CN110229146B - 组蛋白去乙酰化酶抑制剂及其制备方法与用途 - Google Patents
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Abstract
本发明公开了一种组蛋白去乙酰化酶抑制剂,本发明公开了式I所示的化合物或其立体异构体。本发明公开的式I所示的新化合物,表现出了良好的去乙酰化酶抑制活性,为临床治疗与组蛋白去乙酰化酶活性异常相关的疾病提供了一种新的药用可能。
Description
技术领域
本发明涉及一种组蛋白去乙酰化酶抑制剂及其制备方法与用途。
背景技术
在机体中控制细胞生长的基因失活是肿瘤发生的一个标志。引起基因失活的外遗传机制主要包括DNA甲基化,组蛋白乙酰化和染色质高级结构中其他成分的修饰,这些修饰改变染色质构型,导致基因转录调节发生变化,基因转录的失调引起细胞增殖失常,从而导致肿瘤产生。
组蛋白乙酰化对于真核细胞的转录调控起核心作用。组蛋白乙酰化作用受一对功能相互拮抗的蛋白酶组蛋白乙酰化转移酶(HATs)和组蛋白去乙酰化酶(HDACs)调控。在正常细胞中,这一对酶处于动态平衡状态。一般情况下,组蛋白乙酰化水平增强与基因转录活性增强有关,而乙酰化水平过低与基因表达抑制有关(Forsberg EC et al.Bioessays,2001,23(9):820-830)。研究发现,HDAC过度表达并被转录因子募集,导致特定基因的不正常抑制,从而导致肿瘤和其他疾病;而抑制HDAC的活性将引起许多癌细胞的生长抑制和凋亡(Somech R et al.Cancer Treat Rev,2004,30(5):461-472)。因此,HDAC已成为目前抗肿瘤药物研发领域最新和最热门的靶标。
在人类中,已经鉴别出18种HDAC并且可分为四类。其中11种HDAC利用锌作为辅助因子,可分为四类:类别I(HDAC 1、2、3和8)、类别IIa(HDAC 4、5、7和9)、类别IIb(HDAC 6和10)、类别IV(HDAC 11);另外7种HDAC为类别III,需要NAD+作为额外辅助因子(Bolden etal.Nat.Rev.Drug,2006,5(9):769-784)。其中IIa类HDACs可以通过胞浆胞核穿梭调控糖脂代谢相关基因的表达,如糖异生相关葡萄糖6磷酸酶、磷酸烯醇式丙酮酸羧激酶、甘油三酯脂肪酶、葡萄糖转运蛋白等。近年来发现,IIa类HDACs是与临床相关的分子靶标,这类去乙酰化酶在调节肌肉分化以及失活HDAC5和HDAC9基因导致心肌细胞肥大中扮演重要角色。另外IIa类组蛋白去乙酰化酶与临床心血管疾病、呼吸系统疾病和骨软骨疾病的发生、肿瘤进展以及药学研究等密切相关。
HDAC抑制剂作用机制是通过抑制HDAC,阻断由于HDAC募集功能紊乱而导致的基因表达受抑,通过改变组蛋白的乙酰化程度来改变染色质结构,从而调控基因表达治疗癌症。它通过诱导肿瘤细胞的生长停滞、分化或凋亡对治疗血液系统肿瘤和实体瘤疗效显著。HDAC抑制剂具有肿瘤特异性,对增殖和静止的变异细胞均有细胞毒作用,而正常细胞对它有10倍以上的耐受,不会引起正常细胞的生长停滞和凋亡。
目前已研发的HDAC抑制剂,在抗癌活性、毒副作用、亚型选择性等方面也存在一定的问题。因此,开发一种具有组蛋白去乙酰化酶抑制活性的新化合物具有十分重要的社会和经济意义。
发明内容
为了解决上述问题,本发明提供了一种具有组蛋白去乙酰化酶抑制活性的化合物。
本发明提供式I所示的化合物或其立体异构体:
其中,
X选自O、S或NR3;
R’选自C1~6烷基、C2~6烯基、C2~6炔基、5~10元芳环、5~10元芳杂环;其中烷基、烯基、炔基、芳环、芳杂环可进一步被m个R1取代;
m为1、2、3、4或5;
R1分别独自选自卤素、C1~6烷基、C2~6烯基、C2~6炔基、C1~6卤素烷基、3~10元环烷基、3~10元杂环烷基、-CN、-NO2、-C(O)Ra、-C(O)NRaRb、-C(O)ORa、-NRaRb、-NRaC(O)Rb、-NRaC(O)NRbRc、-NRaS(O)Rb、-NRaS(O)2Rb、-NRaS(O)NRbRc、-NRaS(O)2NRbRc、-ORa、-OC(O)Rb、-OC(O)NRaRb;其中烷基、烯基、炔基、环烷基、杂环烷基可进一步被p个Rd取代;
n为0、1、2、3或4;
R2分别独自选自卤素、C1~6烷基、C2~6烯基、C2~6炔基、C1~6卤素烷基、-CN、-NO2、-NRaRb、-ORa;
R3选自氢、C1~6烷基、C2~6烯基、C2~6炔基、3~10元环烷基、3~10元杂环烷基;其中烷基、烯基、炔基、环烷基、杂环烷基可进一步被p个Rd取代;
Ra、Rb、Rc分别独自选自氢、C1~6烷基、C2~6烯基、C2~6炔基、3~10元环烷基、3~10元杂环烷基、5~10元芳环、5~10元芳杂环;其中烷基、烯基、炔基可进一步被p个Re取代;
或者,Ra可与Rb或Rc可相连形成3~10元环烷基、3~10元杂环烷基;
p为1、2、3或4;
Rd分别独自选自3~10元环烷基、3~10元杂环烷基、-C(O)Ra、-C(O)NRaRb、-C(O)ORa、-NRaRb、-NRaC(O)Rb、-NRaS(O)Rb、-NRaS(O)2Rb、-ORa、-OC(O)Rb;
Re分别独自选自3~10元环烷基、3~10元杂环烷基、5~10元芳环、5~10元芳杂环。
在一些实施方案中,式I所示的化合物可进一步用式IIa表示:
其中,
X为S或O;
R’选自C1~6烷基、5~10元芳环、5~10元芳杂环;其中烷基、芳环、芳杂环可进一步被m个R1取代;
m为1、2或3;
R1分别独自选自卤素、C1~6烷基、C1~6卤素烷基、-CN、-NO2、-C(O)Ra、-NRaRb、-ORa;其中烷基可进一步被p个Rd取代;
n为0、1或2;
R2分别独自选自卤素、C1~6烷基、C1~6卤素烷基、-CN、-NO2、-NRaRb、-ORa;
Ra、Rb分别独自选自氢、C1~6烷基、3~10元环烷基、3~10元杂环烷基、5~10元芳环、5~10元芳杂环;其中烷基可进一步被p个Re取代;
或者,Ra可与Rb可相连形成3~6元环烷基、3~6元杂环烷基;
p为1、2或3;
Rd分别独自选自3~6元环烷基、3~6元杂环烷基、-C(O)Ra、-NRaRb、-ORab;
Re分别独自选自3~6元环烷基、3~6元杂环烷基、5~6元芳环、5~6元芳杂环。
在一些实施方案中,式IIa所示的化合物可具体表示为:
在一些实施方案中,式I所示的化合物可进一步用式IIb表示:
其中,
X为S或O;
R’选自C1~6烷基、5~10元芳环、5~10元芳杂环;其中烷基、芳环、芳杂环可进一步被m个R1取代;
m为1、2或3;
R1分别独自选自卤素、C1~6烷基、C1~6卤素烷基、-CN、-NO2、-C(O)Ra、-NRaRb、-ORa;其中烷基可进一步被p个Rd取代;
n为0、1或2;
R2分别独自选自卤素、C1~6烷基、C1~6卤素烷基、-CN、-NO2、-NRaRb、-ORa;
Ra、Rb分别独自选自氢、C1~6烷基、3~10元环烷基、3~10元杂环烷基、5~10元芳环、5~10元芳杂环;其中烷基可进一步被p个Re取代;
或者,Ra可与Rb可相连形成3~6元环烷基、3~6元杂环烷基;
p为1、2或3;
Rd分别独自选自3~6元环烷基、3~6元杂环烷基、-C(O)Ra、-NRaRb、-ORab;
Re分别独自选自3~6元环烷基、3~6元杂环烷基、5~6元芳环、5~6元芳杂环。
在一些实施方案中,式IIb所示的化合物可具体表示为:
本发明的另一目的在于上述化合物或其立体异构体,在制备HDAC抑制剂类药物中的用途。
所述HDAC抑制剂类药物是治疗由HDAC活性异常所导致的疾病的药物。特别是由HDAC4、HDAC5、HDAC7或HDAC9活性异常所导致的疾病的药物。
进一步,所述疾病是细胞增殖疾病、自身免疫疾病、炎症、神经变性疾病或病毒性疾病中的任意一种或多种。
更进一步,所述疾病为癌症。
一种抑制组蛋白去乙酰化酶活性的药物组合物,它是以上述化合物或其晶型、药学上可接受的盐、水合物或溶剂合物为活性成分,加上药学上常用的辅料或辅助性成分制备得到的制剂。
本发明中提供的化合物和衍生物可以根据IUPAC(国际纯粹与应用化学联合会)或CAS(化学文摘服务社,Columbus,OH)命名系统命名。
关于本发明的使用术语的定义:除非另有说明,本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语;对于本文没有具体定义的术语,应该根据公开内容和上下文,给出本领域技术人员能够给予它们的含义。
“取代”是指分子中的氢原子被其它不同的原子或分子所替换。
碳氢基团中碳原子含量的最小值和最大值通过前缀表示,例如,前缀Ca~b烷基表明任何含“a”至“b”个碳原子的烷基。因此,例如,“C1~4烷基”是指包含1~4个碳原子的烷基。
“卤素”为氟、氯、溴或碘。
“卤素烷基”指烷基中的氢原子可被一个或多个卤素原子取代。例如C1~4卤素烷基指氢原子被一个或多个卤素原子取代的包含1~4个碳原子的烷基。
“杂环”、“杂环烷基”指包含至少一个杂原子的饱和环或非芳香性的不饱和环;其中杂原子指氮原子、氧原子、硫原子;
“芳杂环”指包含至少一个杂原子的芳香性不饱和环;其中杂原子指氮原子、氧原子、硫原子;
“立体异构体”包括对映异构体和非对映异构体;
术语“药学上可接受的”是指某载体、运载物、稀释剂、辅料,和/或所形成的盐通常在化学上或物理上与构成某药物剂型的其它成分相兼容,并在生理上与受体相兼容。
术语“盐”和“可药用的盐”是指上述化合物或其立体异构体,与无机和/或有机酸和碱形成的酸式和/或碱式盐,也包括两性离子盐(内盐),还包括季铵盐,例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将上述化合物,或其立体异构体,与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集,或在溶剂蒸发后回收而得到,或在水介质中反应后冷冻干燥制得。本发明中所述盐可以是化合物的盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
本发明具体实施方式中使用的原料、设备均为已知产品,通过购买市售产品获得。
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的的单位给出。NMR的测定是用(Bruker AvanceIII 400和Bruker Avance 300)核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d6),氘代氯仿(CDCl3),氘代甲醇(CD3OD),内标为四甲基硅烷(TMS)。
LC-MS的测定用岛津液质联用仪(Shimadzu LC-MS 2020(ESI))。
HPLC的测定使用岛津高压液相色谱仪(Shimadzu LC-20A)。
反相制备色谱(pre-HPLC)使用Gilson GX-281反相制备色谱仪,通用制备方法为:流动相A:含0.05%三氟乙酸的纯水;流动相B:乙腈;梯度:流动相B含量5%-95%。
薄层层析硅胶板用烟台黄海HSGF254或青岛GF254硅胶板,薄层层析分离纯化产品采用的规格是0.4mm~0.5mm。
柱层析一般使用烟台黄海硅胶200~300目硅胶为载体。
本发明所用原料主要购买于百灵威化学、韶远化学科技有限公司、Alfa Aesar、江苏艾康生物医药研发有限公司和梯希爱(上海)化成工业发展有限公司等供应商。
室温为最适宜的反应温度,一般为20℃~30℃。
实施例中无特殊说明,溶液是指水溶液。
实施例中无特殊说明,反应的温度为室温。
过夜为12±1h。
原料和试剂简称:
DCM:二氯甲烷
HOAc:醋酸
NCS:N-氯代丁二酰亚胺
EtOH:乙醇
DMSO:二甲基亚砜
DMF:N,N-二甲基甲酰胺
PE:石油醚
EA:乙酸乙酯
HATU:2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯
DIPEA:N,N-二异丙基乙胺
Pd2(dba)3:三(二亚苄基丙酮)二钯
XantPhos:4,5–双(二苯基膦)–9,9–二甲基氧杂蒽
实施例1、本发明化合物的制备
步骤1:化合物1的制备
将4–溴–2–氟苯甲醛(100g,493mmol)和2–巯基乙酸甲酯(120g,1.13mol)溶于DMF(1.0L)中,在0℃下加入氢化钠(59.2g,1.48mol,60%),搅拌反应1小时后加入冰水(2.0L),乙酸乙酯(1.0L)萃取4次,合并有机层并用饱和氯化钠溶液洗1次。减压蒸除溶剂,经柱层析(PE:EA=100:1)纯化得化合物1(125g,产率94%)。
步骤2:化合物2的制备
将化合物1(38.20g,151mmol)溶于甲苯(300mL)中,加入苄硫醇(24.50g,197.00mmol)、DIPEA(39.50g,306.00mmol,53.2mL)、4,5–双(二苯基膦)–9,9–二甲基氧杂蒽(8.90g,15.40mmol)和三(二亚苄基丙酮)二钯(6.89g,7.53mmol),回流反应过夜。反应后加入水(500mL),乙酸乙酯(300mL)萃取2次,合并有机层后减压蒸除溶剂。经柱层析纯化(PE:EA=100:1)后得化合物2(27.00g,产率57%)。
步骤3:化合物3的制备
将化合物2(2.00g,6.36mmol)溶于甲醇(20mL)和水(2mL)中,加入NaOH(1.27g,31.80mmol)并在室温下搅拌过夜。旋去甲醇,加1M盐酸调pH至pH=4,用乙酸乙酯。合并有机层,干燥后旋干,得黄色固体化合物3(1.9g,收率99%)。
步骤4:化合物4的制备
将化合物3(1.4g,4.66mmol)溶于DCM(50mL)中,滴于草酰氯(1.18g,9.32mmol)并在室温下搅拌过夜,将溶剂减压旋干,残余物重新溶于DCM。将此DCM溶液倒入冰水冷却的氨水(20mL)中,搅拌10min,过滤析出的沉淀,滤饼干燥后得白色固体化合物4(1.2g,收率:86%)。
步骤5:化合物5的制备
将化合物4(1.20g,4.01mmol)溶于1,4-二氧六环(30mL)中,加入吡啶(1.27g,16.03mmol,1.29mL)和三氟乙酸酐(3.37g,16.03mmol)后,于室温下搅拌3小时。加入水并用乙酸乙酯萃取,合并有机层,旋干后柱层析纯化(PE:EA=10:1)得白色粉末化合物5(1.01g,收率:88%)。
步骤6:化合物6的制备
将化合物5(1.00g,3.55mmol)悬浮于AcOH(10mL)和水(3mL)中,分批加入NCS(1.90g,14.21mmol)并于室温下搅拌2小时。向反应液中加水,并用乙酸乙酯萃取,合并有机层,干燥后旋干,得白色固体粗产物6(1.6g),不进一步纯化,直接用于下一步反应。
步骤7:化合物7的制备
将3-氨基-5-氯吡啶(316mg,2.46mmol)和吡啶(389mg,4.92mmol,0.4mL)溶于DCM(10mL),加入化合物6(423mg,1.64mmol)并在室温下搅拌过夜。向反应液中加水,并用DCM萃取,合并DCM层,旋干后柱层析纯化(PE:EA=3:1 to 1:1),得棕色固体化合物7(578mg,产率:100%)。
步骤8:化合物8的制备
将化合物7(578mg,1.66mmol)溶于EtOH(20mL)中,加入盐酸羟胺(1.15g,16.6mmol)和三乙胺(1.67g,16.6mmol,2.3mL),升温至60℃反应2小时,旋去溶剂,得白色固体化合物8,直接用于下一步。
步骤9:实施例1化合物的制备
将化合物8(634mg,1.66mmol)溶于吡啶(10mL)中,滴入三氟乙酸酐(1.74g,8.28mmol)并于室温下搅拌过夜。将反应夜倒入水中,乙酸乙酯萃取,合并有机层,旋干后pre-HPLC纯化,得白色固体实施例1化合物(405mg,收率:53%)。
MS(ESI)m/z=461[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.08(s,1H),8.81(d,J=1.6Hz,1H),8.47(s,1H),8.33(d,J=2.0Hz,1H),8.30(d,J=2.0Hz,1H),8.25(d,J=2.0Hz,1H),7.86(dd,J=8.4,1.6Hz,1H),7.62(t,J=2.0Hz,1H)。
实施例2、本发明化合物的制备
按照实施例1中步骤1至步骤9的合成方法,并将步骤7中的3-氨基-5-氯吡啶换成2-三氟甲基-3-氨基吡啶,得到实施例2化合物(收率:20%)。
MS(ESI)m/z=495[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.32(s,1H),8.81(d,J=1.6Hz,1H),8.65(d,J=2.4Hz,2H),8.45(s,1H),8.24(d,J=8.4Hz,1H),7.88(dd,J=8.4,1.6Hz,1H),7.82(t,J=2.4Hz,1H)。
实施例3、本发明化合物的制备
按照实施例1中步骤1至步骤9的合成方法,并将步骤7中的3-氨基-5-氯吡啶换成3-氨基吡啶,得到实施例3化合物(收率:32%)。
MS(ESI)m/z=427[M+H]+
1H NMR(400MHz,DMSO-d6)δ10.93(s,1H),8.75(dd,J=1.6,0.8Hz,1H),8.47(d,J=0.8Hz,1H),8.42–8.37(m,1H),8.33(d,J=4.8Hz,1H),8.23(d,J=8.4Hz,1H),7.85(dd,J=8.4,1.6Hz,1H),7.69(ddd,J=8.4,2.4,1.2Hz,1H),7.43(dd,J=8.4,4.8Hz,1H)。
实施例4、本发明化合物的制备
按照实施例1中步骤1至步骤9的合成方法,并将步骤7中的3-氨基-5-氯吡啶换成3-氨基-5-甲氧基吡啶,得到实施例4化合物(收率:41%)。
MS(ESI)m/z=457[M+H]+。
实施例5、本发明化合物的制备
按照实施例1中步骤1至步骤9的合成方法,并将步骤7中的3-氨基-5-氯吡啶换成4-氨基吡啶,得到实施例5化合物(收率:14%)。
MS(ESI)m/z=427[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.76(s,1H),8.45(s,1H),8.18(d,J=8.4Hz,1H),8.13(d,J=6.8Hz,2H),7.91(dd,J=8.4,1.6Hz,1H),7.10(d,J=6.8Hz,2H)。
实施例6、本发明化合物的制备
按照实施例1中步骤1至步骤9的合成方法,并将步骤7中的3-氨基-5-氯吡啶换成2-氨基吡啶,得到实施例6化合物(收率:10%)。
MS(ESI)m/z=427[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.76(s,1H),8.44(s,1H),8.18(d,J=8.4Hz,1H),8.01–7.90(m,2H),7.79–7.70(m,1H),7.25(d,J=8.4Hz,1H),6.84(t,J=6.4Hz,1H)。
实施例7、本发明化合物的制备
按照实施例1中步骤1至步骤9的合成方法,并将步骤7中的3-氨基-5-氯吡啶换成N1-苄基-N1-甲基丙基-1,2-二胺,得到实施例7化合物(收率:12%)。
MS(ESI)m/z=511[M+H]+
实施例8、本发明化合物的制备
按照实施例1中步骤1至步骤9的合成方法,并将步骤1中的2–巯基乙酸甲酯换成2–羟基乙酸甲酯,得到实施例8化合物(收率:21%)。
MS(ESI)m/z=445[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.03(s,1H),8.39(d,J=2.0Hz,1H),8.31(d,J=2.0Hz,1H),8.29(d,J=2.0Hz,1H),8.09(d,J=1.2Hz,1H),8.07–8.03(m,1H),7.95(dd,J=8.8,2.0Hz,1H),7.61(t,J=2.0Hz,1H)。
实施例9、本发明化合物的制备
按照实施例1中步骤1至步骤9的合成方法,并将步骤1中的4–溴–2–氟苯甲醛换成5–溴–2–氟苯甲醛,将2–巯基乙酸甲酯换成2–羟基乙酸甲酯,将步骤7中3-氨基-5-氯吡啶换成3-氨基吡啶,得到实施例9化合物(收率:32%)。
MS(ESI)m/z=411[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),8.34–8.32(m,2H),8.30(d,J=2.0Hz,1H),8.08–8.04(m,2H),7.82(dd,J=8.4,1.6Hz,1H),7.64(t,J=2.0Hz,1H)。
实施例10、本发明化合物的制备
按照实施例1中步骤1至步骤9的合成方法,并将步骤1中的4–溴–2–氟苯甲醛换成5–溴–2–氟苯甲醛,将2–巯基乙酸甲酯换成2–羟基乙酸甲酯,得到实施例10化合物(收率:7%)。
MS(ESI)m/z=445[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),8.34–8.32(m,2H),8.30(d,J=2.0Hz,1H),8.08–8.04(m,2H),7.82(dd,J=8.4,1.6Hz,1H),7.64(t,J=2.0Hz,1H)。
为了说明本发明的有益效果,本发明提供以下试验例:
试验例1 HDACIIa家族细胞水平酶活性检测方法
采用荧光方法检测化合物对HDACIIa家族细胞水平酶活性的抑制能力。
1640培养基配制:0.5%血清,0.5%DMSO,1640基础培养基,混匀。稀释受试化合物至所需终浓度的4倍,取12.5μL化合物至96孔检测板中,在阳性对照孔和阴性对照孔中,分别加入12.5μL 1640培养基。稀释底物至所需终浓度的4倍,取12.5μL底物至96孔检测板中。离心收集细胞,用1640培养基悬浮细胞并计数,接种细胞25μL,密度为100000个/孔至96孔检测板中,阴性对照孔中加入25μL 1640培养基,混匀。置细胞培养箱中培养3小时。在各反应孔中加入50μL胰酶终止液(2%Triton X-100,50μM TSA,胰蛋白酶溶液),混匀,室温避光孵育1小时,反应结束后,酶标仪读取96孔板中的荧光信号值(Ex:355nm,Em:460nm)。计算各浓度剩余活力百分比,公式为:剩余活力(%)=100*(化合物组荧光值-空白对照荧光值)/(阳性对照荧光值-空白对照荧光值),之后用GraphPad 5.0拟合剂效曲线计算EC50值。
试验例2 HDAC4酶学筛选试验
采用荧光方法检测化合物对HDAC4酶活性的抑制能力。
配制酶反应缓冲液,其中Tris 15mM,EDTA 0.25mM,NaCl 250mM,10%(v/v)甘油,用盐酸调节pH至8.1。
用DMSO稀释受试化合物至所需终浓度的1000倍,混匀后吸取2.5μl加入247.5μl酶反应缓冲液液中,充分混匀。吸取2.5μl酶反应缓冲液配制的化合物加入384孔黑板中,阳性对照孔和阴性对照孔分别加入2.5μl含1%DMSO的酶反应缓冲液。用酶反应缓冲液稀释HDAC4蛋白至1.2nM,除空白对照组外其余各孔加入2.5μl稀释好的HDAC4蛋白,空白对照组加入2.5μl酶反应缓冲液,384孔板1200rpm/min离心1min,使化合物和HDAC4室温预孵育10min,之后每孔加入10μl酶反应缓冲液。用酶反应缓冲液配制Boc-Lys(Tfa)-AMC浓度为25μM的底物溶液,于反应各孔中加入10μl,反应板1200rpm/min离心1min,37℃孵育30分钟。用胰酶配制SAHA浓度为2mM的混合终止液,HDAC4酶反应结束后于反应各孔中加入25μl SAHA胰酶的混合终止液,反应板1200rpm/min离心1min,室温孵育50分钟,反应结束后,酶标仪读取384孔板中的荧光信号值(Ex:355nm,Em:460nm)。计算各浓度剩余活力百分比,公式如下:剩余活力(%)=100*(荧光值化合物组-荧光值空白对照)/(荧光值阳性对照-荧光值空白对照)。之后用GraphPad5.0拟合剂效曲线计算IC50值。
试验例3细胞增殖抑制试验
采用CCK8方法检测化合物对细胞增殖的抑制能力。
细胞以每孔3000个细胞的密度接种到96孔细胞培养板中,37℃,5%二氧化碳培养箱过夜。化合物先使用DMSO梯度稀释,再用培养基配制成4×溶液,最后96孔细胞培养板中先加入150μl新鲜培养基后再加入50μl 4×化合物,37℃,5%二氧化碳培养箱培养72h。检测前配制cck-8检测液,取无血清培养基加入10%CCK-8检测液,混合均匀;弃掉96孔板中旧培养基,加入100μlCCK-8工作液,未铺细胞的孔也加入100μl CCK-8工作液为空白对照,37℃孵育1h,使用酶标仪读取450nm吸光值。计算remaining activity%:(各个浓度组吸光值-空白孔吸光值)/(不处理组吸光值-空白孔吸光值)*100%。根据各个化合物的remaining activity%使用Graphpad软件计算IC50。
试验例4乙酰化微管蛋白高内涵分析试验
采用高内涵分析方法检测化合物对微管蛋白乙酰化水平的影响。
HCT116细胞按照每孔5000个细胞的密度接种到96孔透明底黑板(Corning,货号3340)中,于37℃,5%CO2培养箱中培养过夜后更换新培养基,每孔50ul。化合物分别使用DMSO逐级稀释成不同浓度后使用培养基配制成2x终浓度的工作液(阴性对照组使用等体积DMSO替代),取50ul化合物工作液加入到96孔板中,稀释成1x终浓度,于37℃,5%CO2培养箱中培养6小时。细胞在化合物处理6小时后,使用4%多聚甲醛固定,每孔200ul,室温孵育15分钟。细胞固定后使用0.1%(v/v)TritonX-100通透细胞,每孔200ul,室温孵育15分钟。细胞使用1%封闭试剂封闭,每孔100ul,于振荡器上300rpm,孵育30分钟。封闭后每孔加入50ul使用1%(w/v)封闭试剂稀释后的乙酰化微管蛋白抗体(Sigma-Aldrich,货号:T6793,稀释比例为1:2000),于4℃冰箱中孵育过夜。抗体孵育后使用0.05%(v/v)PBST洗板,每孔200ul,重复4次。使用1%(w/v)封闭试剂稀释羊抗鼠荧光二抗(Invitrogen,货号:F-2761)和DAPI抗体(Thermofisher,货号:62247)(羊抗鼠荧光二抗稀释比例为1:500,DAPI的稀释比例为1:2000),每孔加入50ul稀释后的二抗,室温避光,于振荡器上300rpm孵育120分钟。再次使用0.05%(v/v)PBST洗板,每孔200ul,重复4次。使用高内涵成像分析系统(GE,InCell Analyzer,型号:2200)获取数据,每孔扫描9个视野,FITC通道曝光时间设置为0.01s,DAPI通道曝光时间设置为0.02s。使用In cell analyzer workstation软件分析数据,获得每孔细胞灰度值和背景值。使用Excel对获得的数据进行后续的处理,首先将每孔细胞灰度值减去背景灰度值获得标准化后的细胞灰度值,再将各个浓度处理后获得的标准化细胞灰度值分别除以阴性对照(DMSO处理)的标准化细胞灰度值获得不同化合物处理之后乙酰化微管蛋白相对于阴性对照的倍数变化,并在GraphPad Prism软件中拟合和计算相对于log浓度的EC50。
试验例5乙酰化组蛋白H3高内涵分析试验
采用高内涵分析方法检测化合物对组蛋白H3乙酰化水平的影响。
HCT116细胞按照每孔5000个细胞的密度接种到96孔透明底黑板(Corning,货号3340)中,于37℃,5%CO2培养箱中培养过夜后更换新培养基,每孔50ul。化合物分别使用DMSO逐级稀释成不同浓度后使用培养基配制成2x终浓度的工作液(阴性对照组使用等体积DMSO替代),取50ul化合物工作液加入到96孔板中,稀释成1x终浓度,于37℃,5%CO2培养箱中培养24小时。细胞在化合物处理24小时后,使用预冷的无水甲醇固定细胞,每孔200ul,室温孵育15分钟。细胞固定后使用0.1%(v/v)TritonX-100通透细胞,每孔200ul,室温孵育15分钟。细胞使用1%封闭试剂封闭,每孔100ul,于振荡器上300rpm,孵育30分钟。封闭后每孔加入50ul使用1%(w/v)封闭试剂稀释后的乙酰化组蛋白H3抗体(Abcam,货号:ab47915,稀释比例为1:1000),于4℃冰箱中孵育过夜。抗体孵育后使用0.05%(v/v)PBST洗板,每孔200ul,重复4次。使用1%(w/v)封闭试剂稀释羊抗兔荧光二抗(Invitrogen,货号:A11034)和DAPI抗体(Thermofisher,货号:62247)(羊抗兔荧光二抗稀释比例为1:500,DAPI的稀释比例为1:2000),每孔加入50ul稀释后的二抗,室温避光,于振荡器上300rpm孵育120分钟。再次使用0.05%(v/v)PBST洗板,每孔200ul,重复4次。使用高内涵成像分析系统(GE,InCellAnalyzer,型号:2200)获取数据,每孔扫描9个视野,FITC通道曝光时间设置为0.01s,DAPI通道曝光时间设置为0.02s。使用In cell analyzer workstation软件分析数据,获得每孔细胞灰度值和背景值。使用Excel对获得的数据进行后续的处理,首先将每孔细胞灰度值减去背景灰度值获得标准化后的细胞灰度值,再将各个浓度处理后获得的标准化细胞灰度值分别除以阴性对照(DMSO处理)的标准化细胞灰度值获得不同化合物处理之后乙酰化微管蛋白相对于阴性对照的倍数变化,并在GraphPad Prism软件中拟合和计算相对于log浓度的EC50。
本发明化合物HDAC4酶学筛选试验、HDACIIa家族细胞水平酶活性检测结果如下:
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综上所述,本发明公开的式Ⅰ所示的新化合物,表现出了良好的去乙酰化酶抑制活性,为临床治疗与组蛋白去乙酰化酶活性异常相关的疾病提供了一种新的药用可能。
Claims (9)
1.式I所示的化合物:
其中,
X选自O或S;
R’选自C1~6烷基、5~10元芳杂环;其中烷基、芳杂环可进一步被m个R1取代;
m为1、2或3;
R1分别独自选自卤素、C1~6卤素烷基、-NRaRb、-ORa;
n为0;
Ra、Rb分别独自选自氢、C1~6烷基、5~10元芳环。
2.根据权利要求1所述的化合物,其特征在于:所示化合物为:
3.根据权利要求1所述的化合物,其特征在于:所示化合物为:
4.权利要求1~3任一项所述的化合物在制备HDAC抑制剂类药物中的用途。
5.根据权利要求4所述的用途,其特征在于:所述HDAC抑制剂类药物为由HDAC活性异常所导致的疾病的药物。
6.根据权利要求5所述的用途,其特征在于:所述由HDAC活性异常所导致的疾病的药物为由HDAC4、HDAC5、HDAC7、HDAC9活性异常所导致的疾病的药物。
7.根据权利要求5~6任一项所述的用途,其特征在于:所述疾病为细胞增殖疾病、炎症、神经变性疾病或病毒性疾病。
8.一种抑制组蛋白去乙酰化酶活性的药物组合物,其特征在于:它是以权利要求1~3任一项所述的化合物加上药学上可接受的辅料制备而成的制剂。
9.根据权利要求8所述的制剂,其特征在于:所述制剂为口服给药制剂、舌下给药制剂、颊给药制剂、透皮吸收制剂或注射制剂。
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