CN117843638A - 基于rsl3诱导gpx4蛋白降解的双功能分子化合物的制备与应用 - Google Patents
基于rsl3诱导gpx4蛋白降解的双功能分子化合物的制备与应用 Download PDFInfo
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- CN117843638A CN117843638A CN202311852379.4A CN202311852379A CN117843638A CN 117843638 A CN117843638 A CN 117843638A CN 202311852379 A CN202311852379 A CN 202311852379A CN 117843638 A CN117843638 A CN 117843638A
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Abstract
本发明属于化学生物学技术领域,具体涉及基于RSL3诱导GPX4蛋白降解的双功能分子化合物的制备与应用。本发明提供了一种可以降解HT1080细胞中的GPX4,促进脂质ROS堆积并诱发细胞铁死亡的双功能分子化合物。与现有技术相比,本发明提供的双功能分子化合物具有药物起效量低,不需要与目标蛋白长时间和高强度的结合的优点。本发明还提供了该双功能分子化合物的制备方法,该制备方法具有简单易行,成本低,适合大工业生产的优点。
Description
技术领域
本发明属于化学生物学技术领域,具体涉及基于RSL3诱导GPX4蛋白降解的双功能分子化合物的制备与应用。
背景技术
谷胱甘肽过氧化物酶4(Glutathione Peroxidase 4,GPX4)是GPX家族的一员,是铁死亡通路中关键的负调控因子之一,GPX4可以将有毒性的脂质过氧化物还原为无毒的物质,维持细胞内氧化还原平衡。大多数肿瘤细胞中含有较高水平的游离Fe2+,线粒体活性异常提高,这些表现均表明肿瘤细胞具有高度铁死亡敏感性。目前,治疗肿瘤的主要疗法为免疫疗法、化学疗法和放射疗法,其原理均为细胞凋亡。因此当癌症细胞逃避凋亡,导致耐药性和疾病复发时,会出现重大挑战。铁死亡对肿瘤的发生发展有抑制作用,且诱导铁死亡可以克服肿瘤对药物的耐药性并激活肿瘤的免疫反应,因此通过调节铁死亡来治疗肿瘤是一种全新的治疗手段。
RSL3为GPX4的小分子抑制剂,通过与GPX4的含硒半胱氨酸的活性位点结合并抑制GPX4的酶活性,促进脂质ROS堆积并诱发细胞铁死亡。然而RSL3存在毒副作用以及耐药性等问题。PROTAC技术在被提出以来已被广泛用于靶向多种癌症靶点,利用PROTAC降解肿瘤相关蛋白已成为一种非常具有潜力的癌症治疗策略。PROTAC分子能够解决小分子抑制剂的耐药问题,且因为PROTAC主要起催化作用,给药浓度和给药频率均较低,可以减小毒副作用与脱靶的可能性。RSL3-PROTACs从降解层面为抑制GPX4提供一种新型且有效的方法,为肿瘤等疾病提供新的治疗策略。
发明内容
本发明目的是针对现有技术不足,提供一种基于RSL3诱导GPX4蛋白降解的双功能分子化合物及其制备与应用,通过降解细胞中的GPX4,促进脂质ROS堆积并诱发细胞铁死亡。研究发现,以化合物RSL3进行衍生化得到的RSL3-1和RSL3-3选择cIAP为E3连接酶配体,均对GPX4有一定的降解作用;且这一现象可被蛋白酶体抑制剂MG132和ML4924逆转,说明该类化合物是通过泛素蛋白酶体途径来发挥作用的。此外,研究结果显示GPX4降解会促进脂质ROS堆积并诱发细胞铁死亡。因此,设计基于RSL3的GPX4蛋白降解剂,将为癌症治疗提供一种安全性高、抗耐药性强、应用前景广阔的有效策略。
本发明的具体方案如下:
本发明提供了如下式I和式II所示的两种基于RSL3诱导GPX4蛋白降解的双功能分子化合物,或其药学上可接受的盐、水合物或前药;
其中,B为泛素连接酶E3配体,更优选为CRBN、VHL、MDM2、cIAP、UBR7、RNF114、CBLB、KEAP1中的一种。
所述的CRBN为以下结构式中的一种:
其中:
W选自CH2、C=O、SO2、NH和N-烷基中的一种;所述烷基为C1-C4烷基;
X任选自O和S中的一种或两种;
Z选自氢、C1-C4烷基、C3-C6环烷基和卤素中的一种;
G、G′各自独立选自H、C1-C4烷基、-OH和C1-C4烷基取代的5-10元杂环基,所述杂环基含有1-3个N、O或S的杂原子;
R1选自H、D、卤素、硝基、氨基、氰基、羟基、C1-C4烷基、卤代C1-C4烷基和氘代C1-C4烷基中的一种;
所述的VHL的结构式为:
其中:R2选自CH3和H中的一种;
所述的MDM2的结构式为:
其中:
R3为哌嗪基、哌啶基、杂环基团或以下结构的链接基团之一:
上述链接基团中,n为0-3的整数;
其中,R3所述杂环基团为哌嗪酮基、吡咯基、吡唑基、呋喃基、噻吩基、噁唑基、异噁唑基、噻唑基、异噻唑基、吡啶基、嘧啶基、吡嗪基或哒嗪基中的一种;
所述的cIAP的结构为:
R4为H或Boc。
所述L为如下所示的任意结构之一:
其中:m选自1-10之间的整数。
本发明优选以下式III、式IV、式V、式VI、式VII、式VIII、式IX、式X、式XI、式XII和式XIII所示的基于RSL3诱导GPX4蛋白降解的双功能分子化合物或其药学上可接受的盐、水合物或前药:
上述式III、式IV、式V、式VI、式VII、式VIII、式IX、式X、式XI、式XII和式XIII所示的基于RSL3诱导GPX4蛋白降解的双功能分子化合物中,L优选为如下结构中的任意一种:
m选自1-7之间的整数。
一种基于RSL3诱导GPX4蛋白降解的双功能分子化合物,具体选自如下化合物:RSL3-1-1P-C、RSL3-1-3P-C、RSL3-1-5P-C、RSL3-1-3C-V1、RSL3-1-5C-V1、RSL3-1-7C-V1、RSL3-1-3C-V2、RSL3-1-5C-V2、RSL3-1-7C-V2、RSL3-1-1P-M、RSL3-1-3P-M、RSL3-1-5P-M、RSL3-1-3C-B4、RSL3-1-5C-B4、RSL3-1-7C-B4、RSL3-1-1P-B5、RSL3-1-3P-B5、RSL3-1-5P-B5、RSL3-3-1P-C、RSL3-3-3P-C、RSL3-3-5P-C、RSL3-3-3C-V1、RSL3-3-5C-V1、RSL3-3-7C-V1、RSL3-3-3C-V2、RSL3-3-5C-V2、RSL3-3-7C-V2、RSL3-3-1P-M、RSL3-3-3P-M、RSL3-3-5P-M、RSL3-3-3C-B4、RSL3-3-5C-B4、RSL3-3-7C-B4、RSL3-3-1P-B5、RSL3-3-3P-B5和RSL3-3-5P-B5。
本发明提供基于RSL3诱导GPX4蛋白降解的双功能分子化合物的药学上可接受的盐,包括与下列酸形成的加成盐:盐酸、氢溴酸、硫酸、磷酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘二磺酸、乙酸、丙酸、乳酸、三氟乙酸、马来酸、柠檬酸、富马酸、草酸、酒石酸、苯甲酸等。盐酸、氢溴酸、硫酸、柠檬酸、酒石酸、磷酸、乳酸、丙酮酸、乙酸、三氟乙酸、马来酸、苯磺酸、琥珀酸以及类似的已知可以接受的酸成盐。
此外,本发明还包括本发明衍生物的前药。它们自身可能具有较弱的活性甚至没有活性,但是在给药后,在生理条件下(如通过代谢、溶剂分解或另外的方式)被转化成相应的生物活性形式。
本发明还提供了所述的基于RSL3诱导GPX4蛋白降解的双功能分子化合物的制备方法,选自方法A、方法B和方法C,具体包括以下步骤:
方法A:式I所示的GPX4蛋白降解剂的合成路线如下:
在本合成路线中,L为m选自1-7之间的整数;
步骤1-1:化合物3的合成
将对醛基苯甲酸(1.0equiv)溶于二氯甲烷,冷却至0℃,依次加入EDCI(2.0equiv)、HOBt(2.0equiv)、炔丙胺(1.2equiv)和DIPEA(4.0equiv),反应物转移至室温反应,反应完全后用H2O和二氯甲烷萃取。有机层经无水硫酸钠干燥,减压浓缩。残留物经硅胶柱色谱纯化,用石油醚/乙酸乙酯2:1-1:1梯度洗脱,得到化合物3;
步骤1-2:化合物5的合成
将D-色氨酸甲酯盐酸盐(1.0equiv)加入二氯甲烷中,然后加入TEA(1.2equiv),搅拌至完全溶解,并在室温下进行反应,反应结束后对反应体系进行减压浓缩,得到化合物5;
步骤1-3:化合物6的合成
将化合物5(1.0equiv)溶于二氯甲烷中,然后依次加入化合物3(1.1equiv)、TFA(1.5equiv),并在45℃下进行反应,反应结束后,减压浓缩反应溶液,加入DMF使其完全溶解,并用H2O和乙酸乙酯萃取;将有机层用无水硫酸钠干燥并减压浓缩。残留物通过硅胶柱色谱法,用二氯甲烷/甲醇纯化,得到化合物6;
步骤1-4:化合物8的合成
将化合物6(1.0equiv)溶于无水二氯甲烷中,并冷却至0℃。然后加入碳酸氢钠(1.2equiv),分批滴加氯乙酰氯(1.5equiv),将反应升温至室温反应,反应结束后加水淬灭,并用H2O和DCM萃取;有机层用无水硫酸钠干燥并减压浓缩。残留物通过硅胶柱色谱石油醚/乙酸乙酯梯度洗脱,得到化合物8;
步骤1-5:式I化合物的合成
将化合物8(1.2equiv)和B-Linker(1equiv)溶于THF中,加入H2O,随后加入CuSO4(1.2equiv)和抗坏血酸钠(3.0equiv),室温下搅拌直到反应完全。减压浓缩除去THF后用H2O和DCM萃取。有机层用无水硫酸钠干燥并减压浓缩。残留物通过硅胶柱色谱法纯化,使用二氯甲烷和甲醇作为洗脱剂,得到式I化合物;
方法B:式II所示的GPX4蛋白降解剂的合成路线如下:
在本合成路线中,L为m选自1-7之间的整数;
步骤2-1:化合物10的合成
将Boc-D-色氨酸(1.0equiv)溶于无水二氯甲烷中,冷却至0℃,然后在搅拌下依次加入EDCI(2.0equiv)、HOBt(2.0equiv)、炔丙基胺(1.2equiv)、DIPEA(4.0equiv),并移至室温反应3-4小时,然后用H2O和DCM萃取。有机层用无水硫酸钠干燥,然后减压浓缩。残留物通过硅胶柱色谱法用石油醚/乙酸乙酯=2∶1纯化,得到化合物10;
步骤2-2:化合物11的合成
将化合物10(1.0equiv)溶于乙酸乙酯中,加入氯化氢-乙酸乙酯溶液。减压浓缩反应体系,得到化合物11;
步骤2-3:化合物12的合成
将化合物11(1.0equiv)加入二氯甲烷中,然后加入TEA(1.2equiv),搅拌至完全溶解,并在室温下反应1小时。减压浓缩反应体系,得到化合物12;
步骤2-4:化合物14的合成
将化合物12(1.0equiv)溶于二氯甲烷中,然后在搅拌下依次加入化合物13(1.1equiv)、TFA(1.5equiv),并在45℃下进行反应完全后减压浓缩反应溶液,加入DMF使其完全溶解,并用H2O和乙酸乙酯萃取。有机层用无水硫酸钠干燥并减压浓缩。残留物通过硅胶柱色谱法用石油醚/乙酸乙酯纯化,得到化合物14;
步骤2-5:化合物15的合成
将化合物14(1.0equiv)溶于无水二氯甲烷中,并冷却至0℃。然后分批加入碳酸氢钠(1.2equiv)和氯乙酰氯(1.5equiv)。将反应在室温下反应;反应完全后加水淬灭反应,并用H2O和DCM萃取。有机层用无水硫酸钠干燥并减压浓缩。残留物通过硅胶柱色谱法纯化,用石油醚/乙酸乙酯洗脱,得到化合物15;
步骤2-6:式II化合物的合成
将化合物15(1.2equiv)和B-Linker(1equiv)溶于THF中,加入H2O,随后加入CuSO4(1.2equiv)、抗坏血酸钠(3.0equiv),室温下搅拌至反应完全后;先减压浓缩除去THF,然后用H2O和DCM萃取。有机层用无水硫酸钠干燥并减压浓缩。残留物通过硅胶柱色谱法纯化,使用二氯甲烷和甲醇作为洗脱剂,得到式II化合物;
方法C:泛素连接酶E3配体与L(linker)的合成路线如下:
(1)当泛素连接酶E3配体为CRBN时,优选为Tha(沙利度胺衍生物),其合成方法为:
将化合物Tha(沙利度胺衍生物)溶于DMF中,向反应体系中加入DIPEA,1.2equiv的Linker,90℃反应2小时,然后用水和乙酸乙酯萃取,有机层用无水硫酸钠干燥,减压浓缩,残留物通过硅胶柱色谱法纯化,得到化合物Tha-L;
(2)当泛素连接酶E3配体为MDM2时,其合成方法为:
取MDM2溶于DCM中,之后在冰浴下加入2equiv EDCI、2equiv HOBt、4equiv DIPEA,之后加入1.2equiv Linker,反应完全后加入DCM稀释反应体系,用水和DCM萃取,有机层用无水硫酸钠干燥,减压浓缩,经硅胶柱层析纯化,得到化合物MDM2-L;
(3)当泛素连接酶E3配体为VHL时,其合成方法为:
其合成方法同MDM2-L,区别在于将MDM2替换为VHL,相应制得VHL-L;
(4)当泛素连接酶E3配体为cIAP时,其合成方法为:
其合成方法同MDM2-L,区别在于将VHL替换为cIAP,相应制得cIAP-L。
本发明提供一种药物组合物,包括基于RSL3诱导GPX4蛋白降解的双功能分子化合物或其药学上可接受的盐、水合物或前药与药学上接受的载体、稀释剂、辅剂、媒介物或它们的组合。
其中,所述的药物组合物的剂型为注射剂、片剂或胶囊剂中的任意一种。
本发明还提供了上述的基于RSL3诱导GPX4蛋白降解的双功能分子化合物或其药学上可接受的盐、水合物或前药,或上述的药物组合物在制备治疗癌症药物中的应用。
所述的癌症为骨癌、肺癌、胃癌、结肠癌、膜腺癌、乳腺癌、前列腺癌、肺癌、脑癌、卵巢癌、膀肮癌、子宫颈癌、睾丸癌、肾癌、头颈癌、淋巴癌、白血病和皮肤癌中的一种或多种。
本发明的有益效果:
本发明以PROTAC技术为支撑,以GPX4抑制剂RSL3为原料,合成Linker长度不同的基于RSL3诱导GPX4蛋白降解的双功能分子化合物。
本发明提供的基于RSL3诱导GPX4蛋白降解的双功能分子化合物有效地靶向并降解GPX4;类似于催化反应,药物起效剂量低;只提供结合活性,是事件驱动,区别于传统的占有驱动,不需直接抑制目标蛋白的功能活性;药物不需要与目标蛋白长时间和高强度的结合。本发明提供的基于RSL3诱导GPX4蛋白降解的双功能分子化合物为诱导铁死亡治疗肿瘤提供了新的治疗方式。
本发明提供的基于RSL3诱导GPX4蛋白降解的双功能分子化合物的制备方法,具有简单易行,成本低,适合大工业生产的优点。
附图说明
图1为本发明的RSL3-1-B-L和RSL3-3-B-L对GPX4的降解作用;
图2为本发明的RSL3-1-7C-B4对HT1080细胞的细胞毒活性;
图3为本发明中B4和RSL3对RSL3-1-7C-B4降解GPX4的竞争性实验和MG132、ML4924的逆转实验;
具体实施方式
通过实施例对本发明做进一步的说明。但不应理解为本发明的范围仅限于以下实施例。
实施例1化合物3的合成
具体操作过程参见步骤1-1,白色固体,收率:75%。1H NMR(600MHz,Chloroform-d)δ10.09(s,1H),7.99–7.93(m,4H),6.40(s,1H),4.29(dd,J=5.2,2.6Hz,2H),2.32(t,J=2.6Hz,1H).
实施例2化合物5的合成
具体操作过程参见步骤1-2,白色固体,收率:99%。
实施例3化合物6的合成
具体操作过程参见步骤1-3,淡黄色固体,收率:64%。1H NMR(600MHz,DMSO-d6)δ10.34(s,1H),8.93(t,J=5.6Hz,1H),7.89–7.85(m,2H),7.48–7.43(m,3H),7.19(dt,J=8.0,1.0Hz,1H),7.01(ddd,J=8.1,7.0,1.3Hz,1H),6.96(ddd,J=8.0,7.0,1.1Hz,1H),5.28(d,J=5.4Hz,1H),4.06(dd,J=5.6,2.5Hz,2H),3.89(dt,J=11.2,3.5Hz,1H),3.71(s,3H),3.12(t,J=2.5Hz,1H),3.05(ddd,J=14.8,4.1,1.7Hz,1H),2.91–2.82(m,2H).
实施例4化合物8的合成
具体操作过程参见步骤1-4,淡黄色固体,收率:81%。1HNMR(600MHz,Chloroform-d)δ8.29(s,1H),7.61(d,J=7.7Hz,3H),7.31(dd,J=16.0,7.7Hz,3H),7.24–7.20(m,1H),7.20–7.16(m,1H),6.92(s,1H),6.45(s,1H),4.95(s,1H),4.35(d,J=12.6Hz,1H),4.25–4.18(m,3H),3.70(d,J=15.7Hz,1H),3.23(dd,J=15.7,6.8Hz,1H),3.03(s,3H),2.28(t,J=2.3Hz,1H).
实施例5化合物10的合成
具体操作过程参见步骤2-1,白色固体,收率:82%。1HNMR(600MHz,Chloroform-d)δ8.13(s,1H),7.65(d,J=7.9Hz,1H),7.37(dt,J=8.2,0.9Hz,1H),7.21(ddd,J=8.2,7.0,1.2Hz,1H),7.14(ddd,J=8.0,7.0,1.0Hz,1H),7.08–7.05(m,1H),6.00(s,1H),5.12(s,1H),4.44(s,1H),3.93(s,2H),3.09–3.41(m,2H),2.14(t,J=2.6Hz,1H),1.42(s,9H).
实施例6化合物11的合成
具体操作过程参见步骤2-2,白色固体,收率:99%。
实施例7化合物12的合成
具体操作过程参见步骤2-3,白色固体,收率:99%。
实施例8化合物14的合成
具体操作过程参见步骤2-4,淡黄色固体,收率:80%。
实施例9化合物15的合成
具体操作过程参见步骤2-5,淡黄色固体,收率:48%。1HNMR(600MHz,Chloroform-d)δ8.05(s,1H),7.93(s,2H),7.61(d,J=7.8Hz,1H),7.39(d,J=8.1Hz,2H),7.30(d,J=7.9Hz,1H),7.24–7.20(m,1H),7.17(t,J=7.5Hz,1H),7.02(s,1H),5.53(s,1H),4.90(s,1H),4.38–4.23(m,2H),3.90(s,3H),3.81–3.55(m,2H),3.15(s,1H),3.07(s,1H).
实施例10化合物RSL3-1-nP-C的合成(n=1,3,5,以n=1为例)
具体操作过程参见步骤1-5,淡黄色固体,收率:86%。1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),10.92(s,1H),8.89(s,1H),7.88(s,2H),7.73(d,J=7.9Hz,1H),7.56–7.51(m,1H),7.47(d,J=7.8Hz,3H),7.21(d,J=7.5Hz,1H),7.02(td,J=23.4,22.3,8.1Hz,5H),6.58(t,J=5.9Hz,1H),6.01(s,1H),5.39(s,1H),5.06(dd,J=12.9,5.4Hz,1H),4.73(d,J=13.8Hz,1H),4.46(s,4H),3.81(t,J=5.2Hz,2H),3.57(s,2H),3.53(d,J=13.0Hz,4H),3.41(d,J=5.7Hz,2H),2.92–2.81(m,1H),2.65–2.53(m,2H),2.01(t,J=7.9Hz,2H).
实施例11化合物RSL3-1-nC-V1的合成(n=3,5,7,以n=3为例)
具体操作过程参见步骤1-5,淡黄色固体,收率:96%。1H NMR(400MHz,DMSO-d6)δ10.89(s,1H),8.98(d,J=6.2Hz,2H),8.57(t,J=6.1Hz,1H),8.00–7.91(m,2H),7.79(d,J=8.0Hz,2H),7.69(ddd,J=13.5,6.1,3.3Hz,1H),7.57(d,J=7.7Hz,1H),7.39(t,J=7.6Hz,4H),7.29(d,J=7.9Hz,1H),7.17–7.09(m,3H),7.05(t,J=7.4Hz,1H),6.88(s,1H),5.23(d,J=6.7Hz,1H),5.16(d,J=3.5Hz,1H),4.85(d,J=13.8Hz,1H),4.53(d,J=9.2Hz,1H),4.50–4.38(m,5H),4.35(s,1H),4.31(t,J=7.1Hz,2H),4.25–4.22(m,1H),4.22–4.12(m,1H),3.66(s,2H),2.88(s,3H),2.44(s,3H),2.00(dd,J=6.8,3.3Hz,2H),1.27(d,J=6.3Hz,2H),1.24(s,2H),0.93(s,9H).13C NMR(101MHz,DMSO-d6)δ172.43,171.63,170.66,170.08,167.38,166.26,151.97,143.00,139.93,136.89,134.03,130.09,129.86,129.11,129.00,127.88,127.40,123.40,122.15,119.25,118.64,111.76,106.90,69.34,59.16,56.97,56.83,52.96,52.10,51.71,49.36,43.58,42.12,38.53,38.37,35.64,35.32,32.10,26.81,26.68,16.38,14.35.HRMS(ESI+):m/z calculated for C51H57ClN10NaO8S[M+Na]+,1027.3668;found,1027.3685.
实施例12化合物RSL3-1-nC-V2的合成(n=3,5,7,以n=3为例)
具体操作过程参见步骤1-5,淡黄色固体,收率:63.7%。1HNMR(600MHz,DMSO-d6)δ10.90(d,J=4.5Hz,1H),8.98(d,J=4.6Hz,1H),8.39(dd,J=7.9,4.3Hz,1H),7.96–7.90(m,2H),7.79(dd,J=8.3,4.3Hz,2H),7.74–7.63(m,1H),7.56(d,J=7.6Hz,1H),7.45–7.41(m,2H),7.37(ddd,J=8.6,4.5,2.3Hz,2H),7.29(dd,J=8.4,3.8Hz,1H),7.15–7.11(m,2H),7.07–7.02(m,1H),6.88(d,J=4.3Hz,1H),5.23(d,J=6.3Hz,1H),5.13(d,J=3.6Hz,1H),4.90(t,J=7.2Hz,1H),4.85(dd,J=13.9,4.4Hz,1H),4.49(dt,J=8.4,4.9Hz,3H),4.41(td,J=8.1,4.4Hz,1H),4.30(dd,J=7.3,4.5Hz,2H),4.27(s,1H),4.15(q,J=5.7Hz,1H),3.61–3.58(m,2H),3.16(d,J=4.8Hz,2H),3.12(d,J=14.7Hz,1H),2.88(d,J=4.2Hz,2H),2.45(d,J=4.4Hz,2H),2.23(dd,J=13.6,6.2Hz,1H),2.15(d,J=16.3Hz,1H),2.02–1.96(m,3H),1.78(td,J=8.6,4.5Hz,1H),1.63(d,J=8.2Hz,1H),1.46(d,J=6.8Hz,1H),1.36(d,J=6.6Hz,3H),0.92(d,J=4.3Hz,9H).13C NMR(151MHz,DMSO-d6)δ171.56,171.08,170.68,169.98,167.37,151.97,148.18,145.34,145.11,136.89,130.13,129.86,129.28,129.12,126.84,123.38,122.14,119.23,118.62,69.23,59.02,57.03,56.72,52.10,49.35,48.17,40.57,38.16,35.61,32.12,31.61,29.45,26.88,26.67,22.86,16.41,14.35.HRMS(ESI+):m/z calculated for C52H59ClN10NaO8S[M+Na]+,1041.3824;found,1041.3883.
实施例13化合物RSL3-1-nP-M的合成(n=1,3,5,以n=1为例)
具体操作过程参见步骤1-5,淡黄色固体,收率:92%。1H NMR(600MHz,DMSO-d6)δ10.89(s,1H),9.00(t,J=5.7Hz,1H),7.92(d,J=6.7Hz,2H),7.78(d,J=8.2Hz,2H),7.57(d,J=7.8Hz,2H),7.29(d,J=8.1Hz,1H),7.15(dd,J=8.2,6.0Hz,4H),7.13–7.09(m,3H),7.04(d,J=7.6Hz,3H),6.97(d,J=8.0Hz,2H),6.88(s,1H),6.61(d,J=9.1Hz,2H),5.66(d,J=9.4Hz,1H),5.60(s,1H),5.24(d,J=6.8Hz,1H),4.86(d,J=13.9Hz,1H),4.72(p,J=6.0Hz,1H),4.47(q,J=5.9,5.4Hz,5H),3.83(s,3H),3.75(t,J=5.3Hz,2H),3.74–3.66(m,2H),3.59(d,J=16.8Hz,1H),3.48(d,J=15.8Hz,1H),3.43–3.37(m,4H),3.23–3.18(m,1H),3.16–3.08(m,3H),2.98(s,2H),2.87(s,3H),1.26(d,J=5.9Hz,3H),1.21(d,J=5.9Hz,3H).13C NMR(151MHz,DMSO-d6)δ170.67,167.83,167.37,166.24,164.86,162.90,156.98,143.02,136.89,134.05,132.40,131.76,131.62,130.13,129.88,129.21,129.13,127.94,127.91,127.38,126.35,122.13,119.23,118.64,111.75,106.90,105.51,99.80,70.36,69.06,68.92,55.91,52.96,52.07,51.71,49.66,49.01,46.94,43.61,42.48,38.77,35.31,22.18,22.11,21.56.HRMS(ESI+):m/z calculated for C61H62Cl3N11NaO10[M+Na]+,1238.3629;found,1238.3636.
实施例14化合物RSL3-1-nC-B4的合成(n=3,5,7,以n=3为例)
具体操作过程参见步骤1-5,淡黄色固体,收率:50.3%。1HNMR(600MHz,DMSO-d6)δ10.89(s,1H),8.97(t,J=5.8Hz,1H),7.88(s,1H),7.84(d,J=8.5Hz,1H),7.79(d,J=8.1Hz,2H),7.61(d,J=9.0Hz,1H),7.57(d,J=7.8Hz,1H),7.29(d,J=8.0Hz,1H),7.25(t,J=7.5Hz,2H),7.22–7.20(m,2H),7.17–7.12(m,3H),7.11(d,J=8.3Hz,1H),7.04(t,J=7.5Hz,1H),6.88(s,1H),6.18(d,J=6.1Hz,1H),5.23(d,J=6.8Hz,1H),4.85(d,J=13.9Hz,1H),4.48(d,J=5.6Hz,2H),4.46(d,J=8.5Hz,1H),4.33(ddd,J=10.3,8.4,4.6Hz,1H),4.21(d,J=7.1Hz,1H),4.17(td,J=6.9,3.9Hz,2H),3.87(dd,J=6.1,2.7Hz,1H),3.60(s,3H),3.48(d,J=15.8Hz,1H),3.14–3.09(m,1H),2.87(s,3H),2.81(dd,J=13.4,6.9Hz,1H),2.65(dd,J=13.4,8.1Hz,1H),2.07–2.02(m,1H),1.98(dt,J=14.6,7.1Hz,1H),1.87(dq,J=18.7,7.1Hz,2H),1.61(ddd,J=13.1,10.3,4.7Hz,1H),1.52(dq,J=12.3,6.2Hz,1H),1.44(ddd,J=13.5,9.2,4.7Hz,1H),0.81(d,J=6.5Hz,3H),0.75(d,J=6.4Hz,3H).13C NMR(151MHz,DMSO-d6)δ173.18,172.41,171.10,170.67,167.36,166.20,145.33,143.01,139.23,136.89,134.06,129.87,129.66,129.11,128.61,127.40,126.54,126.35,123.36,122.13,119.22,118.64,111.75,106.90,71.67,53.61,52.95,52.37,52.07,51.69,50.04,49.22,49.06,43.61,37.34,35.31,32.42,26.54,24.48,23.24,21.57.HRMS(ESI+):m/z calculated for C46H53ClN8NaO9[M+Na]+,919.3522;found,919.3547.
实施例15化合物RSL3-1-nP-B5的合成(n=1,3,5,以n=1为例)
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具体操作过程参见步骤1-5,淡黄色固体,收率:73%。1H NMR(600MHz,DMSO-d6)δ10.93(s,1H),9.05(t,J=5.8Hz,1H),8.19(t,J=5.7Hz,1H),8.03(d,J=8.0Hz,4H),7.93(s,1H),7.80(d,J=8.1Hz,2H),7.57(d,J=7.8Hz,1H),7.33(t,J=7.4Hz,2H),7.31–7.29(m,3H),7.28–7.24(m,1H),7.13(dd,J=20.1,7.9Hz,3H),7.05(t,J=7.5Hz,1H),6.88(s,1H),5.24(d,J=6.8Hz,1H),4.87(d,J=13.9Hz,1H),4.48(d,J=4.2Hz,2H),4.46–4.44(m,2H),4.26(td,J=8.5,5.9Hz,1H),4.00(d,J=3.3Hz,1H),3.96–3.94(m,1H),3.93–3.90(m,1H),3.57–3.53(m,1H),3.48(d,J=15.8Hz,1H),3.37(t,J=6.0Hz,2H),3.19–3.15(m,1H),3.14–3.10(m,2H),2.93(dd,J=13.7,8.0Hz,1H),2.87(s,3H),1.61–1.55(m,1H),1.54–1.49(m,1H),1.48–1.43(m,1H),1.25–1.22(m,2H),0.87(d,J=6.5Hz,3H),0.85(d,J=6.5Hz,3H).13C NMR(151MHz,DMSO-d6)δ172.24,171.05,170.68,167.38,166.22,145.34,143.03,139.72,136.90,136.78,134.04,130.12,129.90,129.11,129.08,127.39,126.48,123.79,122.12,119.22,118.64,111.76,106.89,69.01,68.73,60.22,54.71,52.07,51.75,49.66,43.63,41.43,38.84,35.30,35.13,24.68,23.29,22.43,21.57,21.23.HRMS(ESI+):m/z calculated for C45H55ClN9O8[M+H]+,884.3862;found,884.3787.
实施例16化合物RSL3-3-nP-C的合成(n=1,3,5,以n=1为例)
具体操作过程参见步骤2-6,淡黄色固体,收率:71%。1H NMR(600MHz,DMSO-d6)δ11.09(s,1H),10.89(s,1H),8.11(s,1H),7.85(d,J=7.9Hz,2H),7.66(s,1H),7.55(t,J=7.8Hz,1H),7.50(d,J=7.9Hz,1H),7.38–7.26(m,3H),7.11–7.06(m,2H),7.02(dd,J=9.9,7.0Hz,2H),6.94(s,1H),6.57(t,J=6.0Hz,1H),5.05(dd,J=12.9,5.4Hz,1H),4.96(d,J=6.2Hz,1H),4.79(s,1H),4.53(d,J=13.4Hz,1H),4.44(s,2H),3.84(s,3H),3.79(t,J=5.4Hz,3H),3.57(t,J=5.5Hz,2H),3.41(q,J=5.7Hz,3H),3.13–2.95(m,2H),2.90–2.82(m,1H),2.62–2.51(m,2H),2.04–1.98(m,1H).
实施例17化合物RSL3-3-nC-V1的合成(n=3,5,7,以n=3为例)
具体操作过程参见步骤2-6,淡黄色固体,收率:82%。1H NMR(400MHz,DMSO-d6)δ10.90(s,1H),8.98(s,1H),8.56(t,J=6.1Hz,1H),8.11(s,1H),7.96(d,J=9.3Hz,1H),7.85(d,J=7.9Hz,2H),7.74–7.61(m,2H),7.52(d,J=7.8Hz,1H),7.42–7.36(m,4H),7.31(d,J=8.1Hz,2H),7.14–7.01(m,2H),6.95(s,1H),5.15(s,1H),4.99(d,J=6.5Hz,1H),4.80(s,1H),4.53(d,J=9.2Hz,1H),4.47–4.38(m,2H),4.35(s,1H),4.23(d,J=6.6Hz,2H),4.17(d,J=5.3Hz,1H),4.13(d,J=5.0Hz,1H),3.84(s,3H),3.66(s,2H),3.31(d,J=4.4Hz,3H),3.01(s,1H),2.44(s,3H),1.96(s,2H),1.27(d,J=6.4Hz,2H),1.24(s,2H),0.93(s,9H).13C NMR(101MHz,DMSO-d6)δ172.43,171.57,170.08,167.96,166.53,151.96,148.15,139.95,136.79,130.07,129.12,129.09,127.86,123.25,121.93,119.11,118.59,111.71,69.34,65.50,59.16,56.95,56.84,52.62,49.28,49.06,42.06,38.54,38.39,35.64,34.71,32.02,30.46,30.25,26.81,26.59,25.21,23.71,22.85,22.48,19.11,16.37,14.35,14.01,11.26.
实施例18化合物RSL3-3-nC-V2的合成(n=3,5,7,以n=3为例)
具体操作过程参见步骤2-6,淡黄色固体,收率:89%。1H NMR(600MHz,DMSO-d6)δ10.90(s,1H),8.99(s,1H),8.39(d,J=7.8Hz,1H),8.11(s,1H),7.92(d,J=9.2Hz,1H),7.86(d,J=8.1Hz,2H),7.68–7.65(m,1H),7.53(d,J=7.8Hz,1H),7.45–7.41(m,2H),7.37(d,J=8.3Hz,2H),7.30(q,J=10.1,8.9Hz,3H),7.13–7.07(m,1H),7.03(t,J=7.5Hz,1H),6.96(s,1H),5.12(d,J=3.5Hz,1H),5.00(d,J=6.4Hz,1H),4.91(t,J=7.3Hz,1H),4.81(s,1H),4.50(d,J=9.2Hz,1H),4.41(t,J=8.1Hz,1H),4.30–4.24(m,3H),4.24–4.20(m,1H),3.85(s,3H),3.60(d,J=5.2Hz,2H),3.00(s,1H),2.45(s,3H),2.22(q,J=7.5Hz,1H),2.15(q,J=7.4Hz,1H),2.01(t,J=7.4Hz,2H),1.98–1.94(m,2H),1.80–1.76(m,1H),1.64(q,J=6.9Hz,1H),1.46(d,J=7.1Hz,1H),1.37(d,J=7.0Hz,3H),0.93(s,9H).13C NMR(151MHz,DMSO-d6)δ171.51,171.07,169.97,166.53,152.00,148.13,145.14,130.11,129.29,129.12,129.01,126.85,123.10,69.23,65.49,59.02,57.03,56.74,52.60,49.31,48.16,35.63,32.08,29.47,29.03,26.89,26.61,23.72,22.87,22.55,19.11,16.40,14.35,11.27.HRMS(ESI+):m/z calculated for C52H59ClN10NaO8S[M+Na]+,1041.3824;found,1041.4177.
实施例19化合物RSL3-3-nP-M的合成(n=1,3,5,以n=1为例)
具体操作过程参见步骤2-6,淡黄色固体,收率:70.3%。1HNMR(600MHz,DMSO-d6)δ10.90(s,1H),8.12(s,1H),7.90(t,J=5.7Hz,1H),7.86(d,J=7.9Hz,2H),7.65(d,J=5.1Hz,1H),7.52(d,J=7.9Hz,2H),7.30(d,J=9.1Hz,2H),7.15(d,J=8.1Hz,2H),7.13–7.07(m,3H),7.03(q,J=7.2Hz,3H),6.97(d,J=8.1Hz,3H),6.61(d,J=8.5Hz,2H),5.66(d,J=9.1Hz,1H),5.61(s,1H),4.98(d,J=6.3Hz,1H),4.80(s,1H),4.72(p,J=6.0Hz,1H),4.54(s,1H),4.40(s,2H),3.84–3.81(m,6H),3.74–3.66(m,4H),3.62–3.56(m,1H),3.45(s,2H),3.34(s,4H),3.23–3.08(m,4H),3.07–2.89(m,4H),1.27(d,J=6.0Hz,3H),1.21(d,J=6.0Hz,3H).13CNMR(151MHz,DMSO-d6)δ167.93,167.83,166.53,164.78,157.13,136.79,131.82,130.11,129.28,129.12,127.99,121.91,119.10,118.58,111.72,105.67,99.87,70.53,69.05,68.88,60.23,55.97,52.61,49.63,49.42,49.01,46.88,42.48,38.75,38.55,34.74,29.48,28.83,22.18,22.10,14.55,14.36.HRMS(ESI+):m/zcalculated for C61H62Cl3N11NaO10[M+Na]+,1238.3629;found,1238.3629.
实施例20化合物RSL3-3-nC-B4的合成(n=3,5,7,以n=3为例)
具体操作过程参见步骤2-6,淡黄色固体,收率:71%。1H NMR(600MHz,DMSO-d6)δ10.90(s,1H),8.10(s,1H),7.86(d,J=8.0Hz,2H),7.83(d,J=8.5Hz,1H),7.60(d,J=9.1Hz,2H),7.52(d,J=7.8Hz,1H),7.30(d,J=8.1Hz,2H),7.26(t,J=7.4Hz,3H),7.21(d,J=7.5Hz,2H),7.16(t,J=7.3Hz,1H),7.10(t,J=7.6Hz,1H),7.03(t,J=7.5Hz,1H),6.96(s,1H),6.18(d,J=6.1Hz,1H),4.98(d,J=6.3Hz,1H),4.81(s,1H),4.54(s,1H),4.35–4.29(m,1H),4.20(q,J=9.0,8.6Hz,1H),4.12(s,2H),3.88–3.85(m,1H),3.84(s,3H),3.76(s,1H),3.60(s,3H),3.49–3.43(m,1H),3.06–3.96(m,2H),2.80(dd,J=13.4,7.0Hz,1H),2.64(dd,J=13.4,8.0Hz,1H),2.07–1.99(m,1H),1.98–1.92(m,1H),1.88–1.79(m,2H),1.63–1.58(m,1H),1.50(d,J=6.8Hz,1H),1.47–1.41(m,1H),0.80(d,J=6.5Hz,3H),0.74(d,J=6.4Hz,3H).13C NMR(151MHz,DMSO-d6)δ173.18,172.41,171.06,169.64,167.91,166.52,145.66,139.23,136.78,134.66,131.57,129.66,129.08,128.61,126.55,123.21,121.91,119.11,118.59,116.79,115.74,111.76,71.62,62.22,54.48,53.62,52.61,52.37,50.04,49.18,49.06,44.32,37.35,34.69,32.33,29.61,29.31,26.46,24.47,23.21,21.56.HRMS(ESI+):m/z calculated for C46H53ClN8NaO9[M+Na]+,919.3522;found,919.3547.
实施例21化合物RSL3-3-nP-B5的合成(n=1,3,5,以n=1为例)
具体操作过程参见步骤2-6,淡黄色固体,收率:61%。1H NMR(600MHz,DMSO-d6)δ10.92(s,1H),8.18–8.15(m,2H),8.00(t,J=6.5Hz,4H),7.92(dd,J=13.2,8.4Hz,1H),7.86(d,J=8.0Hz,2H),7.66(d,J=8.5Hz,1H),7.52(d,J=7.8Hz,1H),7.33(t,J=7.5Hz,3H),7.31–7.28(m,3H),7.27–7.26(m,1H),7.10(t,J=7.5Hz,1H),7.02(t,J=7.7Hz,1H),6.97–6.94(m,1H),4.99(s,1H),4.82(s,1H),4.55(s,1H),4.38(s,2H),4.27–4.21(m,2H),3.99(d,J=3.4Hz,1H),3.84(s,3H),3.70(s,2H),3.37–3.32(m,3H),3.23(dd,J=13.9,5.6Hz,1H),3.11(q,J=6.5Hz,1H),3.03(s,1H),2.93(dd,J=13.7,8.1Hz,1H),2.86(dd,J=13.7,6.3Hz,1H),1.57(dt,J=13.4,6.6Hz,1H),1.53–1.48(m,1H),1.46–1.42(m,1H),1.23(d,J=2.9Hz,2H),0.87–0.85(m,3H),0.84(d,J=6.6Hz,3H).13C NMR(151MHz,DMSO-d6)δ172.25,171.04,170.82,169.18,166.53,144.65,136.77,132.57,129.90,129.46,129.09,127.39,126.48,123.58,121.85,120.58,119.10,116.06,111.72,108.87,102.50,71.49,68.97,68.70,66.77,60.22,55.38,54.70,52.59,51.74,49.62,49.05,41.43,38.84,35.13,24.67,23.27,22.42,21.23,14.55.HRMS(ESI+):m/z calculated forC45H55ClN9O8[M+H]+,884.3862;found,884.3787.
实施例22CCK8法检测细胞毒活性
(1)完全培养基的配置:吸取7.5mL的FBS,500μL含青霉素-链霉素的双抗混合液,再加入DMEM培养基至50mL,使FBS和双抗的最终浓度分别为15%和1%。
(2)细胞冻存:按照FBS:DMSO=9:1的比例配置细胞冻存液。使用梯度冻存的方法冻存细胞,最终在液氮中储存。
(3)细胞传代:在显微镜下观察,HT1080细胞贴壁生长,形态完整边缘清晰,细胞汇合度达到80%~90%即可以进行传代操作。用移液枪弃掉培养瓶/皿中的旧培养基,用4mL新培养基轻轻将细胞吹下,混匀后均匀分散到两个含有4mL培养基的新培养瓶中。摇匀之后在37℃、5%的CO2培养箱中继续培养。
(4)使用血球计数板对生长状态良好的细胞进行计数。在开始之前,用酒精棉球清洗干净计数板和盖玻片并晾干。将盖玻片与计数板H形凹槽边缘对齐,用移液器吸取10μL细胞混悬液沿着盖玻片边缘平稳推入,让悬液利用液体的表面张力充满计数区,不要产生气泡。静置片刻,在显微镜下对血球计数板上方格中的细胞按照“计上不计下,计左不计右”的规定进行计数。每毫升细胞数=细胞总数/4×104。
(5)将生长状态良好且处于对数生长期的细胞离心,完全培养基重悬后,用血球计数板计数。以3.0x104个/孔的浓度接种于96孔板中,放置在37℃、5%CO2培养箱中孵育。待细胞完全贴壁且汇合度达到60%时开始给药。药物作用24h后,每孔中加入10μL的CCK8试剂(注意该试剂需要现配现用,避光保存),在37℃孵育箱中孵育30min后,使用酶标仪在450nm处检测OD值。
(6)使用各组样品的OD值进行计算:
结果如表1和图2所示。
实施例23Western Blot检测GPX4蛋白质表达的变化
(1)细胞蛋白样品制备:
取对数生长期细胞接种于六孔板中,待细胞贴壁并生长到汇合度达60%左右时,用不同浓度的基于RSL3诱导GPX4蛋白降解的双功能分子化合物处理细胞,吹下并收集各组细胞。使用生理盐水洗三次,最后在4℃,3500rpm条件下离心10min。加入一定量含有1mMPMSF的RIPA蛋白裂解液,冰上裂解30min。在4℃,12000rpm的条件下离心10min,小心吸出上清并转移到新的EP管中,不要吸到沉淀。
(2)BCA测定蛋白浓度
用BCA试剂盒进行蛋白浓度的测量。先配置标准蛋白曲线备用液:取8个EP管,向第一个管中加入6μL蛋白标准品(30mg/mL)和54μL生理盐水,其余管中加入30μL生理盐水,使用倍半稀释的方法配置标准曲线备用液。细胞蛋白样品组:取3μL蛋白样品加入到27μL的生理盐水中,将蛋白样品稀释10倍,混匀。将准备好的备用液各取20μL加入96孔板中,再各加入试剂A:试剂B=50:1的混合液200μL,37℃避光孵育30min。使用酶标仪检测562nm处吸光度,根据蛋白标准曲线计算出相应样品的蛋白浓度。为确保上样体积一致,加入相应生理盐水和5x Loading Buffier调整。最后在恒温金属浴中95-100℃,加热5-10min,-20℃储存备用。
(3)SDS-PAGE电泳
根据需要检测的蛋白条带的大小配置不同浓度的分离胶和浓缩胶。平稳放置胶板于电泳槽中,向其中加入足量电泳液,水平垂直拔掉梳子。根据具体实验依次加入Marker和样品,恒压70V,45-55min跑浓缩胶使样品派缩到同一水平线上,恒压110V,60-70min跑分离胶使不同分子量的蛋白分开。
(4)转膜和封闭
采用湿转法转膜:将SDS-PAGE凝胶取下,裁剪成所需要的大小并放置于转膜液中备用。裁剪与凝胶相同大小的PVDF膜并在甲醇中浸泡15s活化。取两层滤纸用转膜液充分浸润挤出气泡。按照滤纸-凝胶-PVDF膜-滤纸组成的“三明治”叠放整齐放入转膜仪器中,再将转膜仪放入冰盒中避免转膜过程中温度过高。恒流200mA,转膜35~110min。转膜结束后取出PVDF膜于含5%脱脂奶粉的封闭液中室温下封闭1h。
(5)免疫印迹杂交和检测
封闭结束后用TBST溶液洗PVDF膜1-2次后置于一抗溶液中,4℃孵育过夜。次日,取出PVDF膜,用TBST清洗3次,每次10min。洗涤结束后,置于二抗溶液中,4℃孵育1h。再使用TBST清洗6次,每次5min。最后在膜上均匀滴入配置好的显影液,放入凝胶成像仪中进行曝光。结果如图1和图3所示。
表1化合物名称对应结构及其在HT1080细胞中的细胞毒活性
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Claims (9)
1.一种基于RSL3诱导GPX4蛋白降解的双功能分子化合物,其特征在于,结构如式I或式II所示:
式I或式II中所述的B为泛素连接酶E3配体,选自CRBN、VHL、MDM2、cIAP、UBR7、RNF114、CBLB和KEAP1中的一种;
式I或式II中所述的L为选自如下范围所示的任意结构:
其中,m选自1-10之间的整数。
2.根据权利要求1所述的基于RSL3诱导GPX4蛋白降解的双功能分子化合物,其特征在于,所述的CRBN为以下结构式中的一种:
其中:
W选自CH2、C=O、SO2、NH和N取代的C1-C4烷基;
X任选自O和S中的一种或两种;
Z选自氢、C1-C4烷基、C3-C6环烷基和卤素中的一种;
G、G′各自独立选自H、C1-C4烷基、-OH和C1-C4烷基取代的5-10元杂环基,所述杂环基含有1-3个N、O或S的杂原子;
R1选自H、D、卤素、硝基、氨基、氰基、羟基、C1-C4烷基、卤代C1-C4烷基和氘代C1-C4烷基中的一种;
所述的VHL的结构式为:
其中:VHL结构中的R2选自CH3和H中的一种;
所述的MDM2的结构式为:
其中:
R3为哌嗪基、哌啶基、杂环基团或以下结构的链接基团之一:
上述链接基团中,n为0-3的整数;
其中,R3所述杂环基团为哌嗪酮基、吡咯基、吡唑基、呋喃基、噻吩基、噁唑基、异噁唑基、噻唑基、异噻唑基、吡啶基、嘧啶基、吡嗪基或哒嗪基中的一种;
所述的cIAP的结构为:
R4为H或Boc。
3.根据权利要求1所述的基于RSL3诱导GPX4蛋白降解的双功能分子化合物,其特征在于,所述式I或式II选自于式III、式IV、式V、式VI、式VII、式VIII、式IX、式X、式XI、式XII和式XIII所示化合物:
其中,式III、式IV、式V、式VI、式VII、式VIII、式IX、式X、式XI、式XII和式XIII所示通式中,L选自以下结构中的任意一种:
m选自1-7之间的整数。
4.根据权利要求3所述的基于RSL3诱导GPX4蛋白降解的双功能分子化合物,其特征在于,具体选自如下化合物:RSL3-1-1P-C、RSL3-1-3P-C、RSL3-1-5P-C、RSL3-1-3C-V1、RSL3-1-5C-V1、RSL3-1-7C-V1、RSL3-1-3C-V2、RSL3-1-5C-V2、RSL3-1-7C-V2、RSL3-1-1P-M、RSL3-1-3P-M、RSL3-1-5P-M、RSL3-1-3C-B4、RSL3-1-5C-B4、RSL3-1-7C-B4、RSL3-1-1P-B5、RSL3-1-3P-B5、RSL3-1-5P-B5、RSL3-3-1P-C、RSL3-3-3P-C、RSL3-3-5P-C、RSL3-3-3C-V1、RSL3-3-5C-V1、RSL3-3-7C-V1、RSL3-3-3C-V2、RSL3-3-5C-V2、RSL3-3-7C-V2、RSL3-3-1P-M、RSL3-3-3P-M、RSL3-3-5P-M、RSL3-3-3C-B4、RSL3-3-5C-B4、RSL3-3-7C-B4、RSL3-3-1P-B5、RSL3-3-3P-B5和RSL3-3-5P-B5。
5.权利要求1-4任一项所述的基于RSL3诱导GPX4蛋白降解的双功能分子化合物的制备方法,选自方法A、方法B和方法C,路线如下所示:
方法A:式I所示的基于RSL3诱导GPX4蛋白降解的双功能分子化合物的合成路线如下:
在本合成路线中,L为m选自1-7之间的整数;
步骤1-1:化合物3的合成
将对1.0equiv醛基苯甲酸溶于二氯甲烷,冷却至0℃,依次加入2.0equiv EDCI、2.0equiv HOBt、1.2equiv炔丙胺和4.0equiv DIPEA,反应物转移至室温反应,反应完全后用H2O和二氯甲烷萃取;有机层经无水硫酸钠干燥,减压浓缩后经硅胶柱色谱纯化,用石油醚/乙酸乙酯(2:1)-(1:1)梯度洗脱,得到化合物3;
步骤1-2:化合物5的合成
将1.0equiv D-色氨酸甲酯盐酸盐加入二氯甲烷中,然后加入1.2equiv TEA,搅拌至完全溶解,并在室温下进行反应,反应结束后对反应体系进行减压浓缩,得到化合物5;
步骤1-3:化合物6的合成
将1.0equiv化合物5溶于二氯甲烷中,然后依次加入1.1equiv化合物3、1.5equiv TFA,并在45℃下进行反应,反应结束后,减压浓缩反应溶液,加入DMF使其完全溶解,并用H2O和乙酸乙酯萃取;将有机层用无水硫酸钠干燥并减压浓缩;残留物通过硅胶柱色谱法,用二氯甲烷/甲醇纯化,得到化合物6;
步骤1-4:化合物8的合成
将1.0equiv化合物6溶于无水二氯甲烷中,并冷却至0℃,加入1.2equiv碳酸氢钠,滴加1.5equiv氯乙酰氯,将反应升温至室温反应,反应结束后加水淬灭,并用H2O和DCM萃取;有机层用无水硫酸钠干燥并减压浓缩;残留物通过硅胶柱色谱石油醚/乙酸乙酯梯度洗脱,得到化合物8;
步骤1-5:式I化合物的合成
将1.2equiv化合物8和1equiv B-Linker溶于THF中,加入H2O,随后加入1.2equiv CuSO4和3.0equiv抗坏血酸钠,室温下反应至反应完全;减压浓缩除去THF后用H2O和DCM萃取;有机层用无水硫酸钠干燥并减压浓缩;残留物通过硅胶柱色谱法纯化,使用二氯甲烷和甲醇作为洗脱剂,得到式I化合物;
方法B:式II所示的基于RSL3诱导GPX4蛋白降解的双功能分子化合物的合成路线如下:
在本合成路线中,L为m选自1-7之间的整数;
步骤2-1:化合物10的合成
将1.0equiv Boc-D-色氨酸溶于无水二氯甲烷中,冷却至0℃,然后在搅拌下依次加入2.0equiv EDCI、2.0equiv HOBt、1.2equiv炔丙基胺、4.0equiv DIPEA后移至室温反应,反应完全后用H2O和DCM萃取;有机层用无水硫酸钠干燥,然后减压浓缩;残留物通过硅胶柱色谱法用石油醚/乙酸乙酯纯化,得到化合物10;
步骤2-2:化合物11的合成
将1.0equiv化合物10溶于乙酸乙酯中,加入氯化氢-乙酸乙酯溶液;减压浓缩反应体系,得到化合物11;
步骤2-3:化合物12的合成
将1.0equiv化合物11加入二氯甲烷中,然后加入1.2equiv TEA,搅拌至完全溶解,并在室温下反应至反应完全,减压浓缩反应体系,得到化合物12;
步骤2-4:化合物14的合成
将1.0equiv化合物12溶于二氯甲烷中,然后在搅拌下依次加入1.1equiv化合物13、1.5equiv TFA,并在45℃下进行反应反应完全后减压浓缩反应溶液,加入DMF使其完全溶解,并用H2O和乙酸乙酯萃取;有机层用无水硫酸钠干燥并减压浓缩;残留物通过硅胶柱色谱法用石油醚/乙酸乙酯纯化,得到化合物14;
步骤2-5:化合物15的合成
将1.0equiv化合物14溶于无水二氯甲烷中,并冷却至0℃后加入1.2equiv碳酸氢钠和1.5equiv氯乙酰氯;将反应在室温下反应;反应完全后加水淬灭反应,并用H2O和DCM萃取;有机层用无水硫酸钠干燥并减压浓缩;残留物通过硅胶柱色谱法纯化,用石油醚/乙酸乙酯洗脱,得到化合物15;
步骤2-6:式II化合物的合成
将1.2equiv化合物15和1equiv B-Linker溶于THF中,加入H2O,随后加入1.2equivCuSO4、3.0equiv抗坏血酸钠,室温下搅拌至反应完全后;先减压浓缩除去THF,然后用H2O和DCM萃取;有机层用无水硫酸钠干燥并减压浓缩;残留物通过硅胶柱色谱法纯化,使用二氯甲烷和甲醇作为洗脱剂,得到式II化合物;
方法C:泛素连接酶E3配体与L的合成路线如下:
(1)当泛素连接酶E3配体为CRBN时,优选为沙利度胺衍生物,其合成方法为:
将化合物沙利度胺衍生物溶于DMF中,向反应体系中加入DIPEA,1.2equiv的Linker,90℃反应至反应完全后用水和乙酸乙酯萃取,有机层用无水硫酸钠干燥,减压浓缩,残留物通过硅胶柱色谱法纯化,得到化合物Tha-L;
(2)当泛素连接酶E3配体为MDM2时,其合成方法为:
取MDM2溶于DCM中,之后在冰浴下加入2equiv EDCI、2equiv HOBt、4equiv DIPEA,之后加入1.2equiv Linker,反应完全后加入DCM稀释反应体系,用水和DCM萃取,有机层用无水硫酸钠干燥,减压浓缩,经硅胶柱层析纯化,得到化合物MDM2-L;
(3)当泛素连接酶E3配体为VHL时,其合成方法为:
其合成方法同MDM2-L,区别在于将MDM2替换为VHL,相应制得VHL-L;
(4)当泛素连接酶E3配体为cIAP时,其合成方法为:
其合成方法同MDM2-L,区别在于将VHL替换为cIAP,相应制得cIAP-L。
6.权利要求1-4任一项所述的基于RSL3诱导GPX4蛋白降解的双功能分子化合物或其药学上可接受的盐在制备治疗肿瘤药物中的应用。
7.一种药物组合物,包含权利要求1-4任一项所述的基于RSL3诱导GPX4蛋白降解的双功能分子化合物或其药学上可接受的盐,以及药学上可接受的辅料。
8.根据权利要求7所述的药物组合物,其特征在于,所述一种药物组合物的剂型为注射剂、片剂或胶囊剂中的任意一种。
9.权利要求7-8任一项所述的一种药物组合物在制备治疗肿瘤药药物中的应用。
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