CN116082308B - 一种降解剂及其制备方法和应用 - Google Patents
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Abstract
本发明公开一种降解剂,所述降解剂为如下结构式(1)的化合物或其医药学上可接受的盐:同时还公开了降解剂的制备方法及其在BPTF的降解、促进NK细胞活化或制备抗肿瘤药物中的应用。本发明制备的降解剂能够靶向降解BPTF,增强肝癌免疫原性,提高NK细胞对肝癌细胞的识别与杀伤,为临床上肝癌的免疫治疗提供了潜在新药物。该BPTF降解剂合成原料便宜、成本较低,具有高特异性、低毒性和安全性等优势。
Description
技术领域
本发明属于药物化学技术领域,具体涉及一种降解剂及其制备方法和应用。
背景技术
BPTF是ATP依赖的核小体重构因子(NuRF)复合体的核心亚基,共有3046个氨基酸残基,包括一个溴结构域和两个植物同源结构域(PHD),通常存在于组蛋白和DNA结合蛋白中。虽然BPTF在胚胎发育、T细胞稳态和乳腺上皮细胞分化等正常细胞发育过程中必不可少,但最近有不少研究证实BPTF具有致癌作用。同时BPTF还能增强癌细胞的抗药性。故BPTF对癌症发展的影响及其作为NURF亚基的关键作用使其成为潜在的新的癌症治疗靶点。
目前以BPTF为靶点的药物开发仍处于早期阶段,虽然有BPTF抑制剂已被发现,但他们的靶向性及治疗效果仍有待提高,如BPTF抑制剂TP-238,对BPTF(Kd=120nM)亲和力比对CECR2(Kd=10nM)高约12倍。研究发现,BPTF能激活肝素酶(HPSE)的表达,导致自然细胞毒性受体(NCR)配体—硫酸乙醯肝素蛋白多醣(HSPGs)在细胞表面的丰度降低,抑制自然杀伤(NK)细胞活性。最近也有研究发现,通过敲低BPTF能使肝癌细胞对化疗药物敏感,克服多药耐药性。因此我们设想基于蛋白降解靶向嵌合体(proteolysis targeting chimeras,PROTACs)的蛋白降解技术,利用泛素-蛋白酶体***特异性地降解BPTF,开发一系列BPTF降解剂,以期增强癌细胞免疫原性,提高NK细胞对肿瘤的杀伤能力,达到***的目的。
蛋白降解靶向嵌合体是一种双功能小分子,一端是结合靶蛋白的配体,另一端是结合E3泛素连接酶的配体,二者通过Linker连接。在体内,PROTACs可以将靶蛋白和E3酶拉近,使靶蛋白被泛素化,通过泛素—蛋白酶体途径降解目标蛋白。这是一种全新的药物设计策略,通过设计这样的三联体小分子药物,理论上能够将过表达或突变的致病蛋白清除,从而达到治疗的目的。基于蛋白质降解靶向嵌合体(PROTACs)策略,以BPTF抑制剂TP-238为骨架化合物,设计合成若干靶向BPTF的PROTAC小分子。目前还没有人对此做出研究。
发明内容
鉴于此,本发明针对现有技术的不足,提出了一种BPTF降解剂的制备及应用。
具体是通过以下技术方案来实现的:
一种降解剂,其结构通式为如下结构式(1)或(2)的化合物或其医药学上可接受的盐,
或
其中,1≤n≤10,R2为-H或-CH3。
所述R1为以下结构式(3)、(4)中任一种:
其中,结构式(3)、(4)中的4位或5位与结构式(1)中的仲胺基团(-NH-)连接。
本发明的第二个发明目的是提供上述一种降解剂的制备方法,其包括如下步骤:
步骤a:将化合物4-氨基-6-氯-2-甲硫基嘧啶、1-(3-氯丙基)-1H-吡唑和Cs2CO3溶于溶剂中,搅拌反应得产物1;
步骤b:在冰浴、氮气保护下,将产物1溶于二氯甲烷(DCM)中,加入m-CPBA,搅拌反应得产物2;
步骤c:氮气保护下,将产物2与4-氨基苯硼酸频哪醇酯、碳酸钾、四三苯基膦钯溶于溶剂中,80-90℃搅拌反应,将反应混合物过滤、柱层析纯化,得产物3;
步骤d:将产物3与溴丙炔、碳酸铯、碘化钾用N,N-二甲基甲酰胺(DMF)溶解,室温搅拌反应得产物4;
步骤e:将产物4、CRBN类E3连接酶配体或VHL类E3连接酶配体、硫酸铜、三[(1-苄基-1H-1,2,3-***-4-基)甲基]胺溶解于N,N-二甲基甲酰胺中,得到混合液;将抗坏血酸钠用水溶解后,加入到混合液中,搅拌反应得降解剂。
进一步方案,所述VHL类E3连接酶配体的制备方法为:将不同长度n的叠氮-PEG-羧酸溶于四氢呋喃(THF),冰浴下搅拌后,依次加入三乙胺、氯甲酸异丁酯,继续搅拌;然后加入VHL ligand,室温反应,分离纯化,得到VHL类E3连接酶配体;
所述CRBN类E3连接酶配体的制备方法为:将氟4-位或5-位取代的沙利度胺衍生物,与不同长度n的叠氮-PEG-胺溶于N,N-二甲基乙酰胺,加入N,N-二异丙基乙胺,80-100℃搅拌反应,得CRBN类E3连接酶配体;
所述叠氮-PEG-胺的长度为1≤n≤10。
进一步方案,步骤a中,所述溶剂为N,N-二甲基甲酰胺(DMF),搅拌反应的温度为70-80℃,反应时间为20-28小时;反应物用水稀释、乙酸乙酯萃取、Na2SO4干燥,浓缩后经柱层析纯化处理;
步骤b中搅拌反应后产物用二氯甲烷稀释、洗涤、干燥、过滤、浓缩、柱层析纯化处理;所述洗涤是依次用硫酸钠饱和溶液、NaOH溶液(1M)和饱和食盐水清洗;
步骤c中溶剂为二氧六环和水按体积比为5:4混合而成。
上述结构式(1)、(2)的降解剂的具体合成路线如下:
1)由化合物4-氨基-6-氯-2-甲硫基嘧啶、1-(3-氯丙基)-1H-吡唑反应生成产物1-产物2-产物3-产物4的合成路线:
2)VHL类E3连接酶配体的合成路线:
3)CRBN类E3连接酶配体的合成路线:
4)降解剂的合成路线:
或
本发明的第三个发明目的是提供一种降解剂组合物,其包含上述降解剂,以及至少一种医药学上可接受的载体或赋形剂。
进一步方案,所述降解剂组合物的剂型为医药学上可接受的任一剂型。
本发明的第四个发明目的是提供上述降解剂的用途,所述降解剂在BPTF的降解、促进NK细胞活化或制备抗肿瘤药物中的应用。
本发明的第五个发明目的是提供一种抗肿瘤药物,包括活性成分和至少一种医药学上可接受的辅料,所述活性成份为上述降解剂。
进一步方案,所述抗肿瘤药物包括治疗肝癌、乳腺癌、肺腺癌、膀胱癌的药物。
本发明具有以下优点及有益效果:
本发明制备的降解剂能够靶向降解BPTF,增加HSPGs在细胞表面的丰度,增强肿瘤细胞免疫原性,促进NK细胞活化,因此,具有作为抗肿瘤药物的应用基础。
本发明方法制备的降解剂具有低毒性、高特异性和优异的促进NK细胞活化的能力,保证了产品的质量和安全性。
本发明方法中所用合成原料便宜、成本较低。
本发明方法制备的BPTF降解剂对BPTF实现了化学降解,在细胞水平实验中,增强了NK对肿瘤细胞的杀伤作用。
附图说明
图1:化合物BP-5、BP-V5、BP-P5降解能力的验证结果图;
图2:化合物BP-5浓度梯度及选择性结果考察结果图;
图3:化合物BP-5对Huh-7及NK细胞的毒性考察流式结果图(附与TP238对比图);
图4:化合物BP-5增强NK细胞对Huh-7杀伤的流式结果图(附与TP238对比图);
图5:化合物BP-5促进NK细胞活化流式结果图(附与TP238对比图)。
具体实施方式
下面对本发明的具体实施方式作进一步详细的说明,但本发明并不局限于这些实施方式,任何在本实施例基本思想上的改进或代替,仍属于本发明权利所要求保护的范围。
实施例1-实施例3中所述BPTF降解剂采用如下合成路线进行合成而得:
1)由化合物4-氨基-6-氯-2-甲硫基嘧啶、1-(3-氯丙基)-1H-吡唑反应生成产物1-产物2-产物3-产物4的合成路线:
2)VHL类E3连接酶配体的合成路线:
3)CRBN类E3连接酶配体的合成路线:
4)降解剂的合成路线:
或
实施例1
所述BPTF降解剂BP-5,其结构式为:
所述BPTF降解剂的合成方法,包括如下步骤:
步骤a:将化合物4-氨基-6-氯-2-甲硫基嘧啶、1-(3-氯丙基)-1H-吡唑和Cs2CO3溶于DMF中,在70℃搅拌过夜。反应混合物用水稀释,乙酸乙酯萃取,Na2SO4干燥,浓缩。产物经柱层析纯化,得到产物1;
步骤b:0℃,氮气保护下,将化合物1溶于二氯甲烷中,加入m-CPBA,室温搅拌2小时,然后用二氯甲烷稀释。用硫酸钠饱和溶液、NaOH溶液(1M)和盐水清洗混合物,然后用Na2SO4干燥。有机相经过滤、浓缩、柱层析纯化,得到化合物2;
步骤c:氮气保护下,将步骤b的产物2与4-氨基苯硼酸频哪醇酯、碳酸钾、四三苯基膦钯溶于二氧六环/水(5/4)的溶剂中,80℃搅拌,反应过夜,将混合物过滤,用柱层析纯化,得产物3;
步骤d:将步骤c的产物3与溴丙炔、碳酸铯、碘化钾用N,N-二甲基甲酰胺溶解,室温搅拌过夜,反应完成后加2-3倍水淬灭反应,用乙酸乙酯萃取,饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩后硅胶柱层析分离纯化,得产物4;
步骤f:将氟4-位取代的沙利度胺衍生物,与不同长度为5PEG的叠氮-PEG-胺溶于N,N-二甲基乙酰胺,加入N,N-二异丙基乙胺,90℃搅拌6h,反应完成后加水淬灭,乙酸乙酯萃取,饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩后硅胶柱层析分离纯化,得到CRBN类E3连接酶配体;
步骤g:将产物4、CRBN类E3连接酶配体(4-位取代)、硫酸铜、三[(1-苄基-1H-1,2,3-***-4-基)甲基]胺溶解于N,N-二甲基甲酰胺中,得到混合液,另取抗坏血酸钠用水溶解后,加入到混合液中,室温搅拌过夜后,加水淬灭反应,用乙酸乙酯萃取,饱和氯化铵、饱和食盐水洗涤,无水硫酸钠干燥,过滤旋干,最后进行柱层析分离纯化即得BPTF降解剂BP-5。
化合物BP-5的13C-NMR、1H-NMR和HR-MS数据
化合物BP-5:1H NMR(600MHz,DMSO-d6):δppm 11.08(s,1H),7.95(s,3H),7.78(s,1H),7.75(d,J=2.0Hz,1H),7.63–7.54(m,2H),7.44(s,1H),7.12(d,J=8.6Hz,1H),7.03(d,J=7.0Hz,1H),6.85(s,1H),6.75(d,J=8.8Hz,2H),6.58(s,1H),6.23(s,1H),5.04(dd,J=12.8,5.4Hz,1H),4.48(t,J=5.2Hz,2H),4.37(s,2H),4.20(s,2H),3.54–3.53(m,2H),3.51–3.50(m,2H),3.49–3.40(m,18H),3.32(s,2H),3.29(s,3H),2.91–2.84(m,1H),2.62–2.52(m,2H),2.07–2.03(m,2H),2.03–2.00(m,1H).13C NMR(150MHz,DMSO-d6):δppm 173.3,170.6,169.5,167.8,164.0,158.9,158.6,146.9,145.5,139.1,136.7,132.6,130.4,128.9,128.3,123.7,118.0,117.0,115.2,112.6,111.2,109.8,105.5,70.34,70.29,70.26,70.14,70.09,69.4,69.3,49.9,49.1,42.2,39.2,38.7,31.5,22.7.HR-MS(ESI)m/z:calcd for C45H56O11N12NaS[M+Na]+,995.3804;found,995.3803.
实施例2
所述BPTF降解剂BP-V5,其结构式为:
上述BPTF降解剂的制备方法,是在实施例1的基础上,将步骤g中CRBN类E3连接酶配体(4-位取代)替换为VHL类E3连接酶配体(如路线4所示,含叠氮化合物);同时限定叠氮-PEG-羧酸的长度n为5。
化合物BP-V5的13C-NMR、1H-NMR和HR-MS数据
化合物BP-V5:1H NMR(600MHz,DMSO-d6):δppm 8.96(s,1H),8.54(t,J=5.8Hz,1H),8.31(s,1H),7.82(s,1H),7.53(t,J=5.1Hz,1H),7.43–7.35(m,5H),6.69(d,J=8.6Hz,2H),6.61(s,1H),6.41(d,J=9.4Hz,1H),6.27(t,J=2.0Hz,1H),5.99(s,1H),5.12(br s,1H),4.47–4.31(m,3H),4.26(t,J=6.3Hz,2H),4.22(dd,J=5.6,15.8Hz,1H),4.14(d,J=9.3Hz,1H),3.68–3.62(m,4H),3.51–3.49(m,4H),3.47–3.46(m,2H)3.44–3.38(m,20H),3.33(s,3H),2.43(s,3H),2.16(m,2H),2.00–2.06(m,3H),1.85–1.93(m,1H),0.92(s,9H).13C NMR(150MHz,DMSO-d6):δppm 173.3,172.1,170.6,170.0,169.5,167.8,164.0,158.9,158.6,146.9,145.4,139.6,139.1,136.7,132.6,131.3,130.4,129.9,128.9,128.3,127.6,123.7,118.0,112.6,111.2,109.8,105.5,70.3,70.29,70.26,70.1,69.4,69.3,69.1,58.9,58.6,56.5,49.9,49.1,42.2,41.9,40.6,39.2,38.7,38.1,35.6,31.5,26.5,22.7,16.1.HR-MS(ESI)m/z:calcd for C45H76O11N13NaS2[M+H]+,1157.5150;found,1157.5148.
实施例3
所述BPTF降解剂BP-P5,其结构是为:
上述BPTF降解剂的制备方法,是在实施例1的基础上,将步骤g中CRBN类E3连接酶配体(4-位取代)替换为CRBN类E3连接酶配体(5-位取代)(如路线5所示,含叠氮化合物);同时限定叠氮-PEG-胺的长度n为5。
化合物BP-P5的13C-NMR、1H-NMR和HR-MS数据
化合物BP-P5:1H NMR(600MHz,DMSO-d6):δppm 11.09(s,1H),8.31(s,1H),7.94(s,2H),7.75(d,J=1.8Hz,2H),7.51(dd,J=24.5,16.5Hz,3H),7.08–6.99(m,2H),6.82(s,1H),6.73(d,J=8.7Hz,2H),6.56(d,J=6.0Hz,1H),6.23(s,1H),5.04(dd,J=12.8,5.4Hz,1H),4.51(t,J=5.1Hz,2H),4.35(d,J=5.4Hz,2H),4.20(t,J=6.6Hz,2H),3.82(t,J=5.1Hz,2H),3.57(t,J=5.3Hz,2H),3.51–3.49(m,2H),3.47–3.46(m,2H),3.44–3.38(m,16H),3.29(s,3H),2.89(s,1H),2.57(d,J=19.4Hz,2H),2.08–2.03(m,2H),1.99(dd,J=9.4,7.0Hz,1H).13C NMR(150MHz,DMSO-d6):δppm 73.2,170.5,169.4,167.7,164.0,158.8,158.5,146.9,145.4,139.0,136.7,132.5,130.4,128.2,125.7,123.7,117.9,116.9,115.0,112.5,111.1,109.7,105.4,70.3,70.20,70.17,70.1,70.0,69.3,69.2,49.8,49.0,42.2,39.1,38.6,31.4,22.6.HR-MS(ESI)m/z:calcd for C45H57O11N12S[M+H]+,973.3985;found,973.3983.
实施例4
验证BPTF降解剂在体外对Huh-7的BPTF降解活性:
采用Western-Blot实验验证化合物BP-5、BP-V5、BP-P5对Huh-7细胞中的BPTF降解效果:用RIPA裂解液提取相关细胞的蛋白。将蛋白与等体积的2x十二烷基硫酸钠(SDS)样品缓冲液温育,并在99℃下加热10分钟,通过SDS-PAGE分离,然后转移至PVDF膜;将膜用5%脱脂牛奶封闭后与相应一抗孵育。随后与辣根过氧化物酶(HRP)连接的二抗孵育诱导化学发光,并通过ECL化学发光观察蛋白质的表达情况;同时用二甲基亚砜(DMSO)处理组(Ctrl)为对照,结果见图1中a、b。结果表明在终浓度为10μM时,BP-5、BP-V5、BP-P5均能引起细胞内一定程度的BPTF降解,并引起相应下游蛋白HPA1下调,其中BP-5的降解效果最佳。
实施例5
采用Western-Blot实验验证化合物BP-5浓度梯度对Huh-7细胞中的BPTF降解效果及对其他溴结构域蛋白的选择性。具体方法如实施例4所述,结果见图2。结果表明降解剂BP-5呈浓度依赖性降解BPTF,其下游蛋白HPA1(HPSE)也相应地呈浓度依赖性下调,并且对其他溴结构域蛋白如CECR2、BRD9均无影响,具有优异的选择性。
实施例6
BPTF降解剂BP-5对Huh-7及NK细胞的毒性:
用流式细胞术检测BP-5对Huh-7及NK的细胞毒性。具体方法为:用10μMBP-5处理Huh-7 28h后(DMSO处理组Ctrl以及BPTF抑制剂TP238为对照),收集Huh-7,通过Annexin-V及7-AAD抗体标记凋亡细胞,流式细胞仪检测。用10μM BP-5处理NK-92/MI 4h后(DMSO处理组为对照),收集NK-92/MI,通过Annexin-V及7-AAD抗体标记凋亡细胞,流式细胞仪检测。结果见图3。结果表明降解剂BP-5不影响Huh-7细胞凋亡(图3(1)),降解剂BP-5不影响NK92/MI细胞凋亡(图3(2)),说明降解剂BP-5毒性较低,具有良好的安全性。
实施例7
化合物BP-5增强NK细胞对Huh-7杀伤:
用流式细胞术检测BP-5对调节NK杀伤Huh-7的作用。具体方法为:用10μMBP-5处理Huh-7 24h后(DMSO处理组Ctrl以及BPTF抑制剂TP238为对照),弃培养基上清,加入10μMBP-5 1640完全培养基重悬的NK92/MI细胞(NK92/MI:Huh-7=1:10或NK92/MI:Huh-7=1:20),共孵育4h。收集细胞,通过Annexin-V及7-AAD抗体标记凋亡细胞,流式细胞仪检测。结果见图4。结果表明:当E:T=1:10(图4(1))或E:T=1:20(图4(2))时降解剂BP-5增强NK对Huh-7杀伤率,说明降解剂BP-5可以有效活化NK细胞,提高NK细胞对肿瘤的杀伤能力。
实施例8
化合物BP-5促进NK细胞活化:
用流式细胞术检测BP-5对促进NK细胞活化的作用。具体方法为:用10μMBP-5处理Huh-7 24h后(DMSO处理组Ctrl以及BPTF抑制剂TP238为对照),弃培养基上清,加入10μMBP-5 1640完全培养基重悬的NK92/MI细胞(NK92/MI:Huh-7=1:20),共孵育4h。收集NK细胞,通过NKp30、NKp44、NKp46、TNF-α、IFN-γ、GZMB、Perforin、CD69、CD107a、NKG2D抗体标记NK细胞,流式细胞仪检测结果分别见图5。结果表明:当E:T=1:20时降解剂BP-5使NK活化指标上调,说明降解剂BP-5可以有促进NK细胞活化。
上述对实施例的描述是为便于该技术领域的普通技术人员能理解和应用本发明。熟悉本领域技术的人员显然可以容易地对实施案例做出各种修改,并把在此说明的一般原理应用到其他实施例中而不必经过创造性的劳动。因此,本发明不限于这里的实施案例,本领域技术人员根据本发明的揭示,不脱离本发明范畴所做出的改进和修改都应该在本发明的保护范围之内。
Claims (9)
1.一种降解剂,其特征在于,所述降解剂为如下结构式的化合物或其医药学上可接受的盐,
。
2.一种如权利要求1所述的降解剂的制备方法,其特征在于,包括如下步骤:
步骤a:将化合物4-氨基-6-氯-2-甲硫基嘧啶、1-(3-氯丙基)-1H-吡唑 和Cs2CO3 溶于溶剂中,搅拌反应得产物1;
步骤b:在冰浴、氮气保护下,将产物1溶于二氯甲烷中,加入m-CPBA,搅拌反应得产物2;
步骤c:氮气保护下,将产物2与4-氨基苯硼酸频哪醇酯、碳酸钾、四三苯基膦钯溶于溶剂中,80-90℃搅拌反应,将反应混合物过滤、柱层析纯化,得产物3;
步骤d:将产物3与溴丙炔、碳酸铯、碘化钾用N,N-二甲基甲酰胺溶解,室温搅拌反应得产物4;
步骤e:将产物4、CRBN类E3连接酶配体、硫酸铜、三[(1-苄基-1H-1,2,3-***-4-基)甲基]胺溶解于N,N-二甲基甲酰胺中,得到混合液;将抗坏血酸钠用水溶解后,加入到混合液中,搅拌反应得降解剂。
3.根据权利要求2所述的制备方法,其特征在于,所述CRBN类E3连接酶配体的制备方法为:将氟4-位或5-位取代的沙利度胺衍生物,与长度n为5的叠氮-PEG-胺溶于N,N-二甲基乙酰胺,加入N,N-二异丙基乙胺,80-100℃搅拌反应,得CRBN类E3连接酶配体。
4.根据权利要求2所述的制备方法,其特征在于,步骤a中,所述溶剂为N,N-二甲基甲酰胺,搅拌反应的温度为70-80℃,反应时间为20-28小时;反应物用水稀释、乙酸乙酯萃取、Na2SO4干燥,浓缩后经柱层析纯化处理;
步骤b中搅拌反应后产物用二氯甲烷稀释、洗涤、干燥、过滤、浓缩、柱层析纯化处理;所述洗涤是依次用硫酸钠饱和溶液、NaOH溶液和饱和食盐水清洗;
步骤c中溶剂为二氧六环和水按体积比为5:4混合而成。
5.一种降解剂组合物,其特征在于:包含如权利要求1所述的降解剂,以及至少一种医药学上可接受的载体或赋形剂。
6.根据权利要求5所述的一种降解剂组合物,其特征在于:所述降解剂组合物的剂型为医药学上可接受的任一剂型。
7.一种如权利要求1所述的降解剂的用途,其特征在于:所述降解剂在制备抗肿瘤药物中的应用。
8.一种抗肿瘤药物,其特征在于:包括活性成分和至少一种医药学上可接受的辅料,所述活性成份为如权利要求1所述的降解剂。
9.根据权利要求8所述的一种抗肿瘤药物,其特征在于:所述抗肿瘤药物为治疗肝癌、乳腺癌、肺腺癌或膀胱癌的药物。
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