.26(m,10H),0.98(s,6H).13CNMR(126MHz,Methanol-d4)δ173.90,173.30,172.99,170.38,168.97,168.29,167.93,154.82,134.56,124.82,116.52,115.19,105.32,57.90,57.82,50.52,49.17,48.91,42.75,42.07,39.06,37.51,30.81,30.59,29.12,29.02,28.95,28.88,28.42,26.65,26.52,26.12,22.66,22.45.HPLC>95％；HRMS(ESI-TOF)m/z:[M+H]+calcd for C37H54ClN6O9S+,793.3356；found,793.3358.
测试例1：IC50测试方法
根据不同细胞的生长速度，将对数生长期的细胞，按照一定的数量接种至96孔板中非边缘孔中，细胞悬液体积为80μL，边缘孔加入100μL已灭菌1×PBS，放置于细胞培养箱中平衡至少30min。将化合物稀释8个浓度梯度，每个浓度设置3个复孔，用相应的培养基稀释后，以20μL体积加入接种好细胞的96孔板中，并以0.2％ DMSO作为对照组，纯培养基为空白对照，板中终体积为100μL。细胞板培养3-7天后，每孔中加入20μL MTS溶液，在细胞培养箱中孵育一定时间，使用多功能酶标仪检测490nM及690nM(参考波长)处的吸收值，最终收集的吸收值OD＝OD490-OD690。细胞存活百分率(％)＝[(实验组OD值-空白组OD值)/(对照组OD值-空白组OD值)]×100(％)。使用GraphPad Prism 9.0软件，非线性回归拟合化合物的IC50值。
用上述方法测量了化合物1-6对白血病MV-4-11细胞的抑制活性，结果见表1。还用上述方法测量了化合物1以及Sulfopin对多种不同AML细胞的抑制活性，所使用的细胞系包括MV-4-11、MOLM-13、HL-60、THP-1、Kasumi-1、BDCM、OCI-AML3，结果见图2。上述结果表明本申请化合物相较于Sulfopin具有更好的肿瘤细胞抑制活性。
测试例2：降解比例测试方法
将培养中的MV-4-11细胞按照50万细胞/孔接种至12孔板中，加入一定浓度的化合物处理24h，以0.2％ DMSO作为对照，板内体积为1mL。收集细胞后，使用wb检测目标蛋白表达量，使用Image Lab软件分析蛋白表达灰度，以内参蛋白Actin进行归一化分析，计算蛋白降解效率。结果见表1。
表1
本申请说明书中未作详细描述的内容属于本领域技术人员的公知常识。
如在通篇说明书及权利要求当中所提及的“包含”为一开放式用语，故应解释成“包含但不限定于”。“大致”是指在可接收的误差范围内，本领域技术人员能够在一定误差范围内解决所述技术问题，基本达到所述技术效果。
还需要说明的是，术语“包括”、“包含”或者其任何其他变体意在涵盖非排他性的包含，从而使得包括一系列要素的商品或者系统不仅包括那些要素，而且还包括没有明确列出的其他要素，或者是还包括为这种商品或者系统所固有的要素。在没有更多限制的情况下，由语句“包括一个……”限定的要素，并不排除在包括所述要素的商品或者系统中还存在另外的相同要素。
上述说明示出并描述了本申请的若干优选实施例，但如前所述，应当理解本申请并非局限于本文所披露的形式，不应看作是对其他实施例的排除，而可用于各种其他组合、修改和环境，并能够在本文所述发明构想范围内，通过上述教导或相关领域的技术或知识进行改动。而本领域人员所进行的改动和变化不脱离本申请的精神和范围，则都应在本申请所附权利要求的保护范围。
Claims (14)
1.一种具有式Ⅰ所示结构的化合物或其药学上可接受的盐、水合物或溶剂化物：
其中：
R1选自
R2为(-CH2-)n，n选自1-4的整数；
L选自C4-18烷基、烷氧基或-R3-C(＝O)NH-R4-组成的组；
R3选自C1-6烷基；
R4选自C3-14烷基或-CH2-(-CH2-O-CH2-)m-CH2-，m选自1-4的整数；X为-CH2-、-NH-或-O-；
A任选以下的组：
2.根据权利要求1所述的化合物或其药学上可接受的盐、水合物或溶剂化物，其特征在于，具有式II所示结构：
L选自C4-18烷基、烷氧基或-R3-C(＝O)NH-R4-组成的组；
R3选自C1-6烷基；
R4选自C3-14烷基或-CH2-(-CH2-O-CH2-)m-CH2-，m选自1-4的整数，m优选3；
X为-CH2-、-NH-或-O-；
A任选以下的组：
3.根据权利要求1或2所述的化合物或其药学上可接受的盐、水合物或溶剂化物，其特征在于，X为-NH-。
4.根据权利要求1所述的化合物或其药学上可接受的盐、水合物或溶剂化物，其特征在于，具有式III所示结构：
X为-CH2-、-NH-或-O-；
n选自1-4的整数；
A任选以下的组：
5.根据权利要求1所述的化合物或其药学上可接受的盐、水合物或溶剂化物，其特征在于，具有式IV所示结构：
n选自1-4的整数；
L选自C4-18烷基、烷氧基或-R3-C(＝O)NH-R4-组成的组；
R3选自C1-6烷基；
R4选自C3-14烷基或-CH2-(-CH2-O-CH2-)m-CH2-，m选自1-4的整数；X为-CH2-、-NH-或-O-。
6.根据权利要求1所述的化合物或其药学上可接受的盐、水合物或溶剂化物，其特征在于，具有式V所示结构：
L选自C4-18烷基、烷氧基或-R3-C(＝O)NH-R4-组成的组；
R3选自C1-6烷基；
R4选自C3-14烷基或-CH2-(-CH2-O-CH2-)m-CH2-，m选自1-4的整数；X为-CH2-、-NH-或-O-。
7.根据权利要求6所述的化合物或其药学上可接受的盐、水合物或溶剂化物，其特征在于，X为-NH-。
8.根据权利要求6所述的化合物或其药学上可接受的盐、水合物或溶剂化物，其特征在于，L为-CH2CH2CONH(-CH2-)12-。
9.根据权利要求1或2所述的化合物或其药学上可接受的盐、水合物或溶剂化物，其特征在于，所述化合物选自：
10.一种如权利要求1-9任一项所述的化合物或其药学上可接受的盐、水合物或溶剂化物在制备预防或治疗与Pin1蛋白活性异常表达相关的疾病的药物中的应用。
11.如权利要求10所述的应用，其特征在于，所述与Pin1蛋白活性异常表达相关的疾病包括：肿瘤、高血糖、糖尿病、肥胖、高血脂症、高胆固醇血症、高脂蛋白血症、高甘油三酯血症、高血压、高胰岛素血症、高尿酸血症、帕金森病、阿兹海默病。
12.一种如权利要求1-9任一项所述的化合物或其药学上可接受的盐、水合物或溶剂化物在制备预防治疗或预防与肿瘤或防止肿瘤术后复发的药物中的应用。
13.如权利要求12所述的应用，其特征在于，所述肿瘤为：非小细胞肺癌、恶性黑色素瘤、前列腺癌、肾癌、膀胱癌、卵巢癌、结肠癌、直肠癌、乳腺癌、宫颈癌、肺癌、喉癌、鼻咽癌、胰腺癌或多发性骨髓瘤、B淋巴瘤、白血病中的一种或几种。
14.一种组合物，其特征在于，含有如权利要求1-9任一项所述的化合物或其药学上可接受的盐、水合物或溶剂化物。
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