CN116903556A - 一种不可逆的hdac6亚型选择性抑制剂及其制备方法和应用 - Google Patents
一种不可逆的hdac6亚型选择性抑制剂及其制备方法和应用 Download PDFInfo
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Abstract
本发明提供一种不可逆的HDAC6亚型选择性抑制剂及其制备方法和应用。本发明不可逆的HDAC6亚型选择性抑制剂具有如下式(I)所示的结构。本发明抑制剂对于HDAC6具有较好的选择性和抑制活性,以较低的浓度即可有效实现HDAC6亚型选择性抑制,同时能够避免抑制其它HDAC亚型引起的毒副作用,安全性高。本发明抑制剂对HDAC6为不可逆抑制作用,药效持久。
Description
技术领域
本发明涉及一种不可逆的HDAC6亚型选择性抑制剂及其制备方法和应用,属于有机化合物合成与医药应用技术领域。
背景技术
盘尼西林、阿司匹林和奥美拉唑等不可逆抑制剂为人类的生命健康做出了重大贡献。与可逆性抑制剂相比,不可逆抑制剂往往具有以下几方面优势:1)更强的靶标亲和力;2)更完全的靶标抑制作用;3)更持久的药效。因此,不可逆抑制剂是当前药物研发领域的一个重要方向(Lonsdale,R.etc.Chem.Soc.Rev.,2018,47,3816-3830;Gehringer,M.etc.J.Med.Chem.2019,62,5673-5724)。值得指出的是,最近几年已有7个不可逆激酶抑制剂(afatinib,ibrutinib,osimertinib,acalabrutinib,neratinib,dacomitinib,zanubrutinib)和1个不可逆KRASG12C抑制剂(sotorasib)被批准上市用于癌症的治疗(Singh,J.etc.Nat.Rev.Drug Discovery,2011,10,307-317;Gehringer,M.etc.J.Med.Chem.2019,62,5673-5724)。
组蛋白去乙酰化酶(HDAC)是一类具有表观遗传和翻译后修饰调控功能的水解酶,它包含18个家族成员,其中HDAC1-11属于锌离子依赖性HDAC。与其它锌离子依赖性HDAC亚型成员不同,HDAC6是唯一含有两个催化结构域(CD1和CD2)的HDAC亚型。HDAC6主要分布在细胞质内,主要催化α-微管蛋白(α-tubulin),皮层肌动蛋白(cortactin),热休克蛋白90(HSP-90)和过氧化物还原酶I/II(peroxiredoxins I/II)等非组蛋白的去乙酰化。HDAC6的另一个显著特征是含有一个锌指泛素结合域和一个动力蛋白马达结合域,这两个结构域赋予了HDAC6招募转运多聚泛素化蛋白进行自噬降解的重要功能。鉴于HDAC6在蛋白翻译后修饰和质量控制方面的重要功能,HDAC6被视为多种癌症、自身免疫性疾病和神经退行性疾病的潜在治疗靶标(Pulya,S.etc.Pharmacological Research2021,163,105274;Zhang,X.etc.J.Med.Chem.2021,64,1362)。目前,ACY-241和ACY-1215等多个HDAC6抑制剂已进入了临床研究阶段,用于多发性骨髓瘤、黑色素瘤、慢性淋巴性白血病、非小细胞肺癌、乳腺癌、胆道癌、亨廷顿氏舞蹈症、类风湿性关节炎、进行性神经性腓骨肌萎缩症、疼痛性糖尿病周围神经病变等疾病的治疗(Zhang,X.etc.J.Med.Chem.2021,64,1362-1391)。然而,ACY-241和ACY-1215的HDAC6亚型选择性均不高(与HDAC1、HDAC2和HDAC3相比仅有10-20倍,Santo,L.etc.Blood,2012,16,2579-2589;Huang,P.etc.Oncotarget,2017,8,2694-2707),仍无法完全避免抑制其它HDAC亚型引起的毒副作用,因此迫切需要研发具有更高亚型选择性的HDAC6抑制剂。此外,目前包括ACY-241和ACY-1215在内的绝大多数HDAC6抑制剂都是异羟肟酸类化合物,由于代谢稳定性差的问题,该类化合物往往需要高剂量多次给药才能维持有效的血药浓度,而不可逆HDAC6抑制剂药效持久的特点有望克服现有抑制剂的上述缺陷。
发明内容
针对现有技术的不足,本发明提供一种不可逆的HDAC6亚型选择性抑制剂及其制备方法和应用。本发明不可逆的HDAC6亚型选择性抑制剂对于HDAC6具有较好的选择性和抑制活性,以较低的浓度即可有效实现HDAC6亚型选择性抑制,同时能够避免抑制其它HDAC亚型引起的毒副作用,安全性高。本发明抑制剂对HDAC6为不可逆抑制作用,药效持久。
本发明的技术方案如下:
一、一种不可逆的HDAC6亚型选择性抑制剂
含有苯磺酰氧化呋咱结构的不可逆的HDAC6亚型选择性抑制剂,具有如下式(I)所示的结构:
二、一种不可逆的HDAC6亚型选择性抑制剂的制备方法
本发明不可逆的HDAC6亚型选择性抑制剂的制备方法,包括步骤:
化合物1与对苯二甲醇反应生成化合物2;化合物2再经过氧化得到羧酸化合物3;化合物3与盐酸羟胺缩合得到HDAC6亚型选择性抑制剂(I)。
根据本发明优选的,化合物2的制备方法包括步骤:在搅拌条件下,向化合物1的THF溶液中加入对苯二甲醇,然后滴加NaOH水溶液;经搅拌反应,然后将反应液浓缩,残留物用乙酸乙酯萃取,萃取液用饱和食盐水洗涤、无水硫酸镁干燥、过滤、浓缩得粗品,然后经硅胶柱层析得到化合物2。
优选的,化合物1的摩尔量和THF的体积比为0.1-1mol/L。
优选的,化合物1和NaOH的摩尔比为1∶1-3。
优选的,化合物1与对苯二甲醇的摩尔比为1∶3.5-4。
优选的,搅拌反应温度为3-8℃。搅拌反应时间为20-40分钟。
根据本发明优选的,化合物3的制备方法包括步骤:在(-5)-5℃下,向化合物2的丙酮溶液中加入Jones试剂,室温搅拌反应;将沉淀滤除,蒸除丙酮后加入乙酸乙酯;有机相用饱和食盐水洗涤后,用无水硫酸镁干燥、过滤、浓缩得粗品,然后经硅胶柱层析得到化合物3。
优选的,化合物2的摩尔量和丙酮的体积比为0.1-1mol/L。
优选的,化合物2的摩尔量和Jones试剂的体积比为2-3mol/L。
优选的,搅拌反应时间为5-15小时。
根据本发明优选的,化合物3与盐酸羟胺缩合制备HDAC6亚型选择性抑制剂(I)的方法包括步骤:在(-5)-5℃、搅拌条件下,向化合物3的无水THF溶液中滴加氯甲酸异丁酯,搅拌0.3-1小时后,滴加三乙胺,继续搅拌0.5-2小时后滤除沉淀得到溶液A;将氢氧化钾和盐酸羟胺溶于无水甲醇中得到溶液B;将溶液A加入溶液B中,进行室温搅拌反应;然后蒸出溶剂,向残留物中加入盐酸并用乙酸乙酯萃取,萃取得到的有机相用饱和食盐水洗涤后,用无水硫酸镁干燥、过滤、浓缩得粗品,然后经硅胶柱层析得到HDAC6亚型选择性抑制剂(I)。
优选的,化合物3的摩尔量和THF的体积比为0.1-1mol/L。
优选的,化合物3、氯甲酸异丁酯和三乙胺的摩尔比为1∶1-1.1∶0.5-0.8。
优选的,氢氧化钾和盐酸羟胺的摩尔比为1∶1;盐酸羟胺的摩尔量和无水甲醇的体积比为0.03-1mol/L。
优选的,化合物3和盐酸羟胺的摩尔比为1∶1-2,优选为1∶1.5。
优选的,将溶液A加入溶液B中后,室温搅拌反应时间为3-5小时。
本发明抑制剂的合成路线如下:
三、一种不可逆的HDAC6亚型选择性抑制剂的应用
本发明还提供了含有苯磺酰氧化呋咱结构的不可逆的HDAC6亚型选择性抑制剂在制备预防或治疗与HDAC6活性或表达异常相关的疾病的药物中的应用。
根据本发明优选的,所述的与HDAC6活性或表达异常相关的疾病为肿瘤疾病或非肿瘤疾病。
优选的,所述的肿瘤疾病为多发性骨髓瘤、黑色素瘤、慢性淋巴性白血病、非小细胞肺癌、乳腺癌或胆道癌;非肿瘤疾病为亨廷顿氏舞蹈症、类风湿性关节炎、进行性神经性腓骨肌萎缩症或疼痛性糖尿病周围神经病变。
四、一种药物组合物
本发明还提供一种适于口服或胃肠外给药的药物组合物,包含本发明HDAC6亚型选择性抑制剂或其药学上可接受的盐以及一种或多种药学上可接受的载体或赋形剂。
本发明的技术特点及有益效果如下:
本发明不可逆的HDAC6亚型选择性抑制剂对于HDAC6具有较好的选择性和抑制活性,以较低的浓度即可有效实现HDAC6亚型选择性抑制,同时能够避免抑制其它HDAC亚型引起的毒副作用,安全性高。本发明抑制剂对HDAC6为不可逆抑制作用,药效持久。
附图说明
图1是不同浓度下,实施例1制备的抑制剂(I)和Tubastatin A(Tub A)对A549细胞内ac-tub和ac-HH4水平的影响;
图2是实施例1制备的抑制剂(I)和Tubastatin A(Tub A)经洗脱后对A549细胞内ac-tub和ac-HH4水平的影响;
图3是不同浓度下,实施例1制备的抑制剂(I)和ACY-241诱导RPMI8266细胞凋亡的结果。
具体实施方式
下面结合实施例对本发明做进一步的说明,但不限于此。
同时,实施例中所用试剂如无特殊说明,均可市购获得;所用方法和设备如无特殊说明,可按现有技术。
实施例1.HDAC6亚型选择性抑制剂(I)的制备
具体合成步骤如下:
(1)化合物2的合成:
在5℃、搅拌条件下,向化合物1(1.0g,2.7mmol)的THF(10mL)溶液中加入对苯二甲醇(1.4g,10mmol),然后滴加25wt%的NaOH水溶液(1mL)。在5℃下搅拌反应30分钟后,将反应液浓缩,残留物用乙酸乙酯萃取。萃取液用饱和食盐水洗涤、无水硫酸镁干燥、过滤、浓缩得粗品,然后经硅胶柱层析得到化合物2(白色固体,0.39g,40%产率)。
产物的核磁数据如下:
1H NMR(400MHz,DMSO-d6)δ8.00-7.95(m,2H),7.90(t,J=7.5Hz,1H),7.73(t,J=7.9Hz,2H),7.40(q,J=8.1Hz,4H),5.46(s,2H),5.27(s,1H),4.53(s,2H)。
(2)化合物3的合成:
在0℃下,向化合物2(0.80g,2.2mmol)的丙酮(10mL)溶液中加入Jones试剂(1mL)。室温搅拌反应10小时后,将沉淀滤除,蒸除丙酮后加入乙酸乙酯。有机相用饱和食盐水洗涤后,用无水硫酸镁干燥、过滤、浓缩得粗品,然后经硅胶柱层析得到化合物3(白色固体,0.65g,78%产率)。
产物的核磁数据如下:
1H NMR(400MHz,DMSO-d6)δ13.09(s,1H),8.03-7.89(m,5H),7.75(t,J=7.8Hz,2H),7.56(d,J=8.0Hz,2H),5.57(s,2H)。
(3)HDAC6亚型选择性抑制剂(I)的合成:
在0℃、搅拌条件下,向化合物3(1.48g,3.8mmol)的无水THF(10mL)溶液中滴加氯甲酸异丁酯(0.9mL,3.9mmol),0.5小时后滴加三乙胺(0.9mL,2.5mmol),继续搅拌1小时后滤除沉淀得到滤液A待用。将氢氧化钾(0.32g,5.7mmol)和盐酸羟胺(0.40g,5.7mmol)一同加入无水甲醇(10mL)中,充分溶解后滤除沉淀得到滤液B。将滤液A加入滤液B中,室温搅拌反应4小时后蒸出溶剂,向残留物中加入1mol/L的盐酸并用乙酸乙酯萃取。萃取得到的有机相用饱和食盐水洗涤后,用无水硫酸镁干燥、过滤、浓缩得粗品,然后经硅胶柱层析得到目标化合物(I)(白色固体,0.62g,42%产率)。
产物的核磁数据如下:
1H NMR(400MHz,DMSO-d6)δ11.30(s,1H),9.12(s,1H),8.02-8.00(m,2H),7.91(t,J=7.5Hz,1H),7.82(d,J=8.0Hz,2H),7.75(t,J=7.8Hz,2H),7.53(d,J=7.9Hz,2H),5.54(s,2H).13C NMR(100MHz,DMSO-d6)δ163.81,158.65,137.30,137.12,136.20,133.11,130.07,128.34,127.96,127.14,110.60,71.80.HRMS(AP-ESI)m/zcalcd for C16H14N3O7S[M+H]+392.0552 found 392.0544。
试验例1.目标化合物体外HDAC6抑制活性和选择性评价实验
以已知的HDAC6亚型选择性抑制剂TubastatinA为阳性对照,测试了实施例1制备的抑制剂(I)对HDAC6和HDAC2的抑制活性和选择性。
表1实验结果表明,化合物(I)对HDAC6的半数抑制浓度(IC50)为0.033μM,远远低于其对HDAC2的IC50(1.5μM),选择性指数(SI)为45.5,高于目前处于临床研究阶段的HDAC6抑制剂ACY-241(SI=17.3)和ACY-1215(SI=10.2)。
表1.体外HDAC6抑制活性和选择性评价结果
a在重复条件下(n≥2)进行,IC50的SD值小于20%平均值。bSI=HDAC2 IC50/HDAC6IC50
试验例2.目标化合物的免疫印迹分析实验
测试不同浓度下,实施例1制备的抑制剂(I)和Tubastatin A(Tub A)对A549细胞内ac-tub和ac-HH4水平的影响,如图1所示。DMSO组为阴性对照组。
从图1的结果可以看出,在0.4μM浓度下,化合物(I)和阳性对照TubastatinA(TubA)都可以显著升高A549细胞内HDAC6底物乙酰-α-微管蛋白(ac-tub)的水平,而不影响I类HDACs(HDAC1/2/3)底物乙酰-组蛋白H4(ac-HH4)的水平,这表明化合物(I)可以选择性抑制胞内HDAC6。值得注意的是,在80nM浓度下,化合物(I)对ac-tub水平的升高效果要显著优于TubastatinA(TubA),这表明在较低浓度下,化合物(I)具有比TubastatinA(TubA)更强的胞内HDAC6抑制作用。
为了验证化合物(I)对胞内HDAC6的选择性不可逆抑制作用,本发明用洗脱实验分别考察了化合物(I)和TubastatinA(TubA)对A549细胞内乙酰-α-微管蛋白(ac-tub)和乙酰-组蛋白H4(ac-HH4)水平的影响。图2的结果表明,TubastatinA(TubA)洗脱1小时后,其对胞内乙酰-α-微管蛋白(ac-tub)水平的升高效果即显著降低,这表明TubastatinA(TubA)是一个可逆的HDAC6抑制剂。与TubastatinA(TubA)形成鲜明对比的是,化合物(I)即使在洗脱24小时后,仍具有极显著的乙酰-α-微管蛋白(ac-tub)升高效果,这证实了其对胞内HDAC6的不可逆抑制作用。与图1的结果一致,TubastatinA(TubA)和化合物(I)对胞内乙酰-组蛋白H4(ac-HH4)水平无显著影响,这进一步证实了它们的HDAC6选择性。
试验例3.目标化合物体外抗人多发性骨髓瘤细胞增殖和对正常细胞毒性实验
以处于临床研究阶段的HDAC6抑制剂ACY-241为阳性对照,本发明用CCK-8实验评价了实施例1制备的抑制剂(I)的体外抗人多发性骨髓瘤细胞增殖活性。表2的结果表明,化合物(I)对各株人多发性骨髓瘤细胞的抑制活性均显著优于阳性对照ACY-241。此外,化合物(I)具有比ACY-241更高的选择性指数(SI),因此有望具有比ACY-241更好的安全性。
表2.化合物的体外抗人多发性骨髓瘤细胞增殖活性和对正常细胞毒性
a在重复条件下(n≥3)进行,值显示为平均值±SD值
b选择性指数=LO2细胞IC50/三株MM细胞IC50的平均值
试验例4.目标化合物诱导RPMI8266细胞凋亡实验
以处于临床研究阶段的HDAC6抑制剂ACY-241为阳性对照,本发明用流式细胞术分析了实施例1制备的抑制剂(I)诱导多发性骨髓瘤细胞RPMI8266凋亡的活性。图3的结果表明,化合物(I)在0.1μM和0.5μM浓度条件下均能显著诱导RPMI8266细胞凋亡,且具有剂量依赖性。与之形成鲜明对比的是,ACY-241的诱导凋亡活性并不明显。
Claims (9)
1.一种不可逆的HDAC6亚型选择性抑制剂,其特征在于,具有如下式(I)所示的结构:
2.如权利要求1所述不可逆的HDAC6亚型选择性抑制剂的制备方法,包括步骤:
化合物1与对苯二甲醇反应生成化合物2;化合物2再经过氧化得到羧酸化合物3;化合物3与盐酸羟胺缩合得到HDAC6亚型选择性抑制剂(I);
3.根据权利要求2所述不可逆的HDAC6亚型选择性抑制剂的制备方法,其特征在于,化合物2的制备方法包括步骤:在搅拌条件下,向化合物1的THF溶液中加入对苯二甲醇,然后滴加NaOH水溶液;经搅拌反应,然后将反应液浓缩,残留物用乙酸乙酯萃取,萃取液用饱和食盐水洗涤、无水硫酸镁干燥、过滤、浓缩得粗品,然后经硅胶柱层析得到化合物2。
4.根据权利要求2所述不可逆的HDAC6亚型选择性抑制剂的制备方法,其特征在于,化合物3的制备方法包括步骤:在(-5)-5℃下,向化合物2的丙酮溶液中加入Jones试剂,室温搅拌反应;将沉淀滤除,蒸除丙酮后加入乙酸乙酯;有机相用饱和食盐水洗涤后,用无水硫酸镁干燥、过滤、浓缩得粗品,然后经硅胶柱层析得到化合物3。
5.根据权利要求2所述不可逆的HDAC6亚型选择性抑制剂的制备方法,其特征在于,化合物3与盐酸羟胺缩合制备HDAC6亚型选择性抑制剂(I)的方法包括步骤:在(-5)-5℃、搅拌条件下,向化合物3的无水THF溶液中滴加氯甲酸异丁酯,搅拌0.3-1小时后,滴加三乙胺,继续搅拌0.5-2小时后滤除沉淀得到溶液A;将氢氧化钾和盐酸羟胺溶于无水甲醇中得到溶液B;将溶液A加入溶液B中,进行室温搅拌反应;然后蒸出溶剂,向残留物中加入盐酸并用乙酸乙酯萃取,萃取得到的有机相用饱和食盐水洗涤后,用无水硫酸镁干燥、过滤、浓缩得粗品,然后经硅胶柱层析得到HDAC6亚型选择性抑制剂(I)。
6.如权利要求1所述不可逆的HDAC6亚型选择性抑制剂在制备预防或治疗与HDAC6活性或表达异常相关的疾病的药物中的应用。
7.根据权利要求6所述的应用,其特征在于,所述的与HDAC6活性或表达异常相关的疾病为肿瘤疾病或非肿瘤疾病。
8.根据权利要求7所述的应用,其特征在于,所述的肿瘤疾病为多发性骨髓瘤、黑色素瘤、慢性淋巴性白血病、非小细胞肺癌、乳腺癌或胆道癌;非肿瘤疾病为亨廷顿氏舞蹈症、类风湿性关节炎、进行性神经性腓骨肌萎缩症或疼痛性糖尿病周围神经病变。
9.一种适于口服或胃肠外给药的药物组合物,包含权利要求1所述HDAC6亚型选择性抑制剂或其药学上可接受的盐以及一种或多种药学上可接受的载体或赋形剂。
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