CN115894439A - 一种靶向降解gpx4的protac嵌合体及其制备方法和应用 - Google Patents
一种靶向降解gpx4的protac嵌合体及其制备方法和应用 Download PDFInfo
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- CN115894439A CN115894439A CN202211316429.2A CN202211316429A CN115894439A CN 115894439 A CN115894439 A CN 115894439A CN 202211316429 A CN202211316429 A CN 202211316429A CN 115894439 A CN115894439 A CN 115894439A
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Images
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Abstract
本发明公开了一种靶向降解GPX4的PROTAC嵌合体及其制备方法和应用法,属于生物医药技术领域。本发明利用PROTAC技术制备了一种基于CRBN和VHL开发了一种新的共价不可逆和共价可逆的GPX4蛋白靶向降解的嵌合体。本发明蛋白靶向降解嵌合体能够结合GPX4蛋白并诱导有效降解,可以有效下调GPX4蛋白的水平,引起铁死亡,对肿瘤靶向治疗具有重要的意义。
Description
技术领域
本发明属于生物医药技术领域,具体涉及一类具有GPX4降解活性的PROTAC嵌合体及其制备方法以及其在抗肿瘤及神经退行性疾病方面中的应用。
背景技术
与凋亡、坏死、焦亡不同,铁死亡的特别之处在于铁依赖性脂质活性氧(ReactiveOxygen Species,ROS)自由基的积累为特征的程序性细胞死亡方式。大量研究发现,谷胱甘肽过氧化物酶4(Glutathione Peroxidase 4,GPX4)可以作为判断细胞铁死亡的指标之一。GPX4催化活性中心为硒代半胱氨酸,以GSH作为辅因子,GPX4能够将细胞内的脂质氢过氧化物还原成为无毒性的脂醇类化合物,同时也能催化过氧化氢等其他有机过氧化物的还原,因而具有保护细胞免受氧化应激、抑制铁死亡发生的作用。因此,抑制GPX4的活性,会影响GPX4清除脂质过氧化物的能力,最终导致细胞铁死亡的发生。此外,抑制GPX4的功能会触发细胞持续性的铁死亡和阻止肿瘤复发,因此是解决耐药的策略之一。
目前对于GPX4靶向的小分子抑制剂仍然存在着一定的挑战性,且还没有进入临床研究阶段的GPX4抑制剂报道。主要原因在于:1)GPX4的分子表面缺少药物样结合口袋;2)目前报道的抑制剂均为共价型抑制剂,与GPX4的活性部位硒代半胱氨酸的结合发挥作用,但存在选择性低等问题。
蛋白靶向降解嵌合体(Proteolysis-Targeting Chimeras,PROTAC)是一种异型双功能分子,可同时结合E3泛素连接酶和靶蛋白。一旦形成三元复合物(靶蛋白-PROTAC-E3),暴露在目标蛋白上的赖氨酸将被E3泛素连接酶泛素化,从而降解靶蛋白。与传统小分子占有驱动的抑制机制不同,PROTAC不需要直接抑制目标蛋白的活性,只需要与靶蛋白有一定的结合能力,并利用泛素-蛋白酶体系诱导蛋白质降解,是一种以事件驱动为主的药理学作用模式。因此,与传统小分子相比,PROTAC在缺乏类药口袋的蛋白以及提高选择性方面有更好的优势。迄今为止,PROTAC技术可用于靶向多种蛋白质,包括转录因子、酶和调控蛋白,而靶向GPX4蛋白的PROTAC的降解剂研究甚少。
发明内容
有鉴于此,本发明的目的在于提供一种靶向降解GPX4的PROTAC嵌合体及其制备方法和应用,本发明的PROTAC嵌合体能够有效降解GPX4蛋白,从而诱导肿瘤细胞铁死亡。
本发明采用以下技术方案加以实现:
本发明提供一种式I和式II所示靶向降解GPX4蛋白的PROTAC嵌合体或其药理或生理上可接受的盐,
其中,R为式R1或式R2所示取代基中的任意一种:
Linker为连接基团,表示-亚烷基或-烷氧基或-哌嗪基或-1,2,3-三氮唑基,所述-亚烷基或-烷氧基或-哌嗪基或-1,2,3-三氮唑基选自以下基团中任一个或它们的任意组合,其中m和n表示1至20的自然数:
-(CH2)n-C(O)NH(CH2CH2O)m-或-(CH2CH2O)n-C(O)NH(CH2CH2O)m-或
E3连接酶配体是指结合E3连接酶的配体分子,E3连接酶包括VHL和CRBN两种,其配体分子包括如下结构:
进一步的,本发明提供的GPX4靶向的PROTAC嵌合体,其为如下所示化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上或生理学可接受的盐或前药;
本发明所述药理或生理上可接受的盐是指,本发明所指的PROTAC嵌合体与药理或生理上可接受的酸或碱生成的盐。
本发明还提出一种药物组合物,该药物组合物包括GPX4-PROTAC化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药。
所述的药物组合物还包括药学上可接受的载体、赋形剂、稀释剂、辅剂、媒介物或其组合。
所述的药物组合物为注射剂、口服剂、黏膜给药剂。
所述的药物组合物进一步包括其它具有治疗或预防肿瘤效果的药物。
本发明还提供了靶向GPX4的PROTAC嵌合体或包含该嵌合体的药物组合物的应用。具体如下:
所述的靶向GPX4的PROTAC嵌合体或包含该嵌合体的药物组合物在制备降解GPX4药物中的应用。
所述的靶向GPX4的PROTAC嵌合体或包含该嵌合体的的药物组合物在制备治疗GPX4相关性疾病药物中的应用。所述GPX4相关性疾病为肿瘤、神经退行性疾病如阿尔茨海默病病,帕金森氏病,亨廷顿病。
所述的靶向GPX4的PROTAC嵌合体或包含该嵌合体的药物组合物在抗肿瘤药物中的应用。所述肿瘤为胃癌、乳腺癌、肺癌、卵巢癌、结肠腺癌、肾嫌色细胞、肾透明细胞癌、肺腺癌、前列腺癌、直肠腺癌、甲状腺癌以及子宫内膜癌。进一步的,所述肿瘤为GPX4高表达的肿瘤。
本发明还提出了通式I或通式II所示的靶向GPX4的PROTAC嵌合体的合成路线,具体包括如下步骤:
通式I或通式II所示的化合物通过泊马度胺或来那度胺或VHL招募配体和GPX4配体之间通过click反应或酰胺缩合反应或亲核取代反应连接而成。GPX4配体为ML-162的类似物,其通过Ugi Reaction制备。酰胺缩合反应需要用到常见的缩合剂HATU和TCFH。
与现有技术比,本发明有益效果主要体现在:
本发明基于GPX4抑制剂ML-162类似物和E3泛素连接酶CRBN和VHL招募配体开发了一种结构新颖多样的GPX4蛋白靶向降解嵌合体。发明人通过Western blot实验证实本发明蛋白靶向降解嵌合体能够结合GPX4蛋白并引发有效降解,进而引起细胞铁死亡。
附图说明
图1为具有GPX4降解活性的嵌合体GD-C-1和GD-C-2的合成路线图;
图2为具有GPX4降解活性的嵌合体GD-C-3~8、GD-C-10~12、GD-C-17和GD-C-21~28的合成路线图;
图3为具有GPX4降解活性的嵌合体GD-C-13~16和GD-C-18~20的合成路线图;
图4为具有GPX4降解活性的嵌合体GD-C-29和GD-C-32的合成路线图;
图5为具有GPX4降解活性的嵌合体GD-C-33的合成路线图;
图6为具有GPX4降解活性的嵌合体GD-C-9的合成路线图。
具体实施方式
以下结合说明书附图及具体实施例对本发明做进一步详细描述,以便更好地理解本技术方案。以下实施例中所使用的技术和科学术语具有于本发明所属领域技术人员普遍理解的相同含义。基础原料试剂从商业途径获得,纯度均在97%及以上。本发明所述室温为25-30℃。本发明对试验中所用到的材料以及实验方法进行一般性和具体性的描述。
实施例1:靶向降解GPX4嵌合体的合成与结构确认
终产物GD-C-1和GD-C-2的合成路线见图1所示。
化合物1的合成:
将对苯二胺(2.97g,27.44mmol)和2-噻吩甲醛(3.08g,27.44mmol)溶解在25mL甲醇中,25℃活化1h后,加入(2-异氰乙基)苯(3g,22.87mmol)、氯乙酸(2.16g,22.87mmol),室温搅拌过夜。反应液减压浓缩,残渣用硅胶柱色谱分离(流动相为体积比1:1的乙酸乙酯:石油醚),得到化合物1(白色固体,2g,产率为20%)。
化合物2的合成:
将化合物1(500mg,1.17mmol)溶于乙腈(5mL)中,加入4-(叔丁氧羰基)哌嗪-1-羧酸(269mg,1.17mmol),四甲基氯代脲六氟磷酸酯(357.62mg,1.4mmol),N-甲基咪唑(259.53mg,4.1mmol),室温搅拌过夜。反应液减压浓缩,硅胶柱色谱分离(流动相为体积比1:1的乙酸乙酯:石油醚),得到化合物2(白色固体,600mg,产率78%)。
化合物3的合成:
将化合物2(600mg,0.918mmol)溶于二氯甲烷(20mL)中,再加入三氟乙酸(4mL),反应2小时后,溶液旋转蒸发至干,置于40℃烘箱干燥,获得化合物3(白色固体,400mg,产率为78%)。
化合物4的合成:
将4-羟基异苯并呋喃-1,3-二酮(3.2g,19.5mmol)与3-氨基哌啶-2,6-二酮(3.2g,19.5mmol)溶于乙酸(60mL)中,加入乙酸钠(3.2g),在110℃下反应10h。蒸干溶剂,加水搅拌0.5h,析出固体,抽滤,置于25℃真空干燥,得到化合物4(白色固体,4.91g,产率91%)。
化合物5的合成:
将化合物4(4.91g,17.9mmol)溶于N,N-二甲基甲酰胺(30ml),再加入2-溴乙酸叔丁酯(4.91g,21.49mmol),碘化钾(300mg,1.79mmol)和碳酸钾(3.7g,26.9mmol),在60℃下反应4h。反应液用乙酸乙酯(200mL)稀释后,依次用水和饱和氯化钠水溶液各洗涤1次,再用硫酸钠干燥后,过滤,滤液旋转蒸发至干,获得浓缩物,硅胶柱色谱分离(洗脱剂为体积比1:1的乙酸乙酯:石油醚),得到化合物5(白色固体,6.3g,产率为90%)。
化合物6的合成:
将化合物5(6.3g,16.22mmol)溶于二氯甲烷(40mL)中,再加入三氟乙酸(10ml),反应2小时后,溶液旋转蒸发至干,置于40℃烘箱干燥,得化合物6(白色固体,4.50g,产率为83%)。
终产物GD-C-1的合成:
将化合物1(100mg,0.24mmol)与化合物6(77.64mg,0.24mmol),2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU,110mg,0.288mmol),DIEA(0.1ml,0.84mmol),加入N,N-二甲基甲酰胺(4mL),室温下搅拌4h。反应液用乙酸乙酯(200mL)稀释后,依次用水和饱和氯化钠水溶液各洗涤1次,再用硫酸钠干燥后过滤,滤液旋转蒸发至干,获得浓缩物用硅胶柱色谱分离(洗脱剂为体积比20:1的二氯甲烷/甲醇),得到化合物GD-C-1(白色固体,30mg,产率:17.3%)。1H NMR(400MHz,CDCl3)δ9.46(d,J=17.3Hz,1H),8.31(d,J=59.7Hz,1H),7.78–7.49(m,4H),7.19(s,3H),7.18–7.00(m,4H),6.79(q,J=4.6Hz,2H),6.08(d,J=13.8Hz,2H),4.96(t,J=6.2Hz,1H),4.70(t,J=3.0Hz,2H),3.88–3.67(m,2H),3.52(d,J=6.5Hz,2H),2.96–2.76(m,4H),2.74(s,2H),2.18–2.10(m,1H)。
终产物GD-C-2按以上相同方法合成。1H NMR(400MHz,CDCl3)δ9.00(s,1H),8.56(s,1H),7.69–7.61(m,2H),7.54–7.37(m,5H),7.29(s,1H),7.07(d,J=7.2Hz,3H),6.79(dt,J=8.7,3.8Hz,2H),6.12–6.00(m,2H),4.92(s,3H),4.24(t,J=6.7Hz,2H),3.73(d,J=3.7Hz,2H),3.49(p,J=6.5Hz,2H),3.14(s,2H),2.88–2.70(m,4H),2.14(td,J=22.3,11.0Hz,3H),1.94(d,J=6.2Hz,1H)。
终产物GD-C-3~8、GD-C-10~12、GD-C-17和GD-C-21~28的合成路线见图2所示。
化合物7a的合成:
将化合物1(500mg,1.17mmol)溶于乙腈(5mL)中,加入6-((叔丁氧基羰基)氨基)己酸(245mg,1.17mmol),四甲基氯代脲六氟磷酸酯(357.62mg,1.40mmol),N-甲基咪唑(259.53mg,4.1mmol),室温搅拌过夜。反应液减压浓缩,用硅胶柱色谱分离(洗脱剂为体积比1:1的乙酸乙酯:石油醚),得到化合物7a(白色固体,600mg,产率80%)。
化合物7b~r按相同方法合成。
化合物8a的合成:
将化合物7a(600mg,0.935mmol)溶于二氯甲烷(10mL)中,再加入三氟乙酸(3mL),反应2小时后,溶液旋转蒸发至干,置于40℃烘箱干燥,得到化合物8a(白色固体,400mg,79%)。
化合物8b~r按相同方法合成。
化合物9a的合成:
将乙酸钠(NaOAc)(2.6g,27.0mmol)加入乙酸(20mL)中,再加入3-氨基-2,6-哌啶二酮盐酸盐(1.5mg,9.0mmol)和3-氟酞酐(1.5mg,10.0mmol),混合物在90℃下搅拌反应8h,然后冷却至室温。反应液用二氯甲烷(200mL)稀释后,依次用水和饱和氯化钠水溶液各洗涤1次,再用硫酸钠干燥后抽滤,滤液旋转蒸发至干,然后置于40℃烘箱干燥,得到化合物9a(白色固体产物,2.1g,产率为84%)。
化合物10a的合成:
将化合物9a(2.76g,10.0mmol)加入N,N-二甲基甲酰胺(20mL)中,再加入3-(2-氨基乙氧基)丙酸叔丁酯(2.08g,11.0mmol)和N,N-二异丙基乙胺(3.54g,35.0mmol),混合物在90℃下搅拌8h后冷却至室温。反应液用乙酸乙酯(200mL)稀释后,依次用水和饱和氯化钠水溶液各洗涤1次,再用硫酸钠干燥后过滤,滤液旋转蒸发至干,获得浓缩物。用硅胶柱色谱分离(洗脱剂为体积比1:1的乙酸乙酯:石油醚)得到化合物10a(绿色固体,3.1g,产率为70%)。
化合物10b按相同方法合成。
化合物11a的合成:
将10a(3.1g,6.96mmol)溶于二氯甲烷(30ml)中,再加入三氟乙酸(8ml),反应2小时后,溶液旋转蒸发至干,再40℃烘箱干燥,得到化合物11a(黄色固体,2.30g,产率为85%)。
化合物11b按相同方法合成。
化合物GD-C-3的合成:
将中间体8a(152.87mg,0.28mmol)溶于乙腈(3mL)与化合物11a(100mg,0.26mmol)中,四甲基氯代脲六氟磷酸酯(87.5mg,0.31mmol),N-甲基咪唑(73.79mg,0.91mmol),室温搅拌过夜。反应液用乙酸乙酯(200mL)稀释后,依次用水和饱和氯化钠水溶液各洗涤1次,再用硫酸钠干燥后过滤,滤液旋转蒸发至干,获得浓缩物,将浓缩物用硅胶柱色谱分离(洗脱剂为乙酸乙酯),得到GD-C-3(黄色固体,60mg,产率为25%)。1H NMR(400MHz,MeOD)δ7.99(t,J=5.9Hz,1H),7.77(t,J=5.8Hz,1H),7.39(td,J=11.3,10.0,7.4Hz,3H),7.18(dd,J=4.0,2.4Hz,1H),7.15–7.07(m,2H),7.07–6.99(m,3H),6.93(dd,J=14.5,7.8Hz,2H),6.73–6.67(m,2H),6.10(s,1H),5.39(s,1H),4.94(dd,J=12.6,5.4Hz,1H),3.81(d,J=1.7Hz,2H),3.63(t,J=6.0Hz,2H),3.56(t,J=5.2Hz,2H),3.48–3.33(m,3H),3.28(ddd,J=13.2,7.2,5.6Hz,1H),3.21(p,J=1.6Hz,2H),3.05(q,J=6.6Hz,2H),2.81–2.52(m,5H),2.32(t,J=6.0Hz,2H),2.21(t,J=7.4Hz,2H),1.99(dtd,J=10.2,4.1,3.2,2.1Hz,1H),1.53(p,J=7.5Hz,2H),1.39(p,J=7.0Hz,2H),1.25(qd,J=7.4,6.8,3.8Hz,2H).
化合物GD-C-4~8、GD-C-10~12、GD-C-17和GD-C-21~28按相同方法合成。
化合物GD-C-4(黄色固体,50mg,产率为20%)。1H NMR(400MHz,MeOD)δ7.82(t,J=5.8Hz,1H),7.41–7.35(m,3H),7.22–7.00(m,7H),6.93(dd,J=11.0,7.8Hz,2H),6.73–6.67(m,2H),6.10(s,1H),4.95(dd,J=12.6,5.5Hz,1H),3.88–3.75(m,2H),3.64(t,J=5.9Hz,2H),3.56(t,J=5.2Hz,2H),3.48–3.32(m,3H),3.32–3.22(m,1H),3.14–3.05(m,2H),2.76–2.60(m,4H),2.34(t,J=5.9Hz,2H),2.23(t,J=7.4Hz,2H),1.65–1.50(m,3H),1.43(tq,J=13.9,6.9Hz,2H)。
化合物GD-C-5(黄色固体,55mg,产率为23%)。1H NMR(400MHz,MeOD)δ8.00–7.85(m,1H),7.39–7.28(m,3H),7.19–6.92(m,8H),6.86(dd,J=7.0,2.1Hz,1H),6.70(dtd,J=8.6,3.6,1.4Hz,2H),6.08(s,1H),4.94(dd,J=12.5,5.5Hz,1H),3.82(d,J=1.2Hz,2H),3.71(t,J=5.9Hz,2H),3.59(t,J=5.2Hz,2H),3.38(t,J=5.3Hz,2H),2.81–2.57(m,6H),2.50(t,J=5.9Hz,2H),1.98(dtd,J=10.9,5.5,2.6Hz,1H)。
化合物GD-C-6(黄色固体,52mg,产率为23%)。1H NMR(400MHz,MeOD)δ7.95(dt,J=16.7,5.8Hz,1H),7.45–7.31(m,4H),7.17(dd,J=4.2,2.2Hz,1H),7.11(tt,J=6.8,1.3Hz,2H),7.07–7.00(m,3H),6.93(dd,J=7.8,6.1Hz,2H),6.72–6.66(m,2H),6.08(s,1H),4.95(dd,J=12.5,5.4Hz,1H),3.79(d,J=1.3Hz,2H),3.63(t,J=5.8Hz,2H),3.54(t,J=5.2Hz,2H),3.42(dtt,J=12.7,6.5,1.9Hz,3H),3.34(t,J=5.2Hz,2H),3.30–3.25(m,1H),2.75–2.56(m,5H),2.46(t,J=6.6Hz,2H),2.34(t,J=5.8Hz,2H),1.97(ddd,J=11.0,5.6,2.1Hz,1H)。
化合物GD-C-7(黄色固体,53mg,产率为23%)。1H NMR(400MHz,MeOD)δ7.87(s,1H),7.40–7.30(m,3H),7.20–6.99(m,7H),6.91(dd,J=18.1,7.8Hz,2H),6.72–6.67(m,2H),6.10(s,1H),4.94(dd,J=12.6,5.4Hz,1H),3.81(d,J=1.6Hz,2H),3.64(t,J=5.9Hz,2H),3.57(t,J=5.2Hz,2H),3.36(t,J=5.2Hz,2H),3.21(p,J=1.6Hz,2H),3.13(t,J=6.8Hz,2H),2.75(s,3H),2.67–2.63(m,2H),2.34(t,J=5.9Hz,2H),2.24(t,J=7.4Hz,2H),2.02–1.94(m,1H),1.74–1.68(m,2H)。
化合物GD-C-8(黄色固体,50mg,产率为22%)。1H NMR(400MHz,MeOD)δ7.48–7.33(m,4H),7.21–6.90(m,9H),6.71(d,J=3.3Hz,2H),6.10(s,1H),4.95(ddd,J=12.3,5.4,2.2Hz,1H),3.82(d,J=1.8Hz,2H),3.66–3.63(m,2H),3.57(t,J=5.3Hz,2H),3.47–3.34(m,4H),3.05(td,J=6.9,4.7Hz,2H),2.75–2.58(m,5H),2.34(t,J=6.0Hz,2H),2.21(t,J=7.4Hz,2H),2.04–1.95(m,1H),1.59–1.46(m,4H),1.36(t,J=6.8Hz,2H)。
化合物GD-C-10(黄色固体,40mg,产率为18%)。1H NMR(400MHz,MeOD)δ7.52–7.32(m,4H),7.19(dd,J=4.7,1.7Hz,1H),7.11(dd,J=7.8,6.5Hz,2H),7.07–7.00(m,4H),6.95(dd,J=10.9,7.8Hz,2H),6.71(d,J=4.8Hz,3H),6.12(s,1H),4.93(dd,J=12.6,5.5Hz,1H),3.83(d,J=1.9Hz,2H),3.70(d,J=6.0Hz,2H),3.63–3.51(m,8H),3.47–3.35(m,4H),3.03(d,J=3.8Hz,2H),2.68(dd,J=8.7,5.9Hz,3H),2.58(dd,J=7.4,4.6Hz,4H),2.43(d,J=4.5Hz,4H)。
化合物GD-C-11(黄色固体,43mg,产率为20%)。1H NMR(400MHz,MeOD)δ7.36(d,J=8.2Hz,2H),7.25–6.96(m,10H),6.78–6.65(m,3H),6.09(d,J=1.9Hz,1H),5.05(dd,J=13.3,5.2Hz,1H),4.23(t,J=2.5Hz,2H),3.78(t,J=1.1Hz,2H),3.60(t,J=5.8Hz,2H),3.55(t,J=5.3Hz,2H),3.37(t,J=6.5Hz,2H),3.25(d,J=5.9Hz,4H),2.80–2.72(m,1H),2.66(t,J=7.2Hz,3H),2.45(t,J=6.5Hz,2H),2.33(t,J=5.8Hz,3H),2.05(dtd,J=12.9,5.3,2.4Hz,1H)。
化合物GD-C-12(黄色固体,30mg,产率为14%)。1H NMR(400MHz,MeOD)δ7.48–6.94(m,12H),6.80–6.65(m,3H),6.10(s,1H),5.04(dd,J=13.3,5.1Hz,1H),4.30–4.16(m,2H),3.81(d,J=2.2Hz,2H),3.67–3.61(m,3H),3.61–3.44(m,3H),3.28(d,J=5.4Hz,2H),3.10(t,J=6.8Hz,2H),2.79(ddd,J=17.6,13.4,5.3Hz,1H),2.69–2.63(m,3H),2.34(q,J=5.6Hz,3H),2.24(t,J=7.4Hz,2H),2.06(dtd,J=12.7,5.3,1.9Hz,1H),1.69(p,J=7.1Hz,2H)。
化合物GD-C-17(黄色固体,30mg,产率为14%)。1H NMR(400MHz,MeOD)δ7.41(dt,J=9.8,7.0Hz,4H),7.22–6.86(m,9H),6.73–6.68(m,2H),6.10(s,1H),4.99–4.90(m,1H),3.81(d,J=1.6Hz,2H),3.63(dq,J=7.5,6.0,5.3Hz,5H),3.55(t,J=5.2Hz,3H),3.45–3.33(m,6H),3.31–3.22(m,4H),2.74–2.56(m,5H),2.47(t,J=5.9Hz,2H),2.31(t,J=6.0Hz,2H),1.99(dtt,J=12.9,5.0,2.6Hz,1H)。
化合物GD-C-21(黄色固体,43mg,产率为20%)。1H NMR(400MHz,DMSO)δ11.10(s,1H),10.03(s,1H),8.32(t,J=5.7Hz,1H),7.91(t,J=5.6Hz,1H),7.57(dd,J=8.6,7.1Hz,1H),7.46(d,J=8.4Hz,2H),7.37(dd,J=5.0,1.4Hz,1H),7.28–7.10(m,7H),7.04(d,J=7.0Hz,1H),6.84–6.77(m,2H),6.57(t,J=5.8Hz,1H),6.22(s,1H),5.05(dd,J=12.9,5.3Hz,1H),4.00–3.87(m,2H),3.65(dt,J=12.6,6.3Hz,4H),3.57(t,J=5.4Hz,2H),3.52–3.42(m,6H),3.37(t,J=5.9Hz,2H),3.20–3.12(m,2H),2.88(ddd,J=17.4,14.0,5.4Hz,1H),2.69(td,J=7.4,5.0Hz,2H),2.63–2.53(m,2H),2.33(t,J=6.5Hz,2H),2.09–1.97(m,1H)。
化合物GD-C-22(黄色固体,60mg,产率为28%)。1H NMR(400MHz,MeOD)δ11.10(s,1H),10.02(s,1H),8.31(t,J=5.7Hz,1H),7.63–7.01(m,14H),6.86–6.74(m,2H),6.60(t,J=5.8Hz,1H),6.22(s,1H),5.06(dd,J=12.9,5.4Hz,1H),4.02–3.86(m,2H),3.66(t,J=6.2Hz,2H),3.59(q,J=5.0,4.4Hz,2H),3.56–3.42(m,11H),3.25(dq,J=13.2,7.0Hz,1H),2.89(s,2H),2.76–2.55(m,4H),2.01(dd,J=11.1,6.0Hz,1H)。
化合物GD-C-23(黄色固体,50mg,产率为24%)。1H NMR(400MHz,MeOD)δ7.90(s,1H),7.55–7.44(m,3H),7.32–7.08(m,7H),7.08–6.98(m,2H),6.83–6.76(m,2H),6.20(s,1H),5.08–5.00(m,1H),3.91(t,J=2.0Hz,2H),3.75(t,J=5.9Hz,1H),3.71–3.66(m,4H),3.65–3.56(m,3H),3.53–3.50(m,2H),3.46(t,J=5.3Hz,2H),2.89–2.66(m,5H),2.58(t,J=5.9Hz,2H),2.39(t,J=6.1Hz,2H),2.13–2.05(m,1H)。
化合物GD-C-24(黄色固体,37mg,产率为16%)。1H NMR(400MHz,MeOD)δ7.63–7.42(m,3H),7.34–6.97(m,9H),6.80(d,J=3.3Hz,2H),6.19(s,1H),5.04(dd,J=12.5,5.5Hz,1H),3.91(d,J=1.5Hz,2H),3.74(dt,J=27.6,5.6Hz,4H),3.65–3.56(m,12H),3.51–3.45(m,2H),3.34(s,7H),2.77–2.73(m,2H),2.73–2.67(m,1H),2.59(t,J=5.9Hz,2H),2.15–2.04(m,1H)。
化合物GD-C-26(黄色固体,50mg,产率为24%)。1H NMR(400MHz,MeOD)δ7.83(s,2H),7.57–7.45(m,2H),7.30–6.99(m,12H),6.86–6.76(m,2H),6.22(s,1H),5.04(ddd,J=12.4,5.7,1.7Hz,1H),3.95–3.89(m,2H),3.74–3.45(m,19H),3.35(s,1H),3.17(d,J=5.2Hz,2H),2.92–2.48(m,12H),2.11(ddd,J=10.7,6.5,2.7Hz,1H)。
化合物GD-C-27(黄色固体,20mg,产率为10%)。1H NMR(400MHz,MeOD)δ7.86(s,1H),7.53–7.48(m,3H),7.28(dd,J=4.7,1.7Hz,1H),7.25–6.99(m,11H),6.84–6.78(m,2H),6.22(s,1H),5.04(dd,J=12.6,5.5Hz,1H),3.92(d,J=2.0Hz,2H),3.73(dt,J=10.7,5.7Hz,4H),3.67–3.47(m,12H),3.13(s,2H),2.79–2.73(m,2H),2.65–2.60(m,2H),2.52(t,J=5.0Hz,5H),2.14–2.05(m,1H)。
化合物GD-C-28(黄色固体,55mg,产率为27%)。1H NMR(400MHz,MeOD)δ7.58–7.47(m,3H),7.31–6.98(m,11H),6.85–6.78(m,2H),6.21(s,1H),5.04(dd,J=12.6,5.5Hz,1H),3.91(d,J=1.9Hz,2H),3.78–3.52(m,16H),3.49(t,J=5.4Hz,2H),3.31(p,J=1.6Hz,5H),3.17(s,2H),2.88–2.47(m,11H),2.13–2.06(m,1H)。
终产物GD-C-13~16和GD-C-18~20的合成路线见图3所示:
化合物12的合成:
将(S)-1-(4-溴苯基)乙胺(3.98g,19.9mmol)和NaHCO3(1.24g,14.8mmol)溶于水(10mL)和乙醇(10mL)中的混合物中,并加入(Boc)2O(5.20g,23.8mmol),室温反应2小时后过滤反应混合物。收集固体部分并将其在正己烷(10mL)和水(10mL)的混合溶液中搅拌0.5小时。过滤混合物,收集固体部分,在50℃烘箱中干燥,得到化合物12(白色固体,5.9g,产率为98.7%)。
化合物13的合成:
将化合物12(4.0g,13.3mmol)、4-甲基噻唑(2.64g,26.6mmol)、乙酸钯(II)(29.6mg,0.13mmol)和乙酸钾(2.61g,26.6mmol)在N,N-二甲基乙酰胺(10mL)中于氮气保护条件下90℃搅拌18小时。冷却至室温后,抽滤除去不溶性固体。向滤液中加入水(50ml),并将所得混合物在室温下搅拌4小时后抽滤。收集固体部分置于50℃烘箱中干燥,得到化合物13(灰色固体,3.48g,产率为82.3%)。
化合物14的合成:
将化合物13(1.9g,6.0mmol)溶解在4N HCl的甲醇溶液(5mL,20mmol)中,于室温下搅拌3小时。反应混合物抽滤,收集固体部分置于50℃烘箱中干燥,得到化合物14(浅绿色固体,1.3g,产率为85%)。
化合物15的合成:
将化合物14(0.98g,5.4mmol),四甲基氯代脲六氟磷酸酯(2.15g,5.7mmol)和N,N-二异丙基乙胺(2.43g,18.9mmol)在N,N-二甲基甲酰胺(10mL)中在氮气保护下在室温搅拌18小时。将反应混合物用水(30mL)淬灭并用乙酸乙酯(200mL)萃取。将合并的有机层用5%柠檬酸(10mL)洗涤两次,用饱和NaHCO3溶液(10ml)洗涤两次,用盐水(10ml)洗涤两次,得到的有机层用Na2SO4干燥。将有机溶液浓缩,得到化合物15(淡色黄色油状物,1.93g,产率为100%)。
化合物16的合成:
将化合物15(1.93g)和氢氧化锂水合物(2.2g,54mmol)放入到四氢呋喃(20mL)和水(10mL)中。将所得反应混合物在室温条件下搅拌18小时。旋转蒸发溶剂,将残余物用冰水(10mL)稀释,并用3N HCl将pH值缓慢调节至2-3。过滤所得固体并用水洗涤,收集固体部分置于50℃烘箱中干燥,得到化合物16(白色固体,1.4g,产率为75%)。
化合物17的合成:
在0℃条件下将四甲基氯代脲六氟磷酸酯(1.6g,4.2mmol),化合物16(1.21g,3.5mmol),化合物14(0.9g,3.5mmol)和N,N-二异丙基乙胺(1.36g,10.5mmol)溶于无水四氢呋喃(15ml)。滴加完毕后将体系升温至室温并搅拌2小时。反应完毕后反应液减压浓缩。向浓缩液中加入水(15ml)并搅拌4小时,然后过滤。收集固体部分置于在50℃烘箱中干燥,得到化合物17(白色固体,1.41g,产率为74.2%)。
化合物18的合成:
将化合物17(1.04g,1.9mmol)溶解在4N HCl的甲醇溶液(3.0ml)中,并将混合物在室温下搅拌3小时。减压浓缩反应混合物,得到淡黄色固体。将固体加入到叔丁基甲基醚(5ml)中,并将所得混合物在环境温度下搅拌4小时。过滤混合物,收集固体部分,在50℃烘箱中干燥,得到化合物18(白色固体,0.92g,产率为100%)。
化合物19a的合成:
将化合物18(500mg,1.12mmol)与6-(叔丁氧基)-6-氧代己酸(250.2mg,1.24mmol),四甲基氯代脲六氟磷酸酯(511mg,1.34mmol)和N,N-二异丙基乙胺(508mg,3.92mmol)溶于四氢呋喃中,于室温下搅拌3h。减压浓缩,用乙酸乙酯(200mL)稀释后,依次用水和饱和氯化钠水溶液各洗涤1次,有机层用硫酸钠干燥后,过滤,滤液旋转蒸发至干得浓缩物,用硅胶柱色谱分离(洗脱剂为体积比2:1的乙酸乙酯:石油醚),得到化合物19a(白色固体,600mg,产率为84%)。
化合物19b~g按相同方法合成。
化合物20a的合成:
将化合物19a(600mg,0.955mmol)溶于二氯甲烷(15mL)中,再加入三氟乙酸(3mL),反应2小时后,溶液旋转蒸发至干,再置于40℃烘箱干燥,得到化合物20a(白色固体,450mg,产率为82%)。
化合物20b~g按相同方法合成。
化合物GD-C-13的合成:
将化合物3b(290.25mg,0.55mmol)和化合物20a(300mg,0.55mmol),四甲基氯代脲六氟磷酸酯(255.5mg,0.66mmol)和N,N-二异丙基乙胺(254mg,1.96mmol)溶于四氢呋喃中,于室温下搅拌3h。减压浓缩后用乙酸乙酯(200mL)稀释后,依次用水和饱和氯化钠水溶液各洗涤1次,有机相用硫酸钠干燥后,过滤,滤液旋转蒸发至干,获得浓缩物,用硅胶柱色谱分离(洗脱剂为体积比30:1的二氯甲烷:甲醇醚),得到化合物GD-C-13(白色固体,105mg,产率为18%)。1H NMR(400MHz,MeOD)δ8.77(s,1H),7.85–7.76(m,1H),7.44(d,J=8.3Hz,2H),7.36–7.27(m,5H),7.15–7.08(m,3H),7.07–7.01(m,4H),6.73–6.68(m,2H),6.12(s,1H),4.90(td,J=7.1,4.8Hz,1H),4.55–4.44(m,2H),4.32(d,J=4.7Hz,1H),3.83–3.76(m,3H),3.69(s,2H),3.60–3.55(m,2H),3.52(d,J=5.4Hz,2H),3.46–3.38(m,1H),3.31–3.25(m,1H),3.11(s,2H),2.67(t,J=7.2Hz,2H),2.51(q,J=5.6,5.1Hz,2H),2.46(t,J=5.2Hz,2H),2.38(s,3H),2.32(t,J=7.0Hz,2H),2.29–2.15(m,2H),2.13–2.05(m,1H),1.54(td,J=11.2,9.6,6.3Hz,4H),1.40(d,J=7.1Hz,3H),0.95(s,9H)。
化合物GD-C-14(白色固体,14mg,产率为14%)。1H NMR(400MHz,MeOD)δ8.77(s,1H),8.47(d,J=7.4Hz,1H),8.03(t,J=5.8Hz,1H),7.79(d,J=8.7Hz,1H),7.39(d,J=8.1Hz,2H),7.36–7.30(m,4H),7.22–7.00(m,7H),6.74–6.65(m,2H),6.11(s,1H),4.95–4.84(m,1H),4.54–4.43(m,2H),4.33(s,1H),3.82(d,J=1.7Hz,2H),3.79–3.72(m,1H),3.65(dd,J=11.0,4.0Hz,1H),3.48–3.38(m,1H),3.33–3.24(m,1H),2.67(t,J=7.1Hz,2H),2.37(s,3H),2.31–2.20(m,4H),2.09(dd,J=13.0,8.0Hz,1H),1.85(ddd,J=13.3,9.0,4.6Hz,1H),1.70–1.43(m,5H),1.40(d,J=7.0Hz,3H),1.26(s,2H),0.94(s,9H)。
化合物GD-C-15(白色固体,13mg,产率为13%)。1H NMR(400MHz,MeOD)δ8.76(d,J=5.0Hz,1H),8.48(dd,J=7.5,1.4Hz,1H),8.03(t,J=6.0Hz,1H),7.73(d,J=8.9Hz,1H),7.46–7.24(m,7H),7.18(td,J=4.1,2.3Hz,1H),7.11(tt,J=7.0,1.2Hz,2H),7.08–7.00(m,3H),6.74–6.67(m,2H),6.23(dd,J=17.3,1.7Hz,1H),6.11(d,J=1.3Hz,1H),5.74(dd,J=10.4,1.7Hz,1H),4.89(q,J=7.2Hz,1H),4.55–4.44(m,2H),4.33(dp,J=4.1,1.8Hz,1H),3.85–3.75(m,3H),3.65(dd,J=11.0,4.0Hz,1H),3.47–3.37(m,1H),3.32–3.23(m,1H),2.67(t,J=7.2Hz,2H),2.40–2.35(m,3H),2.25(t,J=7.5Hz,2H),2.18(td,J=7.2,2.8Hz,1H),1.84(ddd,J=13.3,9.0,4.5Hz,1H),1.53(ddd,J=32.3,16.2,7.1Hz,3H),1.38(d,J=7.0Hz,2H),1.34–1.24(m,4H),1.19(t,J=3.7Hz,2H),0.94(s,9H)。
化合物GD-C-16(白色固体,9mg,产率为9%)。1H NMR(400MHz,MeOD)δ8.77(s,1H),7.47–7.26(m,7H),7.24–6.97(m,6H),6.79–6.64(m,2H),6.16–5.97(m,2H),4.89(q,J=7.0Hz,1H),4.62–4.43(m,2H),4.33(dd,J=4.3,2.4Hz,1H),3.94–3.74(m,3H),3.74–3.60(m,1H),3.55–3.36(m,1H),3.34–3.25(m,1H),2.67(t,J=7.2Hz,2H),2.38(s,3H),2.32–2.04(m,4H),1.84(ddd,J=13.3,9.0,4.5Hz,1H),1.67–1.46(m,6H),1.40(d,J=7.0Hz,3H),1.19(d,J=3.8Hz,6H),0.94(s,9H),0.86–0.71(m,4H)。
化合物GD-C-18(白色固体,19mg,产率为15%)。1H NMR(400MHz,MeOD)δ8.86(d,J=4.7Hz,1H),7.56–7.34(m,6H),7.28(tt,J=2.8,0.8Hz,1H),7.26–7.07(m,5H),6.89–6.69(m,2H),6.20(s,1H),4.99(q,J=7.0Hz,1H),4.67–4.52(m,2H),4.47–4.37(m,1H),3.95–3.88(m,2H),3.74(dd,J=11.0,3.9Hz,1H),3.58–3.47(m,1H),3.41–3.33(m,1H),2.77(t,J=7.1Hz,2H),2.43–2.13(m,5H),2.02–1.87(m,1H),1.75–1.56(m,2H),1.49(d,J=7.0Hz,3H),1.42–1.23(m,8H),1.04(s,9H).
化合物GD-C-19(白色固体,13mg,产率为12%)。1H NMR(400MHz,MeOD)δ8.86(d,J=4.7Hz,1H),7.56–7.34(m,6H),7.28(tt,J=2.8,0.8Hz,1H),7.26–7.07(m,5H),6.89–6.69(m,2H),6.20(s,1H),4.99(q,J=7.0Hz,1H),4.67–4.52(m,2H),4.47–4.37(m,1H),3.95–3.88(m,2H),3.74(dd,J=11.0,3.9Hz,1H),3.58–3.47(m,1H),3.41–3.33(m,1H),2.77(t,J=7.1Hz,2H),2.43–2.13(m,5H),2.02–1.87(m,1H),1.75–1.56(m,2H),1.49(d,J=7.0Hz,3H),1.42–1.23(m,12H),1.04(s,9H)。
化合物GD-C-20(白色固体,10mg,产率为11%)。1H NMR(400MHz,MeOD)δ8.77(s,1H),7.46–7.24(m,7H),7.21–6.98(m,7H),6.78–6.63(m,2H),6.11(s,1H),4.90(q,J=7.0Hz,1H),4.58–4.42(m,2H),4.32(dd,J=4.4,2.3Hz,1H),3.85–3.75(m,3H),3.64(dd,J=11.0,3.9Hz,1H),3.50–3.36(m,1H),3.34–3.25(m,1H),2.67(t,J=7.2Hz,2H),2.30–2.05(m,6H),1.84(ddd,J=13.4,9.1,4.6Hz,1H),1.53(dq,J=30.9,6.9Hz,5H),1.40(d,J=7.0Hz,3H),1.32–1.22(m,20H),0.94(s,9H)。
终产物GD-C-29~32的合成路线见图4所示。
化合物20的合成:
将3-氯-4-甲氧基苯胺(4.33g,27.44mmol)和4-氨基苯甲醛(3.32g,27.44mmol)溶解在25mL甲醇中,25℃活化1h后,加入(2-异氰乙基)苯(3g,22.87mmol)、氯乙酸(2.16g,22.87mmol),室温搅拌过夜。反应液减压浓缩,残渣用硅胶柱色谱分离(洗脱剂为体积比1:1的乙酸乙酯:石油醚),得到化合物21(白色固体,2g,产率为18%)。
化合物22的合成:
将化合物21(200mg,0.41mmol)溶于乙腈(5mL)中,加入6-((叔丁氧基羰基)氨基)己酸(115mg,0.49mmol),四甲基氯代脲六氟磷酸酯(138mg,0.49mmol),N-甲基咪唑(118mg,1.44mmol),室温搅拌过夜。反应液减压浓缩,残渣用硅胶柱色谱分离(洗脱剂为体积比1:1的乙酸乙酯:石油醚),得到化合物22(白色固体,230mg,产率80%)。
化合物23的合成:
将化合物22(230mg,0.328mmol)溶于二氯甲烷(10mL)中,再加入三氟乙酸(3mL),反应2小时后,溶液旋转蒸发至干,置于40℃烘箱干燥,得到化合物23(白色固体,150mg,76%)。
化合物GD-C-29的合成:
将化合物21(67.9mg,0.14mmol)溶于乙腈(5ml)与化合物11a(50mg,0.13mmol)中,四甲基氯代脲六氟磷酸酯(43.4mg,0.16mmol),N-甲基咪唑(36.87mg,0.45mmol),室温搅拌过夜。反应液用乙酸乙酯(200mL)稀释后,依次用水和饱和氯化钠水溶液各洗涤1次,有机相再用硫酸钠干燥后,过滤,滤液旋转蒸发至干,获得浓缩物,将浓缩物用硅胶柱色谱分离(洗脱剂为乙酸乙酯)得到GD-C-29(黄色固体,20mg,产率为18%)。1H NMR(400MHz,MeOD)δ8.03(d,J=6.9Hz,1H),7.71(d,J=82.6Hz,1H),7.44–7.26(m,3H),7.23–7.01(m,6H),6.95–6.80(m,3H),6.62(d,J=54.9Hz,2H),5.96(s,1H),5.03(ddd,J=12.6,5.5,1.2Hz,1H),3.97–3.89(m,2H),3.80(t,J=5.9Hz,2H),3.69(t,J=5.3Hz,2H),3.61–3.51(m,1H),3.49(qd,J=4.6,3.9,2.1Hz,2H),2.83–2.61(m,4H),2.58(t,J=5.9Hz,2H),2.13–2.04(m,1H)。
化合物GD-C-30~32按相同方法合成。
化合物GD-C-30(黄色固体,25mg,产率为20%)。1H NMR(400MHz,MeOD)δ7.81(s,1H),7.51(dd,J=8.6,7.1Hz,1H),7.35(d,J=8.5Hz,2H),7.25–6.85(m,10H),6.84–6.47(m,2H),5.95(s,1H),5.02(ddd,J=12.2,5.4,2.3Hz,1H),3.92(d,J=1.1Hz,2H),3.79(t,J=5.9Hz,5H),3.66(d,J=14.6Hz,6H),3.61–3.45(m,1H),3.45–3.33(m,3H),2.96–2.50(m,7H),2.06(ddt,J=12.9,4.9,2.8Hz,1H)。
化合物GD-C-31(黄色固体,22mg,产率为19%)。1H NMR(400MHz,MeOD)δ7.82(s,1H),7.52(ddd,J=8.6,7.1,0.7Hz,1H),7.37(d,J=8.3Hz,2H),7.23–6.88(m,10H),6.65(d,J=64.8Hz,2H),5.95(s,1H),5.04(dd,J=12.5,5.5Hz,1H),3.92(s,2H),3.76(t,J=6.0Hz,2H),3.69–3.51(m,11H),3.50–3.41(m,2H),2.81–2.64(m,4H),2.55(t,J=5.9Hz,2H),2.18(d,J=7.5Hz,1H),2.05(dd,J=15.6,9.1Hz,3H)。
化合物GD-C-32(黄色固体,15mg,产率为13%)。1H NMR(400MHz,MeOD)δ7.51(dd,J=8.6,7.1Hz,1H),7.45–7.33(m,2H),7.25–6.86(m,10H),6.65(d,J=60.7Hz,2H),5.96(s,1H),5.09–4.98(m,1H),3.92(d,J=1.1Hz,2H),3.84–3.33(m,16H),2.92–2.60(m,5H),2.55(t,J=5.9Hz,2H),2.40(t,J=6.0Hz,2H),2.12–2.01(m,1H)。
终产物GD-C-33的合成路线见图5所示。
化合物24的合成:
将对苯二胺(2.97g,27.44mmol)和2-噻吩甲醛(3.08g,27.44mmol)溶解在25mL甲醇中,25℃活化1h后,加入(2-异氰乙基)苯(3g,22.87mmol)、2-氟丙烯酸(2.06g,22.87mmol),室温搅拌过夜。反应液减压浓缩,残渣用硅胶柱色谱分离(洗脱剂为体积比1:1的乙酸乙酯:石油醚),得到化合物24(白色固体,2.4g,产率为25%)。
化合物25的合成:
将化合物24(500mg,1.18mmol)溶于乙腈(5mL)中,加入3-(2-((叔丁氧基羰基)氨基)乙氧基)丙酸(330mg,1.42mmol),四甲基氯代脲六氟磷酸酯(357.62mg,1.40mmol),N-甲基咪唑(259.53mg,4.1mmol),室温搅拌过夜。反应液减压浓缩,残渣用硅胶柱色谱分离(洗脱剂为体积比1:1的乙酸乙酯:石油醚),得到化合物25(白色固体,580mg,产率为77%)。
化合物26的合成:
将化合物25(580mg,0.909mmol)溶于二氯甲烷(15ml)中,再加入三氟乙酸(3ml),反应2小时后,溶液旋转蒸发至干,得到化合物26(白色固体,400mg,产率为81%)。
化合物GD-C-33的合成:
将化合物26(200mg,0.37mmol)溶于乙腈(8mL)与化合物11a(144mg,0.37mmol)中,四甲基氯代脲六氟磷酸酯(124mg,0.44mmol),N-甲基咪唑(106mg,1.30mmol),室温搅拌过夜。反应完毕后用乙酸乙酯(200mL)稀释后,依次用水和饱和氯化钠水溶液各洗涤1次,有机相用硫酸钠干燥后抽滤,滤液减压蒸馏获得浓缩物,将浓缩物用硅胶柱色谱分离(洗脱剂为乙酸乙酯),得到GD-C-33(黄色固体,67mg,产率为19%)。1H NMR(400MHz,MeOD)δ7.92(dt,J=29.8,5.7Hz,1H),7.52–7.40(m,3H),7.31(dd,J=4.6,1.9Hz,1H),7.25–6.98(m,10H),6.83(q,J=2.8Hz,2H),6.14(s,1H),5.16–4.94(m,3H),3.71(q,J=6.1Hz,4H),3.63(t,J=5.2Hz,2H),3.55–3.47(m,3H),3.43(t,J=5.2Hz,2H),3.40–3.27(m,5H),2.81–2.71(m,3H),2.56(t,J=5.9Hz,2H),2.41(t,J=6.0Hz,2H),2.06(dtd,J=12.7,4.9,2.1Hz,1H)。
终产物GD-C-9的合成路线见图6所示。
化合物27的合成:
将化合物8c(200mg,0.38mmol)溶于乙腈(5mL)中,加入2-叠氮乙酸(340mg,0.38mmol),四甲基氯代脲六氟磷酸酯(128.94mg,0.46mmol),N-甲基咪唑(109.2mg,1.33mmol),室温搅拌过夜。反应液减压浓缩,残渣用硅胶柱色谱分离(洗脱剂为体积比10:1的乙酸乙酯:石油醚),得到化合物27(白色固体,200mg,产率为80%)。
化合物28的合成:
将化合物4(0.98g,3.58mmol)溶于N,N-二甲基甲酰胺(30mL),再加入3-溴丙-1-炔(506mg,4.30mmol),碘化钾(60mg,0.36mmol)和碳酸钾(740mg,5.38mmol),在60℃下反应4h。反应液用乙酸乙酯(200ml)稀释后,依次用水和饱和氯化钠水溶液各洗涤1次,有机相用硫酸钠干燥后,过滤,滤液旋转蒸发至干,浓缩物用硅胶柱色谱分离(洗脱剂为体积比1:1的乙酸乙酯:石油醚),得到化合物28(白色固体,600mg,产率为53%)。
化合物GD-C-9的合成:
将化合物27(200mg,0.33mmol)和化合物28(102mg,0.33mmol)溶于四氢呋喃(5mL)中,硫酸铜(10mg,0.066mmol)和维生素C钠(13mg,0.066mmol)溶于水(0.2mL)中,在氮气保护的条件下室温反应过夜。反应液用乙酸乙酯(200mL)稀释后,依次用水和饱和氯化钠水溶液各洗涤1次,有机相用硫酸钠干燥后抽滤,滤液旋转蒸发至干,获得浓缩物用硅胶柱色谱分离(洗脱剂为乙酸乙酯),得到化合物GD-C-9(白色固体,40mg,产率为13%)。1H NMR(400MHz,MeOD)δ8.07(s,1H),7.67(dd,J=8.5,7.3Hz,1H),7.51(d,J=8.5Hz,1H),7.43–7.33(m,3H),7.21–7.17(m,1H),7.15–7.08(m,3H),7.07–7.00(m,3H),6.71(d,J=3.4Hz,2H),6.10(s,1H),5.36(s,2H),5.06(s,2H),4.99(dd,J=12.4,5.5Hz,1H),3.82(d,J=1.9Hz,2H),3.42(dt,J=13.8,7.1Hz,1H),3.34–3.22(m,1H),3.16(t,J=6.7Hz,2H),2.80–2.59(m,5H),2.27(t,J=7.3Hz,2H),2.04–1.96(m,1H),1.60(dq,J=12.0,7.2Hz,2H),1.49(dt,J=10.0,6.8Hz,2H)。
实施例2:验证合成的嵌合体对细胞内的GPX4的降解效应
免疫印迹:将MGC803细胞(3×105个细胞)接种到添加有2mL含有10%胎牛血清(FBS)和1%青霉素链霉素的1640培养基的6孔培养板(Titan)中,37℃培养24h。细胞生长至70%融合后,弃去原有培养基后,每孔换入2mL含有10μM浓度待测化合物分子的含10%胎牛血清(FBS)和1%青霉素链霉素的1640培养基,37℃孵育24h后,弃培养液,将细胞用PBS洗涤两次,弃去洗涤液,培养孔中加入100μL含有1%苯甲基磺酰氟(PMSF)和10%磷酸酶抑制剂的RIPA,冰上裂解10min后,用刮刀将细胞刮取下来并置于1.5mL EP管中。在EP管中加入20μL 5×SDS上样缓冲液,99℃加热10min。样品通过15%SDS-PAGE分离并转移到PVDF膜上。膜在室温下用5%脱脂牛奶(在TBST缓冲液中)封闭1.5h后,将膜从30kD左右剪开,<30kD膜部分与兔抗anti-GPX4(1:1000稀释)孵育4℃过夜,然后加入HRP偶联的山羊抗兔IgG(1:2000稀释),室温孵育2小时;>30kD的PVDF膜与HRP偶联小鼠anti-GAPDH(1:100000稀释)孵育4℃过夜,然后加入HRP偶联的鼠抗IgG(1:1000稀释)室温孵育2小时。并使用InvitrogeniBright 1500记录印迹。
合成的化合物(10μM)对GPX4的降解效果,如表1所示(不排除“HOOK”效应对降解率的影响):
表1
WB经灰度分析转化为抑制率的结果显示:目标化合物对GPX4有较好的降解效应,代表性的化合物有GD-C-3和GD-C-17,在10μM能够显著降解GPX4蛋白。
Claims (9)
1.一种靶向降解GPX4的PROTAC嵌合体或其药理或生理上可接受的盐,其特征在于,该靶向降解GPX4的嵌合体或其药理或生理上可接受的盐的通式子为式I或式II所示:
所述式I或式II中,R的取代基为R1或R2所示结构中的任意一种:
所述式I或式II中,Linker为连接基团,表示-亚烷基或-烷氧基或-哌嗪基或-1,2,3-三氮唑基,所述-亚烷基或-烷氧基或-哌嗪基或-1,2,3-三氮唑基选自以下基团中任一个或任意一个以上的组合,其中m和n均表示1至20的自然数:
-(CH2)n-C(O)NH(CH2CH2O)m-或-(CH2CH2O)n-C(O)NH(CH2CH2O)m-或
所述式I或式II中,E3连接酶配体是指结合E3连接酶的配体分子,E3连接酶包括VHL和CRBN两种,其配体分子包括如下结构:
4.一种药物组合物,其特征在于,所述的药物组合物包括权利要求1-2任一项所述的靶向降解GPX4的PROTAC嵌合体或其药理或生理上可接受的盐,以及药学上可接受的载体、赋形剂、稀释剂、辅剂、媒介物或其组合。
5.一种权利要求1-2任一项所述的靶向降解GPX4的PROTAC嵌合体或其药理或生理上可接受的盐或权利要求4所述的药物组合物在制备降解GPX4或抑制GPX4药物中的应用。
6.一种权利要求1-2任一项所述的靶向降解GPX4的PROTAC嵌合体或其药理或生理上可接受的盐或权利要求4所述的药物组合物在制备治疗GPX4相关性疾病药物中的应用。
7.根据权利要求6所述的应用,其特征在于,所述GPX4相关性疾病为肿瘤、神经退行性疾病。
8.一种权利要求1-2任一项所述的靶向降解GPX4的PROTAC嵌合体或其药理或生理上可接受的盐或权利要求4所述的药物组合物在抗肿瘤药物中的应用,所述肿瘤为胃癌、乳腺癌、肺癌、卵巢癌、结肠腺癌、肾嫌色细胞、肾透明细胞癌、肺腺癌、前列腺癌、直肠腺癌、甲状腺癌以及子宫内膜癌。
9.根据权利要求8所述的应用,其特征在于,所述肿瘤为GPX4高表达的肿瘤。
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