CN117736201A - 靶向组蛋白去乙酰化酶8蛋白水解嵌合体、制备方法及其应用 - Google Patents
靶向组蛋白去乙酰化酶8蛋白水解嵌合体、制备方法及其应用 Download PDFInfo
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Abstract
本发明公开了靶向组蛋白去乙酰化酶8蛋白水解嵌合体、制备方法及其应用,涉及药物设计合成技术领域。本发明提供的靶向组蛋白去乙酰化酶8蛋白水解嵌合体是基于PCI‑34051结构和VHL为E3连接酶而设计的HDAC8‑PROTACs靶向蛋白水解嵌合体,实验证明其能够显著降解肿瘤细胞中的去乙酰化酶8,提示其在制备预防或治疗与HDAC8活性或表达异常相关疾病药物,尤其是抗肿瘤活性药物方面的价值。
Description
技术领域
本发明涉及药物设计合成技术领域,尤其涉及靶向组蛋白去乙酰化酶8蛋白水解嵌合体、制备方法及其应用。
背景技术
蛋白降解靶向嵌合体(PROTACs)技术是一种通过泛素-蛋白酶体途径化学诱导靶蛋白降解的新型策略。PROTACs诱导蛋白降解的作用机制为:PROTACs在进入细胞后,其结构中的靶蛋白配体(POI ligand)特异性地与靶蛋白(POI)结合,另一端的E3连接酶配体(E3ligand)与E3连接酶(E3 ligase)结合,从而形成POI-PROTAC-E3 ligase的三元复合物,然后E3连接酶介导泛素结合酶E2,将三元复合物中的靶蛋白POI泛素化,三元复合物解离后,被多泛素化标记的靶蛋白会被输送到蛋白酶体中进行降解,从而选择性地降低靶蛋白水平。
截至2021年12月,可被PROTACs降解的蛋白质靶标增加至130多个,涵盖癌症、免疫紊乱、病毒感染、神经退行性疾病等多个疾病领域,其中又以癌症领域的应用为主。其中,Arvinas的ARV-110和ARV-471已进入临床II期,是PROTAC药物中临床进展最快的。一些研发初创企业已经获得了罗氏、赛诺菲、默克、辉瑞、吉利德等全球大型制药公司的关注。
组蛋白去乙酰化酶(histone deacetylases,HDACs)作为表观遗传学调控的重要功能蛋白,近些年已经引起科学家的广泛关注。HDAC8是Ⅰ类HDACs,即Zn2+依赖性HDACs,其主要分布于细胞核和细胞质中,通常诱导组蛋白去乙酰化并抑制基因转录。HDAC8的失调与多种疾病的发生发展紧密相关,尤其是肿瘤,如胃癌、结肠癌、肺癌和乳腺癌等。随着对HDAC8靶点结构与功能研究的不断深入,以HDAC8为靶标的小分子选择性抑制剂陆续被报道。如:PCI-34051、NCC149、OJI-1、A8B4等。但是这些抑制剂效果不佳,副作用大。鉴于PROTACs的独特作用机制,例如能够靶向蛋白的非酶功能等特点,发展针对HDAC8的PROTACs相关药物,对于肿瘤及其它疾病的治疗具有重要意义。截止目前,仅有一例文献报道的基于HDAC8抑制剂NCC-149而发展的HDAC8-PROTACs降解剂(Chem.Commun.2022,58,4635-4638.),发明人课题组正在开发基于HDAC8抑制剂PCI-34051结构和CRBN为E3连接酶而设计的HDAC8-PROTACs降解剂(CN202210122650.8)。在此基础上,开发更多地选择性靶向组蛋白去乙酰化酶8的降解药物具有重要意义。
发明内容
本发明所要解决的技术问题是背景技术中所述的现有技术缺陷,提供靶向组蛋白去乙酰化酶8蛋白水解嵌合体、制备方法及其应用。
为了解决上述问题,本发明提出以下技术方案:
第一方面,本发明提供靶向组蛋白去乙酰化酶8蛋白水解嵌合体,所述嵌合体具有如式9X-1、9X-2所示的至少一化合物或其药学上可接受的盐:
式9X-1、9X-2中的手性位点可任意为R或S,m为1~4的整数,n为1~4的整数。
第二方面,本发明提供一种如第一方面所述的靶向组蛋白去乙酰化酶8蛋白水解嵌合体的制备方法,所述制备方法包括包括以下步骤:
S1、将化合物1和化合物2分别溶于有机溶剂中得到第一溶液和第二溶液,往第一溶液中加入NaH进行反应得到反应液,然后将第二溶液滴加至反应液中继续进行反应,得到化合物3;
S2、将化合物3溶于甲醇溶液中,加入Pd/C反应得到化合物4;
S3、将化合物4、化合物5A或化合物5B、及碳酸钾溶于无水DMF中,搅拌加热至90℃,反应8h,反应完毕,得到化合物6a-6h;
S4、将化合物6a-6h溶于无水二氯甲烷中,与三氟乙酸在常温下反应,得到反应液;向反应液中加入石油醚,搅拌均匀后,在真空下抽除溶剂,得到浓缩的残留物;将化合物7、EDCI、HOBt溶于DMF中,加入到上述浓缩的残留物中,冷却至5℃,再加入DIPEA,温度恢复至室温,继续反应18h,得到化合物8X-1或8X-2;
S5、取NH2OH溶液冷却至5℃,加入碱试剂,搅拌溶解得到羟胺溶液;将化合物8X-1或8X-2溶于MeOH/THF溶液中,再加入羟胺溶液中,反应完毕后加入酸试剂中和,得到化合物9X-1或9X-2;
其中,步骤S1-S2的合成路线如下:
步骤S3的合成路线如下:
步骤S4的合成路线如下:
其中,化合物7的手性位点可任意为R或S;m为1~4的整数、n为1~4的整数。
具体地,由于手性结构不同,本发明的化合物7可任意为以下5种结构:
具体地,当化合物7的结构式如下7-1所示时,
化合物5A的m=1,合成的化合物为9a:
化合物5A的m=2,合成的化合物为9b:
化合物5A的m=3,合成的化合物为9c:
化合物5A的m=4,合成的化合物为9d:
化合物5B的n=1,合成的化合物为9e:
化合物5B的n=2,合成的化合物为9f:
化合物5B的n=3,合成的化合物为9g:
化合物5B的n=4,合成的化合物为9h:
进一步地,步骤S1-S5中,还包括对各步骤得到的产物进行浓缩分离纯化的步骤。
具体地,步骤S1-S5中,为了提高相应产物的收率和纯度,在得到初步反应产物后还包括进一步采用萃取、洗涤、浓缩以及通过硅胶柱分离的手段对产物进行浓缩分离纯化的步骤。
进一步地,步骤S1中,所述有机溶剂为N,N-二甲基乙酰基胺。
进一步地,步骤S4中,所述浓缩的残留物无需纯化。
进一步地,步骤S5中,所述碱试剂为氢氧化钠;所述酸试剂为醋酸。
进一步地,步骤S5中,所述MeOH/THF溶液中MeOH和THF的体积比为1:1。
第三方面,本发明提供了一种药物组合物,所述药物组合物包括如第一方面所述的靶向组蛋白去乙酰化酶8蛋白水解嵌合体,或者包括如第二方面所述制备方法制得的靶向组蛋白去乙酰化酶8蛋白水解嵌合体。
进一步地,所述药物组合物还包括药学上可接受的载体和/或辅剂。
本发明所述的药物组合物,该药物组合物以第一方面所述的靶向组蛋白去乙酰化酶8蛋白水解嵌合体作为活性成分,不排除配制体系和给药方式的变动、对上述嵌合体进行简单化学修饰调整后的衍生物、药用盐、多化合物以及多降解剂合用等情况。
具体地,本发明提供的如上所述的化合物的药学上可接受的盐可以为:钠盐、钾盐、铵盐、氨基酸盐、乳酸盐、盐酸盐、磷酸盐、醋酸盐、苹果酸盐、枸椽酸盐或天冬氨酸盐等,本发明不对药物盐做具体限定。
在本发明中,可将本发明的靶向组蛋白去乙酰化酶8蛋白水解嵌合体作为活性成分配制于无毒的、惰性的和药学上可接受的载体介质;配制好的药物可以通过常规途径进行给药,包括但并不限口服、肌内、腹膜内、静脉内、皮下、皮内、或局部给药。
当本发明的药物组合物的剂型为用于口服施用的药物时,其含有安全有效量的本发明的靶向组蛋白去乙酰化酶8蛋白水解嵌合体以及药学上可接受的载体和/或辅剂,口服施用的药物可制成片剂、丸剂、散剂、颗粒剂、胶囊剂、乳剂、糖浆剂、软膏剂、栓剂等常用剂型;本发明中,不对载体和/或辅剂做具体限定。
本发明的药物组合物还可以被制成注射剂,可以在无菌操作环境下与注射用水、生理盐水、葡萄糖水制成注射剂,上述注射剂可通过常规方法进行制备。
第四方面,本发明提供了如第一方面所述的靶向组蛋白去乙酰化酶8蛋白水解嵌合体、第三方面所述的药物组合物在制备用于预防或治疗与HDAC8活性或表达异常相关疾病的药物中的应用。
具体地,上述相关疾病为血液瘤、实体瘤等肿瘤、病毒感染以及寄生虫病。
与现有技术相比,本发明所能达到的技术效果包括:
本发明提供的靶向组蛋白去乙酰化酶8蛋白水解嵌合体是基于PCI-34051结构和VHL为E3连接酶而设计的HDAC8-PROTACs,具有选择性靶向组蛋白去乙酰化酶8降解的效果,实验证明其能够显著降解肿瘤细胞中的去乙酰化酶8,提示其在制备预防或治疗与HDAC8活性或表达异常相关疾病药物,尤其是抗肿瘤活性药物方面的价值。
附图说明
为了更清楚地说明本发明实施例技术方案,下面将对实施例描述中所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图是本发明的一些实施例,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据这些附图获得其他的附图。
图1为本发明的蛋白降解实验的测试结果示意图。
具体实施方式
下面将结合本发明实施例中的附图,对实施例中的技术方案进行清楚、完整地描述。显然,以下将描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
术语“包含”为开放式表达,即包括本发明所指明的内容,但并不排除其他方面的内容。
术语“药物组合物”表示一种或多种本文所述化合物或者其生理学上/药学上可以接受的盐或前体药物或与其他活性药物联用的混合物。
实施例1
本实施例提供上述靶向组蛋白去乙酰化酶8蛋白水解嵌合体的制备方法,具体地,该制备方法包括以下步骤:
化合物3的合成
合成路线如下所示:
具体步骤为:
称取化合物1(3.0g,17.1mmol)溶于5mLN,N-二甲基乙酰基胺,将溶液冷却至0℃,分批缓慢加入NaH(1.1g,42.8mmol),继续反应1h。然后称取化合物2(4-苄氧基苄氯)(4.8g,21.1mmol)溶于5mLN,N-二甲基乙酰基胺,缓慢滴加至上述反应溶液中,继续在0℃下反应15min.后,缓慢恢复至常温,继续反应2h。TLC板监测反应完毕后,缓慢加入冰水5mL,再搅拌5分钟后,用乙酸乙酯萃取,有机相合并用饱和食盐水洗涤3次(30mL),有机相洗涤浓缩后,通过硅胶柱分离(VEA:VPE=1:4)纯化得化合物3(4.8g),白色固体,收率为75%。
化合物3的结构表征数据如下:
1H NMR(600MHz,d6-DMSO):δ=8.94(brs,1H),8.09(s,1H),7.73-7.75(m,1H),7.60-7.62(m,1H),7.13(d,J=8.2Hz,1H),7.00(d,J=8.2Hz,2H),6.75-6.78(m,2H),6.53-6.54(m,1H),5.28(s,2H),3.90(s,3H).13C NMR(125MHz,d6-DMSO):δ=167.9,157.1,135.4,132.3,131.6,129.4,128.4,127.4,122.9,120.4,115.7,112.0,101.7,51.8,49.7.HRMS(EI)calcd.For[C24H22NO3](M+H)+:372.1594,found:372.1596.
化合物4的合成
合成路线如下:
具体步骤为:
称取化合物3(3.6g,9.7mmol),加入10mL甲醇溶解,加入Pd/C(0.4g),常温下反应24h。反应完毕后减压称取溶剂,通过硅胶柱分离(VEA:VPE=1:3)纯化得化合物4(2.5g),白色固体,收率为92%。
化合物4的结构表征数据如下:
1H NMR(600MHz,d6-DMSO):δ=8.09(s,1H),7.62-7.67(m,3H),7.40(d,J=8.4Hz,2H),7.36(d,J=8.4Hz,2H),7.13(d,J=8.2Hz,2H),6.92-6.95(m,3H),6.53(d,J=10.0Hz,1H),6.56-6.58(m,1H),5.44(s,2H),5.04(s,2H),3.84(s,3H).13C NMR(125MHz,d6-DMSO):δ=167.5,158.2,155.4,137.3,135.4,132.1,132.4,130.4,128.7,127.9,127.5,122.8,120.7,120.2,115.4,112.4,101.8,69.7,52.1,49.2.HRMS(EI)calcd.For[C17H16NO3](M+H)+:282.1125,found:282.1126.
化合物6的合成
合成路线如下:
具体步骤为:
以6a合成为例:将化合物4(112mg,0.4mmol)、对甲基苯磺酸酯衍生物5A(m=1)(289mg,1.2mmol)、碳酸钾(0.2g,1.6mmol)溶于4mL无水DMF,搅拌加热至90℃,反应8h。反应完毕后,将反应体系冷却至室温,用乙酸乙酯萃取反应液三次,饱和食盐水洗两次,有机层分液后浓缩,剩余物过硅胶柱纯化得到化合物6a(103mg,61%)为无色油状物。
化合物6a的化学式如下:
化合物6a的结构表征数据如下:
Methyl 1-(4-(4-(tert-butoxy)-4-oxobutoxy)benzyl)-1H-indole-6-carboxylate(6a).Colorless oil(103mg,61%).1H NMR(600MHz,CDCl3):δ=8.09(s,1H),7.80(d,J=8.0Hz,1H),7.65(d,J=8.0Hz,1H),7.20(d,J=6.0Hz,1H),7.04(d,J=8.0Hz,2H),6.81(d,J=8.0Hz,2H),6.54(d,J=6.0Hz,1H),5.26(s,2H),3.91(s,3H),3.90(t,J=6.0Hz,2H),2.21(t,J=6.0Hz,2H),1.67-1.70(m,2H),1.47(s,9H).HRMS(EI)calcd.For[C25H30NO5](M+H)+:424.2118,found:424.2123.
化合物6b的合成方法参照化合物6a的合成方法,具体为采用化合物4与对甲基苯磺酸酯衍生物5A(m=2)反应合成,得到的化合物6b为无色油状物(91mg),收率为52%。
化合物6b的化学式如下:
化合物6b的结构表征数据如下:
Methyl 1-(4-((5-(tert-butoxy)-5-oxopentyl)oxy)benzyl)-1H-indole-6-carboxylate(6b).Colorless oil(91mg,52%).1H NMR(600MHz,CDCl3):δ=8.10(s,1H),7.79(d,J=8.0Hz,1H),7.66(d,J=8.0Hz,1H),7.20(d,J=6.0Hz,1H),7.04(d,J=8.0Hz,2H),6.82(d,J=8.0Hz,2H),6.53(d,J=6.0Hz,1H),5.27(s,2H),3.91(s,3H),3.90(t,J=6.0Hz,2H),2.21(t,J=6.0Hz,2H),1.68-1.71(m,2H),1.86-1.70(m,2H),1.47(s,9H).HRMS(EI)calcd.For[C26H32NO5](M+H)+:438.2275,found:438.2270.
化合物6c的合成方法参照化合物6a的合成方法,具体为采用化合物4与对甲基苯磺酸酯衍生物5A(m=3)反应合成,得到的化合物6c为无色油状物(71mg),收率为39%。
化合物6c的化学式如下:
化合物6c的结构表征数据如下:
Methyl 1-(4-((6-(tert-butoxy)-6-oxohexyl)oxy)benzyl)-1H-indole-6-carboxylate(6c).Colorless oil(71mg,39%).1H NMR(600MHz,CDCl3):δ=8.09(s,1H),7.80(d,J=8.0Hz,1H),7.65(d,J=8.0Hz,1H),7.19(d,J=6.0Hz,1H),7.04(d,J=8.0Hz,2H),6.82(d,J=8.0Hz,2H),6.54(d,J=6.0Hz,1H),5.26(s,2H),3.91(s,3H),3.90(t,J=6.0Hz,2H),2.20(t,J=6.0Hz,2H),1.68-1.72(m,2H),1.85-1.69(m,4H),1.47(s,9H).HRMS(EI)calcd.For[C27H34NO5](M+H)+:452.2431,found:452.2430.
化合物6d的合成方法参照化合物6a的合成方法,具体为采用化合物4与对甲基苯磺酸酯衍生物5A(m=4)反应合成,得到的化合物6d为无色油状物(70mg),收率为38%。
化合物6d的化学式如下:
化合物6d的结构表征数据如下:
Methyl 1-(4-((7-(tert-butoxy)-7-oxoheptyl)oxy)benzyl)-1H-indole-6-carboxylate(6d).Colorless oil(70mg,38%).1H NMR(600MHz,CDCl3):δ=8.09(s,1H),7.79(d,J=8.0Hz,1H),7.65(d,J=8.0Hz,1H),7.20(d,J=6.0Hz,1H),7.04(d,J=8.0Hz,2H),6.82(d,J=8.0Hz,2H),6.53(d,J=6.0Hz,1H),5.26(s,2H),3.91(s,3H),3.90(t,J=6.0Hz,2H),2.21(t,J=6.0Hz,2H),1.68-1.72(m,2H),1.86-1.70(m,6H),1.47(s,9H).HRMS(EI)calcd.For[C28H35NO5](M+H)+:465.2510,found:465.2515.
化合物6e的合成方法参照化合物6a的合成方法,具体为采用化合物4与溴代物5B(n=1)反应合成,得到的化合物6e为无色油状物(132mg),收率为75%。
化合物6e的化学式如下:
化合物6e的结构表征数据如下:
Methyl 1-(4-(2-(2-(tert-butoxy)-2-oxoethoxy)ethoxy)benzyl)-1H-indole-6-carboxylate(6e).Colorless oil(132mg,75%).1H NMR(600MHz,CDCl3):δ=8.09(s,1H),7.79(d,J=8.0Hz,1H),7.63(d,J=8.0Hz,1H),7.21(d,J=6.0Hz,1H),7.03(d,J=8.0Hz,2H),6.83(d,J=8.0Hz,2H),6.54(d,J=6.0Hz,1H),5.26(s,2H),4.10(t,J=6.0Hz,2H),4.06(s,2H),3.90(s,3H),3.87(t,J=6.0Hz,2H),1.47(s,9H).HRMS(EI)calcd.For[C25H30NO6](M+H)+:440.2068,found:440.2070.
化合物6f的合成方法参照化合物6a的合成方法,具体为采用化合物4与溴代物5B(n=2)反应合成,得到的化合物6f为无色油状物(116mg),收率为60%。
化合物6f的化学式如下:
化合物6f的结构表征数据如下:
Methyl 1-(4-(2-(2-(2-(tert-butoxy)-2-oxoethoxy)ethoxy)ethoxy)benzyl)-1H-indole-6-carboxyl ate(6f).Colorless oil(116mg,60%).1H NMR(600MHz,CDCl3):δ=8.12(s,1H),7.81(d,J=8.0Hz,1H),7.66(d,J=8.0Hz,1H),7.25(d,J=6.0Hz,1H),7.07(d,J=8.0Hz,2H),6.87(d,J=8.0Hz,2H),6.58(d,J=6.0Hz,1H),5.32(s,2H),4.11(t,J=6.0Hz,2H),4.04(s,2H),3.93(s,3H),3.86(t,J=6.0Hz,2H),3.74(t,J=6.0Hz,2H),3.50(t,J=6.0Hz,2H),1.48(s,9H).HRMS(EI)calcd.For[C27H34NO7](M+H)+:484.2330,found:484.2332.
化合物6g的合成方法参照化合物6a的合成方法,具体为采用化合物4与溴代物5B(n=3)反应合成,得到的化合物6g为无色油状物(148mg),收率为70%。
化合物6g的化学式如下:
化合物6g的结构表征数据如下:
Methyl 1-(4-((13,13-dimethyl-11-oxo-3,6,9,12-tetraoxatetradecyl)oxy)benzyl)-1H-indole-6-ca rboxylate(6g).Colorless oil(148mg,70%).1H NMR(600MHz,CDCl3):δ=8.10(s,1H),7.79(d,J=8.0Hz,1H),7.65(d,J=8.0Hz,1H),7.24(d,J=6.0Hz,1H),7.06(d,J=8.0Hz,2H),6.85(d,J=8.0Hz,2H),6.56(d,J=6.0Hz,1H),5.31(s,2H),4.09(t,J=6.0Hz,2H),4.01(s,2H),3.92(s,3H),3.84(t,J=6.0Hz,2H),3.67-3.72(m,8H),1.46(s,9H).HRMS(EI)calcd.For[C29H38NO8](M+H)+:528.2592,found:528.2594.
化合物6h的合成方法参照化合物6a的合成方法,具体为采用化合物4与溴代物5B(n=4)反应合成,得到的化合物6h为无色油状物(128mg),收率为56%。
化合物6h的化学式如下:
化合物6h的结构表征数据如下:
Methyl 1-(4-((16,16-dimethyl-14-oxo-3,6,9,12,15-pentaoxaheptadecyl)oxy)benzyl)-1H-indole-6-carboxylate(6h).Colorless oil(128mg,56%).1H NMR(600MHz,CDCl3):δ=8.10(s,1H),7.79(d,J=8.0Hz,1H),7.64(d,J=8.0Hz,1H),7.24(d,J=6.0Hz,1H),7.05(d,J=8.0Hz,2H),6.84(d,J=8.0Hz,2H),6.56(d,J=6.0Hz,1H),5.31(s,2H),4.09(t,J=6.0Hz,2H),4.01(s,2H),3.92(s,3H),3.83(t,J=6.0Hz,2H),3.69-3.72(m,6H),3.66-3.68(m,6H),1.47(s,9H).HRMS(EI)calcd.For[C31H42NO9](M+H)+:572.2854,found:572.2856.
化合物8(8X-1或8X-2)的合成
合成路线如下:
由于化合物7的手性位点可任意为R或S;因此,在本实施例中,以化合物7-1为例,介绍合成化合物8(8X-1或8X-2)的具体方法。
具体步骤为:
以8a合成为例:将6a(70mg,0.2mmol)溶于2mL的无水二氯甲烷中,在3分钟之内缓慢滴加0.35mL三氟乙酸。滴加完毕后,在常温下继续反应3-5h。向反应液中加入10mL石油醚,搅拌10分钟后,在真空下抽除溶剂,得到浓缩的残留物,此残留物未经纯化用于下一步偶联反应。称取化合物7-1(89mg,0.2mmol)、EDCI(96mg,0.5mmol)、HOBt(76mg,0.5mmol)溶于DMF(3mL)中,加入到上述浓缩的残留物中,冷却至5℃,再加入DIPEA(0.1mL,0.6mmol)。温度恢复至室温,继续反应18h。反应完毕后,旋蒸除去溶剂,再用硅胶柱纯化得到化合物8a(87mg,56%),为白色固体。
化合物8a的化学式如下:
化合物8a的结构表征数据如下:
Methyl 1-(4-(4-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)ca rbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-4-oxobutoxy)benzyl)-1H-indole-6-carboxylate(8a).Whitesolid(87mg,56%).1H NMR(600MHz,CDCl3):δ=8.65(s,1H),8.15(s,1H),7.78(d,J=8.0Hz,1H),7.64(d,J=8.0Hz,1H),7.74(d,J=8.0Hz,1H),7.34-7.40(m,5H),7.23(d,J=6.0Hz,1H),7.05(d,J=8.0Hz,2H),6.96(d,J=8.0Hz,2H),6.58(d,J=6.0Hz,1H),5.31(s,2H),5.08-5.10(m,1H),4.76(t,J=6.0Hz,1H),4.55(d,J=6.0Hz,1H),4.50-4.51(m,1H),4.30-4.31(m,2H),3.92(s,3H),3.80(t,J=6.0Hz,3H),2.47(s,3H),2.35-2.45(m,2H),2.05-2.09(m,4H),1.49(d,J=6.0Hz,3H),1.05(s,9H).HRMS(EI)calcd.for[C44H52N5O7S](M+H)+:794.3582,found:794.3588.
化合物8b的合成方法参照化合物8a的合成方法,具体为将化合物6a替换为化合物6b与化合物7-1进行合成反应,得到的化合物8b为白色固体(81mg),收率为51%。
化合物8b的化学式如下:
化合物8b的结构表征数据如下:
Methyl 1-(4-((5-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-5-oxopentyl)oxy)benzyl)-1H-indole-6-carboxylate(8b).White solid(81mg,51%).1H NMR(600MHz,CDCl3):δ=8.66(s,1H),8.15(s,1H),7.78(d,J=8.0Hz,1H),7.66(d,J=8.0Hz,1H),7.74(d,J=8.0Hz,1H),7.34-7.40(m,5H),7.24(d,J=6.0Hz,1H),7.05(d,J=8.0Hz,2H),6.96(d,J=8.0Hz,2H),6.59(d,J=6.0Hz,1H),5.31(s,2H),5.09-5.10(m,1H),4.77(t,J=6.0Hz,1H),4.56(d,J=6.0Hz,1H),4.50-4.51(m,1H),4.31-4.32(m,2H),3.91(s,3H),3.79(t,J=6.0Hz,3H),2.46(s,3H),2.36-2.45(m,2H),2.06-2.09(m,4H),1.51-1.68(m,2H),1.49(d,J=6.0Hz,3H),1.06(s,9H).HRMS(EI)calcd.for[C45H54N5O7S](M+H)+:808.3738,found:808.3740.
化合物8c的合成方法参照化合物8a的合成方法,具体为将化合物6a替换为化合物6c与化合物7-1进行合成反应,得到的化合物8c为白色固体(78mg),收率为48%。
化合物8c的化学式如下:
化合物8c的结构表征数据如下:
Methyl 1-(4-((6-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-6-oxohexyl)oxy)benzyl)-1H-indole-6-carboxylate(8c).Whitesolid(78mg,48%).1H NMR(600MHz,CDCl3):δ=8.67(s,1H),8.16(s,1H),7.78(d,J=8.0Hz,1H),7.64(d,J=8.0Hz,1H),7.74(d,J=8.0Hz,1H),7.35-7.40(m,5H),7.25(d,J=6.0Hz,1H),7.06(d,J=8.0Hz,2H),6.96(d,J=8.0Hz,2H),6.70(d,J=6.0Hz,1H),5.32(s,2H),5.09-5.10(m,1H),4.78(t,J=6.0Hz,1H),4.56(d,J=6.0Hz,1H),4.50-4.52(m,1H),4.30-4.31(m,2H),3.90(s,3H),3.79(t,J=6.0Hz,3H),2.47(s,3H),2.38-2.44(m,2H),2.07-2.09(m,4H),1.51-1.69(m,2H),1.49(d,J=6.0Hz,3H),1.28-1.29(m,2H),1.06(s,9H).HRMS(EI)calcd.for[C46H56N5O7S](M+H)+:822.3895,found:822.3900.
化合物8d的合成方法参照化合物8a的合成方法,具体为将化合物6a替换为化合物6d与化合物7-1进行合成反应,得到的化合物8d为白色固体(82mg),收率为49%。
化合物8d的化学式如下:
化合物8d的结构表征数据如下:
Methyl 1-(4-((7-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptyl)oxy)benzyl)-1H-indole-6-carboxylate(8d).Colorless oil(82mg,49%).1H NMR(600MHz,CDCl3):δ=8.67(s,1H),8.16(s,1H),7.77(d,J=8.0Hz,1H),7.64(d,J=8.0Hz,1H),7.75(d,J=8.0Hz,1H),7.36-7.40(m,5H),7.26(d,J=6.0Hz,1H),7.06(d,J=8.0Hz,2H),6.97(d,J=8.0Hz,2H),6.71(d,J=6.0Hz,1H),5.31(s,2H),5.09-5.10(m,1H),4.78(t,J=6.0Hz,1H),4.57(d,J=6.0Hz,1H),4.50-4.52(m,1H),4.31-4.32(m,2H),3.91(s,3H),3.79(t,J=6.0Hz,3H),2.47(s,3H),2.39-2.45(m,2H),2.07-2.09(m,4H),1.52-1.69(m,2H),1.50(d,J=6.0Hz,3H),1.43-1.46(m,2H),1.33-1.35(m,2H),1.06(s,9H).HRMS(EI)calcd.for[C47H58N5O7S](M+H)+:836.4051,found:836.4054.
化合物8e的合成方法参照化合物8a的合成方法,具体为将化合物6a替换为化合物6e与化合物7-1进行合成反应,得到的化合物8e为白色固体(98mg),收率为62%。
化合物8e的化学式如下:
化合物8e的结构表征数据如下:
Methyl 1-(4-(2-(2-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)ethoxy)benzyl)-1H-indole-6-carboxylate(8e).Colorless oil(98mg,62%).1H NMR(600MHz,CDCl3):δ=8.66(s,1H),8.15(s,1H),7.78(d,J=8.0Hz,1H),7.63(d,J=8.0Hz,1H),7.74(d,J=8.0Hz,1H),7.33-7.39(m,5H),7.23(d,J=6.0Hz,1H),7.05(d,J=8.0Hz,2H),6.94(d,J=8.0Hz,2H),6.58(d,J=6.0Hz,1H),5.31(s,2H),5.08-5.10(m,1H),4.76(t,J=6.0Hz,1H),4.54(d,J=6.0Hz,1H),4.50-4.51(m,1H),4.07-4.08(m,4H),3.92(s,3H),3.81(t,J=6.0Hz,3H),3.25-3.30(m,2H),2.47(s,3H),2.35-2.46(m,2H),1.48(d,J=6.0Hz,3H),1.05(s,9H).HRMS(EI)calcd.for[C44H52N5O8S](M+H)+:810.3531,found:810.3534.
化合物8f的合成方法参照化合物8a的合成方法,具体为将化合物6a替换为化合物6f与化合物7-1进行合成反应,得到的化合物8f为白色固体(97mg),收率为57%。
化合物8f的化学式如下:
化合物8f的结构表征数据如下:
Methyl 1-(4-(2-(2-(2-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)ethoxy)ethoxy)benzyl)-1H-indole-6-carboxylate(8f).White solid(97mg,57%).1H NMR(600MHz,CDCl3):δ=8.68(s,1H),8.12(s,1H),7.81(d,J=8.0Hz,1H),7.65(d,J=8.0Hz,1H),7.48(d,J=8.0Hz,1H),7.41(d,J=8.0Hz,2H),7.36(d,J=8.0Hz,2H),7.33(d,J=6.0Hz,1H),7.24(d,J=d,J=6.0Hz,1H),7.06(d,J=8.0Hz,2H),6.84(d,J=8.0Hz,2H),6.57(d,J=6.0Hz,1H),5.31(s,2H),5.07-5.10(m,1H),4.75(t,J=6.0Hz,1H),4.51-4.55(m,2H),4.11-4.16(m,6H),3.92(s,3H),3.85-3.88(m,2H),3.71-3.76(m,4H),3.60-3.62(m,1H),2.52-2.54(m,2H),2.47(s,3H),2.06(s,1H),1.46(d,J=6.0Hz,3H),1.06(s,9H).HRMS(EI)calcd.for[C46H56N5O9S](M+H)+:854.3793,found:854.3795.
化合物8g的合成方法参照化合物8a的合成方法,具体为将化合物6a替换为化合物6g与化合物7-1进行合成反应,得到的化合物8g为白色固体(90mg),收率为50%。
化合物8g的化学式如下:
化合物8g的结构表征数据如下:
Methyl 1-(4-(((S)-13-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carbonyl)-14,14-dimethyl-11-oxo-3,6,9-trioxa-12-azapentadecyl)oxy)benzyl)-1H-indole-6-carboxylate(8g).Colorless oil(90mg,50%).1H NMR(600MHz,CDCl3):δ=8.66(s,1H),8.10(s,1H),7.78(d,J=8.0Hz,1H),7.63(d,J=8.0Hz,1H),7.47(d,J=6.0Hz,1H),7.41(d,J=8.0Hz,2H),7.38(d,J=8.0Hz,2H),7.33(d,J=6.0Hz,1H),7.24(d,J=6.0Hz,1H),7.05(d,J=8.0Hz,2H),6.83(d,J=8.0Hz,2H),6.56(d,J=6.0Hz,1H),5.30(s,2H),5.06-5.09(m,1H),4.73(t,J=6.0Hz,1H),4.53(d,J=6.0Hz,1H),4.50-4.51(m,1H),4.07-4.09(m,4H),3.91(s,3H),3.81(t,J=6.0Hz,3H),3.66-3.70(m,4H),3.58-3.61(m,2H),3.28(t,J=6.0Hz,2H),3.23-3.25(m,2H),2.47(s,3H),2.45-2.46(m,2H),1.48(d,J=6.0Hz,3H),1.05(s,9H).HRMS(EI)calcd.for[C48H60N5O10S](M+H)+:898.4055,found:898.4058.
化合物8h的合成方法参照化合物8a的合成方法,具体为将化合物6a替换为化合物6h与化合物7-1进行合成反应,得到的化合物8h为白色固体(85mg),收率为45%。
化合物8h的化学式如下:
化合物8h的结构表征数据如下:
Methyl 1-(4-(((S)-16-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)car bamoyl)pyrrolidine-1-carbonyl)-17,17-dimethyl-14-oxo-3,6,9,12-tetraoxa-15-azaocta decyl)oxy)benzyl)-1H-indole-6-carboxylate(8h).White solid(85mg,45%).1H NMR(600MHz,CDCl3):δ=8.66(s,1H),8.09(s,1H),7.78(d,J=8.0Hz,1H),7.63(d,J=8.0Hz,1H),7.52(d,J=6.0Hz,1H),7.35-7.39(m,5H),7.23(d,J=6.0Hz,1H),7.04(d,J=8.0Hz,2H),6.83(d,J=8.0Hz,2H),6.55(d,J=6.0Hz,1H),5.29(s,2H),5.06-5.08(m,1H),4.71(t,J=6.0Hz,1H),4.56(t,J=6.0Hz,1H),4.47-4.59(m,1H),4.06(t,J=6.0Hz,2H),3.96-4.05(m,4H),3.90(s,3H),3.80(t,J=6.0Hz,2H),3.70-3.71(m,2H),3.66-3.67(m,10H),3.60-3.62(m,1H),2.48(s,3H),2.41-2.43(m,2H),1.46(d,J=6.0Hz,3H).HRMS(EI)calcd.For[C50H64N5O11S](M+H)+:942.4323,found:942.4323.
化合物9(9X-1、9X-2)的合成
接上述合成的化合物8a-8h,现以9a合成为例介绍化合物9的合成:称取100mg氢氧化钠,缓慢加入到冷却(5℃)的0.5mL羟胺(50wt%)溶液中,继续搅拌10分钟。称取8a(79mg,0.1mmol),溶解在2mL由THF/MeOH组成的混合溶剂中,再将该溶液缓慢滴加至上述混合溶液中,恢复至常温,继续反应2h。反应完毕后,加入醋酸调节反应体系pH值到7左右,向反应体系中加入乙酸乙酯进行有机相的萃取,再用饱和食盐水洗涤3次后,对有机层进行浓缩,过柱纯化得化合物9a(44mg,收率56%),为浅白色固体。
化合物9a的化学式如下:
化合物9a的结构表征数据如下:
N-Hydroxy-1-(4-(4-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-4-oxo butoxy)benzyl)-1H-indole-6-carboxamide(9a).Off-white solid(44mg,56%).1HNMR(600MHz,d6-DMSO):δ=10.95(brs,2H),8.98(s,1H),8.37(d,J=8.0Hz,1H),7.94(s,1H),7.88(d,J=8.0Hz,1H),7.16(d,J=8.0Hz,1H),6.86(d,J=8.0Hz,2H),6.51(d,J=6.0Hz,1H),5.36(s,2H),5.09(s,1H),4.91(t,J=6.0Hz,1H),4.50(d,J=6.0Hz,1H),4.41(t,J=6.0Hz,1H),4.27(brs,1H),3.88-3.91(m,2H),3.59-3.60(m,2H),2.45(s,3H),2.34-2.38(m,1H),2.25-2.30(m,1H),1.98-2.02(m,1H),1.84-1.90(m,2H),1.75-1.80(m,3H),1.37(d,J=6.0Hz,3H),0.91(s,9H).13C NMR(150MHz,d6-DMSO):δ=176.7,175.8,174.7,163.1,156.8,156.6,152.9,149.8,145.9,140.8,140.2,136.3,135.4,135.1,134.8,134.0,133.6,132.6,131.5,131.4,125.2,119.7,106.3,73.9,72.1,70.1,63.7,61.6,52.9,42.3,40.4,36.4,31.6,30.2,27.6,21.2,20.4.HRMS(EI)calcd.for[C43H51N6O7S](M+H)+:795.3534,found:795.3593.
化合物9b的合成方法参照化合物9a的合成方法,具体为将化合物8a替换为化合物8b进行反应,得到的化合物9b为浅白色固体(40mg),收率为50%。
化合物9b的化学式如下:
化合物9b的结构表征数据如下:
N-Hydroxy-1-(4-((5-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-5-oxopentyl)oxy)benzyl)-1H-indole-6-carboxamide(9b).Off-white solid(40mg,50%).1H NMR(600MHz,d6-DMSO):δ=10.94(brs,2H),8.98(s,1H),8.38(d,J=8.0Hz,1H),7.95(s,1H),7.88(d,J=8.0Hz,1H),7.15(d,J=8.0Hz,1H),6.87(d,J=8.0Hz,2H),6.50(d,J=6.0Hz,1H),5.36(s,2H),5.10(s,1H),4.91(t,J=6.0Hz,1H),4.51(d,J=6.0Hz,1H),4.40(t,J=6.0Hz,1H),4.28(brs,1H),3.88-3.91(m,2H),3.58-3.59(m,2H),2.46(s,3H),2.35-2.38(m,1H),2.26-2.29(m,1H),1.98-2.01(m,1H),1.84-1.91(m,2H),1.76-1.80(m,5H),1.38(d,J=6.0Hz,3H),0.90(s,9H).13C NMR(150MHz,d6-DMSO):δ=175.9,175.3,174.8,163.2,157.1,156.5,153.0,149.9,145.9,141.0,140.1,136.3,135.6,135.3,134.9,134.1,133.8,132.4,131.8,131.6,125.0,119.8,107.0,74.0,72.0,70.2,63.8,61.9,53.0,42.5,40.6,36.6,31.8,30.4,27.8,26.6,21.3,20.5.HRMS(EI)calcd.for[C44H53N6O7S](M+H)+:809.3691,found:809.3693.
化合物9c的合成方法参照化合物9a的合成方法,具体为将化合物8a替换为化合物8c进行反应,得到的化合物9c为浅白色固体(41mg),收率为50%。
化合物9c的化学式如下:
化合物9c的结构表征数据如下:
N-Hydroxy-1-(4-((6-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-6-oxohexyl)oxy)benzyl)-1H-indol e-6-carboxamide(9c).Off-white solid(41mg,50%).1H NMR(600MHz,d6-DMSO):δ=11.02(brs,2H),8.99(s,1H),8.37(d,J=8.0Hz,1H),7.96(s,1H),7.81(d,J=8.0Hz,1H),7.62(s,1H),7.58(d,J=8.0Hz,1H),7.45-7.46(m,3H),7.39(d,J=8.0Hz,2H),7.17(d,J=8.0Hz,2H),6.86(d,J=8.0Hz,2H),6.51(d,J=6.0Hz,1H),5.37(s,2H),5.10(s,1H),4.92(t,J=6.0Hz,1H),4.51(d,J=6.0Hz,1H),4.42(t,J=6.0Hz,1H),4.28(s,1H),3.89(t,J=6.0Hz,2H),3.58-3.63(m,2H),2.46(s,3H),2.24-2.28(m,1H),2.12-2.14(m,1H),1.99-2.02(m,1H),1.77-1.81(m,2H),1.64-1.68(m,2H),1.48-1.56(m,3H),1.37(d,J=6.0Hz,3H),0.93(s,9H).13CNMR(150MHz,d6-DMSO):δ=172.4,172.1,171.0,158.4,151.9,148.2,145.1,139.8,135.4,131.8,131.5,130.7,130.2,130.1,129.2,128.8,126.8,120.5,118.2,114.8,110.1,109.7,101.5,69.2,67.7,65.4,58.9,56.7,49.1,48.1,38.1,35.6,35.2,28.8,26.9,25.6,22.9,16.5,16.4.HRMS(EI)calcd.for[C45H55N6O7S](M+H)+:823.3847,found:823.3850.
化合物9d的合成方法参照化合物9a的合成方法,具体为将化合物8a替换为化合物8d进行反应,得到的化合物9d为白色固体(38mg),收率为45%。
化合物9d的化学式如下:
化合物9d的结构表征数据如下:
N-Hydroxy-1-(4-((7-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptyl)oxy)benzyl)-1H-indole-6-carboxamide(9d).White solid(38mg,45%).1H NMR(600MHz,d6-DMSO):δ=11.01(brs,2H),8.99(s,1H),8.38(d,J=8.0Hz,1H),7.96(s,1H),7.80(d,J=8.0Hz,1H),7.61(s,1H),7.58(d,J=8.0Hz,1H),7.46-7.47(m,3H),7.40(d,J=8.0Hz,2H),7.18(d,J=8.0Hz,2H),6.87(d,J=8.0Hz,2H),6.51(d,J=6.0Hz,1H),5.36(s,2H),5.10(s,1H),4.91(t,J=6.0Hz,1H),4.50(d,J=6.0Hz,1H),4.41(t,J=6.0Hz,1H),4.28(s,1H),3.90(t,J=6.0Hz,2H),3.59-3.64(m,2H),2.47(s,3H),2.24-2.28(m,1H),2.13-2.14(m,1H),1.99-2.01(m,1H),1.78-1.81(m,2H),1.65-1.69(m,2H),1.47-1.58(m,5H),1.38(d,J=6.0Hz,3H),0.93(s,9H).13C NMR(150MHz,d6-DMSO):δ=172.2,172.0,171.0,158.6,152.0,148.1,145.0,139.8,135.6,131.9,131.6,130.7,130.3,130.0,129.2,128.9,126.8,120.6,118.2,115.0,110.2,109.7,101.6,69.8,67.8,65.6,59.0,56.8,49.3,48.0,38.0,35.8,35.0,29.0,27.0,25.8,22.9,16.8,16.6,16.4.HRMS(EI)calcd.for[C46H57N6O7S](M+H)+:837.4004,found:837.4010.
化合物9e的合成方法参照化合物9a的合成方法,具体为将化合物8a替换为化合物8e进行反应,得到的化合物9e为浅白色固体(48mg),收率为60%。
化合物9e的化学式如下:
化合物9e的结构表征数据如下:
N-Hydroxy-1-(4-(2-(2-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)ethoxy)benzyl)-1H-indole-6-carboxamide(9e).Off-white solid(48mg,60%).1H NMR(600MHz,d6-DMSO):δ=11.09(brs,2H),9.0(s,1H),8.90(brs,1H),8.43(d,J=6.0Hz,1H),7.96(s,1H),7.63(s,1H),7.57(d,J=8.0Hz,1H),7.44-7.46(m,3H),7.34(d,J=8.0Hz,2H),7.17(d,J=8.0Hz,2H),6.97(d,J=8.0Hz,2H),6.52(d,J=6.0Hz,1H),5.39(s,2H),5.13(s,1H),4.90-4.92(m,1H),4.56(d,J=4.0Hz,1H),4.43(t,J=6.0Hz,1H),4.29(s,1H),4.08-4.12(m,2H),4.01-3.96(m,2H),3.80-3.81(m,2H),3.55-3.62(m,2H),2.47(s,3H),2.02-2.06(m,1H),1.76-1.80(m,1H),1.33(d,J=6.0Hz,3H),0.93(s,9H).13C NMR(150MHz,d6-DMSO):δ=170.9,169.4,168.8,158.2,151.9,148.2,145.1,135.5,131.8,131.5,130.7,130.1,129.3,128.7,126.8,127.7,126.0,120.5,118.2,115.0,109.7,101.5,99.9,70.0,69.2,67.2,65.4,59.0,57.0,56.1,49.0,48.1,38.1,36.2,26.7,22.9,16.4.HRMS(EI)calcd.for[C43H51N6O8S](M+H)+:811.3484,found:811.3533.
化合物9f的合成方法参照化合物9a的合成方法,具体为将化合物8a替换为化合物8f进行反应,得到的化合物9f为白色固体(55mg),收率为64%。
化合物9f的化学式如下:
化合物9f的结构表征数据如下:
N-Hydroxy-1-(4-(2-(2-(2-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)ethoxy)ethoxy)benzyl)-1H-indole-6-carboxamide(9f).White solid(55mg,64%).1HNMR(600MHz,d6-DMSO):δ=11.11(brs,2H),8.98(s,1H),8.44(s,1H),7.94(s,1H),7.59(s,1H),7.56(d,J=8.0Hz,1H),7.35-7.47(m,5H),7.16(d,J=8.0Hz,2H),6.88(d,J=8.0Hz,2H),6.50(d,J=6.0Hz,1H),5.36(s,2H),5.16(s,1H),4.89(t,J=6.0Hz,1H),4.54(d,J=6.0Hz,1H),4.44(d,J=6.0Hz,1H),4.29(s,1H),4.05-4.07(m,2H),3.95-3.96(m,2H),3.73-3.75(m,2H),3.60-3.64(m,6H),2.46(s,3H),2.03-2.07(m,1H),1.75-1.77(m,1H),1.34(d,J=6.0Hz,3H),0.92(s,9H).13C NMR(150MHz,d6-DMSO):δ=170.9,169.5,169.0,168.1,158.2,151.9,148.2,145.1,135.5,131.5,130.4,130.1,130.0,129.3,128.8,126.7,126.0,120.4,118.1,114.9,109.7,101.5,99.8,70.8,70.1,69.4,69.2,59.0,56.9,56.1,49.0,48.2,38.1,36.2,31.7,26.7,25.6,22.9,16.4.HRMS(EI)calcd.For[C45H55N6O9S](M+H)+:855.3746,found:855.3804.
化合物9g的合成方法参照化合物9a的合成方法,具体为将化合物8a替换为化合物8g进行反应,得到的化合物9g为浅白色固体(52mg),收率为58%。
化合物9g的化学式如下:
化合物9g的结构表征数据如下:
N-Hydroxy-1-(4-(((S)-13-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carbonyl)-14,14-dimethyl-11-oxo-3,6,9-trioxa-12-azapentadecyl)oxy)benzyl)-1H-indole-6-carboxamide(9g).Off-white solid(52mg,58%).1H NMR(600MHz,d6-DMSO):δ=10.98(brs,2H),8.99(s,1H),8.44(d,J=6.0Hz,1H),7.96(s,1H),7.62(d,J=6.0Hz,1H),7.56(d,J=8.0Hz,1H),7.44-7.45(m,3H),7.34-7.39(m,3H),7.17(d,J=8.0Hz,2H),6.89(d,J=8.0Hz,2H),6.51(d,J=6.0Hz,1H),5.37(s,2H),5.14(brs,1H),4.89-4.91(m,1H),4.54(d,J=6.0Hz,1H),4.45(t,J=6.0Hz,1H),4.29(s,1H),4.03-4.04(m,2H),3.95(s,2H),3.70-3.72(m,2H),3.55-3.62(m,10H),2.46(s,3H),2.04-2.07(m,1H),1.75-1.79(m,1H),1.37(d,J=6.0Hz,3H),0.93(s,9H).13C NMR(150MHz,d6-DMSO):δ=170.9,169.4,168.9,158.2,151.9,148.2,145.1,135.5,131.7,131.5,130.4,130.1,129.3,129.2,128.8,126.7,120.5,118.1,115.0,114.9,109.6,101.5,99.9,70.8,70.3,70.0,69.3,69.2,67.5,65.3,59.0,56.9,56.1,49.0,48.2,38.2,36.2,26.7,25.6,22.9,16.4.HRMS(EI)calcd.for[C47H59N6O10S](M+H)+:899.4008,found:899.4018.
化合物9h的合成方法参照化合物9a的合成方法,具体为将化合物8a替换为化合物8h进行反应,得到的化合物9h为白色固体(46mg),收率为49%。
化合物9h的化学式如下:
化合物9h的结构表征数据如下:
N-Hydroxy-1-(4-(((S)-16-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carbonyl)-17,17-dimethyl-14-oxo-3,6,9,12-tetr aoxa-15-azaoctadecyl)oxy)benzyl)-1H-indole-6-carboxamide(9h).White solid(46mg,49%).1H NMR(600MHz,d6-DMSO):δ=11.10(brs,2H),8.99(s,1H),8.44(d,J=6.0Hz,1H),7.96(s,1H),7.62(d,J=6.0Hz,1H),7.57(d,J=8.0Hz,1H),7.43-7.45(m,3H),7.36-7.39(m,3H),7.18(d,J=8.0Hz,2H),5.88(d,J=8.0Hz,1H),6.51(d,J=6.0Hz,1H),5.37(s,2H),5.14(brs,1H),4.89-4.92(m,1H),4.54(d,J=6.0Hz,1H),4.45(t,J=6.0Hz,1H),4.29(s,1H),4.02-4.04(m,2H),3.95(s,2H),3.70-3.71(m,2H),3.52-3.60(m,14H),2.46(s,3H),2.04-2.07(m,1H),1.75-1.78(m,1H),1.37(d,J=6.0Hz,3H),0.93(s,9H).13C NMR(150MHz,d6-DMSO):δ=170.9,169.4,168.9,168.1,158.2,151.9,148.2,145.1,135.4,131.8,131.5,130.8,130.4,130.1,129.3,129.2,128.8,126.7,120.5,118.1,114.9,109.6,101.5,70.8,70.3,70.2,70.0,69.3,69.2,67.5,65.4,59.0,56.9,56.1,49.0,48.2,38.2,36.2,26.6,22.9,16.5,15.6.HRMS(EI)calcd.For[C49H63N6O11S](M+H)+:943.4270,found:943.4275.
下面以化合物9a-9h为例验证本发明提供的靶向组蛋白去乙酰化酶8蛋白水解嵌合体的HDAC8蛋白降解实验
实验1、化合物9a-9h的HDAC8蛋白降解效率实验
将A549细胞种植在96孔板中,每孔含5×104个/100μL,12h后,加入相应剂量的降解剂或DMSO(对照孔)。在培养箱中孵育20h后,每孔加入75μL含8%的甲醛TBS溶液,常温下固定20min。除去溶液,再用200μL/孔的TBST洗涤两次,加入50μL/孔含0.1%的TtitonPBS溶液,放置15min。除去96孔板中溶液,用TBST 150μL/孔,洗涤两次。然后加入100μL/孔含1%的H2O2TBS溶液,常温下孵育20min。除去溶液,再用适量的TBST洗涤3次。每孔加入50μL封闭液,4℃下孵育过夜。除去封闭液,每孔加入100μL含1:2000稀释的HDAC8抗体封闭液,对照组加入含DMSO的封闭液,常温下孵育2h。再回收HDAC8一抗,用适量的TBST洗涤两次,每孔加入150μL的含HRP标记的兔抗,常温下孵育1h。除去二抗,用TBST洗涤3次。每孔加入100μL预先配置好的TMB底物溶液,避光常温下孵育20min。每孔加入10μL含1N HCl终止液,摇晃5min。在光密度计上测试记录450和570nm的吸光度值并计算HDAC8蛋白相对含量。
测试结果如表1所示。
表1:A549细胞HDAC8降解效率
实验2、用Western blot analysis分析化合物9a-9h的HDAC8蛋白降解实验
A549细胞分别用上述合成化合物9a-9h(2μM)处理后,在冰浴下加入RIPA裂解30分钟后,加入蛋白酶降解剂,用BCA试剂盒定量测试蛋白浓度。取等量的蛋白用10-12%的聚丙烯酰胺跑电泳,蛋白条带用PVDF膜转膜后,用5%的脱脂牛奶封闭1h。目的条带在4℃下用一抗封闭12h,洗涤后再用二抗在常温下孵育1h,加入免疫荧光底物后迅速化学荧光成像。测试结果如图1所示。
根据图1的测试结果显示,部分化合物如9b、9d、9e、9f能够显著降解肿瘤细胞中的去乙酰化酶8;其他化合物如9a、9c、9g、9h对肿瘤细胞中的去乙酰化酶8具有一定的降解作用。
综上所述,本发明提供的靶向组蛋白去乙酰化酶8蛋白水解嵌合体能够显著降解肿瘤细胞中的去乙酰化酶8,提示其在制备预防或治疗与HDAC8活性或表达异常相关疾病药物,尤其是抗肿瘤活性药物方面的价值。
在上述实施例中,对各个实施例的描述都各有侧重,某个实施例中没有详细描述的部分,可以参见其他实施例的相关描述。
以上所述,为本发明的具体实施方式,但本发明的保护范围并不局限于此,任何熟悉本技术领域的技术人员在本发明揭露的技术范围内,可轻易想到各种等效的修改或替换,这些修改或替换都应涵盖在本发明的保护范围之内。因此,本发明的保护范围应以权利要求的保护范围为准。
Claims (10)
1.靶向组蛋白去乙酰化酶8蛋白水解嵌合体,其特征在于,所述嵌合体具有如式9X-1、9X-2所示的至少一化合物或其药学上可接受的盐:
式9X-1、9X-2中的手性位点可任意为R或S,m为1~4的整数,n为1~4的整数。
2.一种如权利要求1所述的靶向组蛋白去乙酰化酶8蛋白水解嵌合体的制备方法,其特征在于,包括以下步骤:
S1、将化合物1和化合物2分别溶于N,N-二甲基乙酰基胺中得到第一溶液和第二溶液,往第一溶液中加入NaH进行反应得到反应液,然后将第二溶液滴加至反应液中继续进行反应,得到化合物3;
S2、将化合物3溶于甲醇溶液中,加入Pd/C反应得到化合物4;
S3、将化合物4、化合物5A或化合物5B、及碳酸钾溶于无水DMF中,搅拌加热至90℃,反应8h,反应完毕,得到化合物6a-6h;
S4、将化合物6a-6h溶于无水二氯甲烷中,与三氟乙酸在常温下反应,得到反应液;向反应液中加入石油醚,搅拌均匀后,在真空下抽除溶剂,得到浓缩的残留物;将化合物7、EDCI、HOBt溶于DMF中,加入到上述浓缩的残留物中,冷却至5℃,再加入DIPEA,温度恢复至室温,继续反应18h,得到化合物8X-1或8X-2;
S5、取NH2OH溶液冷却至5℃,加入碱试剂,搅拌溶解得到羟胺溶液;将化合物8X-1或8X-2溶于MeOH/THF溶液中,再加入羟胺溶液中,反应完毕后加入酸试剂中和,得到化合物9X-1或9X-2;
其中,步骤S1-S2的合成路线如下:
步骤S3的合成路线如下:
步骤S4的合成路线如下:
其中,化合物7的手性位点可任意为R或S;m为1~4的整数,n为1~4的整数。
3.如权利要求2所述的制备方法,其特征在于,所述化合物7选自下述5种结构中的任一种:
4.如权利要求3所述的制备方法,其特征在于,步骤S1-S5中,还包括对各步骤得到的产物进行浓缩分离纯化的步骤。
5.如权利要求2所述的制备方法,其特征在于,步骤S4中,所述浓缩的残留物无需纯化。
6.如权利要求2所述的制备方法,其特征在于,步骤S5中,所述碱试剂为氢氧化钠;所述酸试剂为醋酸。
7.如权利要求2所述的制备方法,其特征在于,步骤S5中,所述MeOH/THF溶液中MeOH和THF的体积比为1:1。
8.一种药物组合物,其特征在于,所述药物组合物包括权利要求1所述的靶向组蛋白去乙酰化酶8蛋白水解嵌合体,或者包括由权利要求2-7任一项所述的制备方法制得的靶向组蛋白去乙酰化酶8蛋白水解嵌合体。
9.根据权利要求8所述的药物组合物,其特征在于,所述药物组合物还包括药学上可接受的载体和/或辅剂。
10.如权利要求1所述的靶向组蛋白去乙酰化酶8蛋白水解嵌合体、权利要求8或9所述的药物组合物在制备用于预防或治疗与HDAC8活性或表达异常相关疾病的药物中的应用。
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