CN108794398A - 具有荧光的选择性组蛋白去乙酰化酶抑制剂及其制备方法和应用 - Google Patents
具有荧光的选择性组蛋白去乙酰化酶抑制剂及其制备方法和应用 Download PDFInfo
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- CN108794398A CN108794398A CN201710297000.6A CN201710297000A CN108794398A CN 108794398 A CN108794398 A CN 108794398A CN 201710297000 A CN201710297000 A CN 201710297000A CN 108794398 A CN108794398 A CN 108794398A
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Abstract
本发明公开了一种具有荧光的选择性组蛋白去乙酰化酶抑制剂及其制备方法和应用。所述的具有荧光的选择性组蛋白去乙酰化酶抑制剂，其结构通式为(I)或(II)。所述的式(I)或(II)结构化合物可用于制备检测组蛋白去乙酰化酶组织分布、细胞及组织成像，治疗或诊断与组蛋白去乙酰化酶功能异常相关的疾病的药物。
Description
技术领域
本发明涉及有机化合物合成与医药应用技术领域，特别涉及一种具有荧光的选择性组蛋白去乙酰化酶抑制剂及其制备方法和应用。
背景技术
组蛋白去乙酰化酶(HDACs)的命名来源于其早期被发现的生物学功能：使组蛋白核小体N末端赖氨酸残基的ε-氨基去乙酰化。去乙酰化的组蛋白带正电，与负电性的DNA结合更加紧密，阻碍了各种转录因子与DNA结合，从而抑制包括抑癌基因在内的各种基因转录(参见Wolffe,A.P.Science,1996,272,371)。随着HDACs生物学功能的深入研究，越来越多的非组蛋白被证实为HDACs的底物，如转录因子，细胞骨架蛋白，分子伴侣等(参见Glozak,M.A.,et al.Gene,2005,363,15)。正是由于HDACs具有如此复杂的功能，它的表达和活性失调会导致许多疾病发生，如：肿瘤，神经退行性疾病，病毒感染，炎症，疟疾和糖尿病等，其中肿瘤无疑是对人类生命健康威胁最为严重的疾病。研究表明，HDACs与肿瘤发生发展密切相关，如：抑制肿瘤细胞分化和凋亡，促进肿瘤细胞增殖，迁移和血管生成，增强肿瘤细胞对化疗药物的抵抗力等(参见Witt,O.,et al.Cancer Letter,2009,277,8)。
目前在人体中发现的HDACs家族有18个成员，根据其结构、功能和分布的不同可分为四类。其中，I类(HDAC1，2，3和8)，II类(IIa：HDAC4，5，7和9；IIb：HDAC6，10)，IV类(HDAC11)属于锌离子依赖性水解酶，而III类HDACs(SIRT 1-7)是NAD+依赖性的。其中锌离子依赖性HDACs(HDAC1-11)中数个亚型的过度表达或激活在多种癌症病例中都有发现且与预后不良密切相关(参见Witt,O.,et al.Cancer Letter,2009,277,8)。随着HDACs与癌症发生和发展关系的阐明，越来越多的天然和人工合成的HDACs抑制剂被用于癌症治疗和研究，并显示出了高效的体内外抗癌活性和多重的抗癌机制。目前，已有4个HDACs抑制剂SAHA、FK228、PXD101和LBH589被美国FDA批准上市用于癌症治疗，我国深圳微芯生物科技有限责任公司自主研发的Chidamide也于2015年初被CFDA批准上市。因此，HDACs抑制剂已成为抗肿瘤药物研发领域的热点。
在众多HDACs亚型当中，HDAC6由于其独特的生物学功能而引起了广泛关注。越来越多的研究表明，HDAC6选择性抑制剂有望开发得到肿瘤、神经退行性疾病(如阿尔茨海默病)、炎症和自身免疫性疾病的治疗药物(参见Kalin,J.H.et al.Journal of MedicinalChemistry,2013,56,6297)。目前，两个HDAC6选择性抑制剂ACY-1215和ACY-241分别处于临床II期和I期研究用于多发性骨髓瘤的治疗，但该两个化合物对HDAC6的选择性仅比HDAC1/2/3好10倍左右。此外，对于帕金森病等慢性神经退行性疾病，只有在病人表现出典型的症状之后才能够诊断出来，而此时大部分多巴胺神经细胞已经死亡，故没有治愈的可能了，因此，帕金森病的早期诊断对于该病的有效治疗至关重要。值得指出的是，HDAC6是蛋白聚集体(aggresome)的组成成分，而蛋白聚集体则是多种神经退行性疾病，如帕金森病(Parkinson’ s disease)和路易体痴呆(Dementia with Lewy body；DLB)等的重要标志物(参见Kawaguchi,Y.et al.Cell,2003,115,727)，因此，HDAC6选择性分子探针还有望用于神经退行性疾的诊断。最近，一个具有荧光的HDACs抑制剂4MS被报道(参见Fleming,C.L.etal.Chemical Communications,2015,51,7827)，但该化合物不具有HDAC6亚型选择性。
发明内容
本发明针对现有技术的不足，提供一种具有荧光的选择性HDACs抑制剂及其制备方法和应用。
本发明的技术方案如下：
1.具有荧光的选择性组蛋白去乙酰化酶抑制剂
本发明的具有荧光的选择性组蛋白去乙酰化酶抑制剂，具有如下结构通式(I)或(II)所示的结构：
其中，n是0-10；R1是氢或烷基；R2是氢或烷基；
根据本发明优选的，结构通式(I)或(II)中，n是1或2；R1是氢或甲基或乙基；R2是氢或甲基或乙基；
进一步优选的，具有荧光的选择性HDACs抑制剂，其结构为下列之一：
2.具有荧光的选择性组蛋白去乙酰化酶抑制剂的制备方法
本发明的具有荧光的选择性组蛋白去乙酰化酶抑制剂的制备包括以下步骤：起始原料1和2在乙醇中通过微波反应得到中间体化合物3；在4,5-双二苯基膦-9,9-二甲基氧杂蒽、双(二亚苄基丙酮)钯和碳酸铯存在条件下，中间体化合物3与吗啉或各种胺在甲苯中反应分别得到中间体化合物4或4’；中间体化合物4或4’水解分别得到羧酸中间体化合物5或5’；最后，中间体化合物5或5’分别与羟胺缩合得到目标化合物(I)或(II)。
式(I)化合物合成路线如下：
其中，n同通式(I)或(II)中所述；
上述合成路线中的试剂及反应条件：
a：三乙胺，乙醇，微波加热，100℃；
b：吗啉，4,5-双二苯基膦-9,9-二甲基氧杂蒽，双(二亚苄基丙酮)钯，碳酸铯，甲苯，65℃；
c：氢氧化锂，水/四氢呋喃；
d：草酰氯，N,N-二甲基甲酰胺，二氯甲烷，盐酸羟胺，三乙胺，水/四氢呋喃。
式(II)化合物合成路线如下：
其中，n、R1、R2同通式(I)或(II)中所述；
上述合成路线中的试剂及反应条件：
a：三乙胺，乙醇，微波加热，100℃；
b：各种胺，4,5-双二苯基膦-9,9-二甲基氧杂蒽，双(二亚苄基丙酮)钯，碳酸铯，甲苯，65℃；
c：氢氧化锂，水/四氢呋喃；
d：草酰氯，N,N-二甲基甲酰胺，二氯甲烷，盐酸羟胺，三乙胺，水/四氢呋喃。
所述化合物的具体操作步骤在实施例中加以详细说明。
3.具有荧光的选择性组蛋白去乙酰化酶抑制剂的应用
体外HDACs抑酶活性评价结果表明，已报道的具有荧光的HDACs抑制剂4MS对classI亚族的HDAC1、HDAC2、HDAC3和class IIb亚族的HDAC6无选择性，而本发明的具有荧光的化合物6b对class IIb亚族的HDAC6显示了很强的亚型选择性，本发明的具有荧光的化合物6a对class I亚族的HDAC1、HDAC2、HDAC3，以及class IIb亚族的HDAC6均具有很强的抑制活性。
蛋白免疫印记(Western blot)评价结果表明，已报道的具有荧光的HDACs抑制剂4MS和本发明的具有荧光的化合物6a都能上调细胞内乙酰化组蛋白H4(Ac-HH4，class I亚族HDACs的底物)和乙酰化微管蛋白(Ac-Tub，HDAC6的底物)的水平，而本发明的具有荧光的化合物6b只能上调乙酰化微管蛋白的水平，对乙酰化组蛋白H4无影响。
免疫荧光染色(Immunofluorescence staining)评价结果表明，本发明的具有荧光的化合物6b能与蛋白酶体抑制剂MG-132处理的A549细胞内HDAC6共定位，而已报道的具有荧光的HDACs抑制剂4MS和本发明的具有荧光的化合物6a未观察到这种共定位现象。
以上结果表明，化合物6a和已报道的化合物4MS都是具有荧光的广谱HDACs抑制剂，而化合物6b是具有荧光的HDAC6选择性抑制剂。
因此，本发明提供具有荧光的HDACs抑制剂在制备治疗或诊断与HDACs功能异常相关疾病的药物中的应用，所述的与HDACs功能异常相关疾病包括：肿瘤、神经退行性疾病、炎症和自身免疫性疾病等；本发明还提供具有荧光的HDACs抑制剂在制备检测HDACs组织分布、细胞及组织成像的药物中的应用。
附图说明
图1是实施例3化合物免疫印迹试验结果图；
图2是实施例4化合物免疫荧光染色试验结果图。
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。
实施例1.化合物6a和6b的合成
合成路线：
试剂和条件：a)三乙胺，乙醇，微波加热100℃；b)吗啉，5-双二苯基膦-9,9-二甲基氧杂蒽，双(二亚苄基丙酮)钯，碳酸铯，甲苯，65℃；c)氢氧化锂，水/四氢呋喃；d)草酰氯，N,N-二甲基甲酰胺，二氯甲烷，然后盐酸羟胺，三乙胺，水/四氢呋喃。
具体合成方法和步骤如下：
中间体3a：4-((6-溴-1,3-二氧-1H-苯并[de]异喹啉-2(3H)-基)甲基)苯甲酸甲酯
起始原料6-溴-1H,3H-苯并[de]异苯并吡喃-1,3-二酮(1,1.35g,4.87mmol)、4-(氨甲基)苯甲酸甲酯盐酸盐(2a,4-982mg,4.87mmol)和三乙胺(493mg,4.87mmol)溶于20mL乙醇，微波加热至100℃反应45分钟。反应液用100mL水稀释后，用乙酸乙酯萃取三次。有机相合并后用0.1M盐酸、饱和碳酸氢钠和饱和食盐水洗涤，无水硫酸钠干燥后蒸干有机溶剂得到黄色固体中间体3a(1.00g,2.36mmol,产率48％)。1H NMR(DMSO-d6)δ8.58-8.62(m,2H),8.37(d,J＝8.0Hz,1H),8.25(d,J＝8.0Hz,1H),8.02(t,J＝7.6Hz,1H),7.89(d,J＝8.0Hz,2H),7.49(d,J＝8.0Hz,2H),5.31(s,2H),3.82(s,3H)。
中间体3b：4-(2-(6-溴-1,3-二氧-1H-苯并[de]异喹啉-2(3H)-基)乙基)苯甲酸甲酯
中间体3b的合成方法与3a一致。所不同的是起始原料为6-溴-1H,3H-苯并[de]异苯并吡喃-1,3-二酮(1)和4-(2-氨乙基)苯甲酸甲酯盐酸盐(2b)反应，得黄色固体中间体3b。1H NMR(DMSO-d6)δ8.57-8.60(m,2H),8.35(d,J＝7.6Hz,1H),8.24(d,J＝8.0Hz,1H),8.02(t,J＝8.4Hz,1H),7.89(d,J＝8.4Hz,2H),7.43(d,J＝8.0Hz,2H),4.27-4.31(m,2H),3.84(s,3H),3.01-3.06(m,2H)。
中间体4a：4-((6-吗啉基-1,3-二氧-1H-苯并[de]异喹啉-2(3H)-基)甲基)苯甲酸甲酯
在氮气保护下，向中间体3a(1.00g,2.36mmol)和吗啉(617mg,7.08mmol)的10mL甲苯溶液中加入,5-双二苯基膦-9,9-二甲基氧杂蒽(54.6mg,94.4μmol)，双(二亚苄基丙酮)钯(54.3mg,94.4μmol)和碳酸铯(2.31g,7.09mmol)。65℃搅拌反应12小时后，过滤去掉沉淀，蒸干溶剂，粗产品经硅胶柱层析得到黄色固体中间体4a(500mg,1.16mmol,产率49％)。1H NMR(CDCl3)δ8.55-8.63(m,2H),8.45(d,J＝8.4Hz,1H),7.97(d,J＝8.4Hz,2H),7.70-7.74(m,1H),7.57(d,J＝8.8Hz,2H),7.25(d,J＝8.4Hz,1H),5.47(s,2H),4.02(t,J＝4.4Hz,4H),3.89(s,3H),3.28(t,J＝4.4Hz,4H)。
中间体4b：4-(2-(6-吗啉基-1,3-二氧-1H-苯并[de]异喹啉-2(3H)-基)乙基)苯甲酸甲酯
中间体4b的合成方法与4a一致。1H NMR(CDCl3)δ8.53-8.61(m,2H),8.43-8.46(m,1H),7.98(d,J＝8.0Hz,2H),7.72-7.75(m,1H),7.43(d,J＝8.4Hz,2H),7.25(d,J＝7.6Hz,1H),4.39-4.44(m,2H),4.04(t,J＝4.4Hz,4H),3.91(s,3H),3.29(t,J＝4.4Hz,4H),3.07-3.11(m,2H)。
中间体5a：4-((6-吗啉基-1,3-二氧-1H-苯并[de]异喹啉-2(3H)-基)甲基)苯甲酸
将中间体4a(500mg,1.16mmol)溶于5mL水和5mL四氢呋喃的混合溶剂，并向其中加入一水合氢氧化锂(486mg,11.6mmol)。室温搅拌反应12小时后，蒸除四氢呋喃，然后用2M盐酸调节pH至3。水相用二氯甲烷萃取，有机相合并后用饱和食盐水洗涤，无水硫酸钠干燥，蒸干得到黄色固体中间体5a(470mg,1.13mmol,产率97％)。1H NMR(CDCl3)δ8.55-8.63(m,2H),8.45(d,J＝8.4Hz,1H),8.02(d,J＝8.4Hz,2H),7.70-7.75(m,1H),7.60(d,J＝8.4Hz,2H),7.25(d,J＝8.4Hz,1H),5.44(s,2H),4.03(t,J＝4.4Hz,4H),3.28(t,J＝4.4Hz,4H)。
中间体5b：4-(2-(6-吗啉基-1,3-二氧-1H-苯并[de]异喹啉-2(3H)-基)乙基)苯甲酸
中间体5b的合成方法与5a一致。1H NMR(CDCl3)δ8.54-8.62(m,2H),8.44-8.47(m,1H),8.03(d,J＝8.0Hz,2H),7.71-7.76(m,1H),7.46(d,J＝8.4Hz,2H),7.25(d,J＝6.4Hz,1H),4.41-4.45(m,2H),4.03(t,J＝4.4Hz,4H),3.28-3.34(m,4H),3.09-3.14(m,2H)。
目标化合物6a：N-羟基-4-((6-吗啉基-1,3-二氧-1H-苯并[de]异喹啉-2(3H)-基)甲基)苯甲酰胺
向中间体5a(470mg,1.13mmol)的10mL二氯甲烷溶液中，加入草酰氯(301mg,2.37mmol)和N,N-二甲基甲酰胺(100μL)。室温反应0.5小时后，将上述反应液加入盐酸羟胺(314mg,4.52mmol)和三乙胺(686mg,6.78mmol)的四氢呋喃/水溶液中。室温反应1小时后，蒸除二氯甲烷和四氢呋喃，向残留物中加入适量水并用二氯甲烷萃取。有机相合并后用饱和食盐水洗涤，无水硫酸钠干燥，蒸干得到黄色固体目标化合物6a(100mg,232μmol,产率21％)。1H NMR(DMSO-d6)δ11.16(s,1H),8.99(s,1H),8.50-8.55(m,2H),8.44(d,J＝8.4Hz,1H),7.84(t,J＝8.8Hz,1H),7.67(d,J＝8.0Hz,2H),7.38(d,J＝8.4Hz,3H),5.27(s,2H),3.92(s,4H),3.24(s,4H)。HRMS(AP-ESI)m/z calcd for C24H22N3O5[M+H]+432.1559,found432.1567
目标化合物6b：N-羟基-4-(2-(6-吗啉基-1,3-二氧-1H-苯并[de]异喹啉-2(3H)-基)乙基)苯甲酰胺
目标化合物6b的合成方法与6a一致。1H NMR(DMSO-d6)δ11.16(s,1H),8.98(s,1H),8.48-8.53(m,2H),8.42(d,J＝8.0Hz,1H),7.80-7.85(m,1H),7.68(d,J＝8.0Hz,2H),7.33-7.38(m,3H),4.24-4.29(m,2H),3.91(t,J＝4.4Hz,4H),3.24(br.s,4H),2.95-3.00(m,2H)。HRMS(AP-ESI)m/z calcd for C25H24N3O5[M+H]+446.1716,found 446.1736。
实施例2.目标化合物体外HDACs抑制活性评价实验
参照文献[Duan,W.；Li,J.；Inks,E.S.；Chou,C.J.；Jia,Y.；Chu,X.；Li,X.；Xu,W.*；Zhang,Y.*Design,Synthesis and Antitumor Evaluation of Novel HistoneDeacetylase(HDAC)InhibitorsEquipped with Phenylsulfonylfuroxan Module asNitric Oxide(NO)Donor.J.Med.Chem.2015,58(10),4325-4338.]相关方法，测试已报道的HDACs抑制剂4MS和本发明的化合物6a、6b的体外HDACs抑制活性。
试验结果(表1)表明，本发明的化合物6a和已报道的HDACs抑制剂4MS对class I亚族的HDAC1、HDAC2、HDAC3和class IIb亚族的HDAC6均有很强的抑制活性，无亚型选择性；而本发明的化合物6b对class IIb亚族的HDAC6显示了很强的亚型选择性。
表1.化合物体外HDACs抑制活性和亚型选择性评价结果a
a数值以三次独立重复试验平均值+标准误差的形式来表示。
实施例3.目标化合物蛋白免疫印记(Western blot)评价实验
用Western blot试验评价已报道的HDACs抑制剂4MS和本发明的化合物6a、6b在细胞内的HDACs抑制活性。
试验原理：class I亚族的HDAC1、HDAC2和HDAC3能使乙酰化组蛋白H4(Ac-HH4)去乙酰化，从而降低细胞内Ac-HH4的蛋白水平；class IIb亚族的HDAC6能使乙酰化微管蛋白(Ac-Tub)去乙酰化，从而降低细胞内Ac-Tub的蛋白水平。因此，通过Western blot试验测定经化合物处理后细胞内的Ac-HH4和Ac-Tub蛋白水平，就可以评价化合物对细胞内HDACs的抑制作用。
试验材料和方法：用终浓度为500nM的4MS、6a和6b分别处理人非小细胞肺癌A549细胞后收集细胞，用RIPA缓冲液裂解细胞，高速离心后吸取上清得蛋白样品。蛋白样品定量后，加入Laemmli缓冲液和β-巯基乙醇，100℃煮沸后对各样品进行SDS-PAGE凝胶电泳。之后将蛋白转移到PVDF膜，用5％的脱脂牛奶进行封闭，然后依次用相应的一抗和二抗孵育，最后利用增强化学发光法(ECL)进行显影。
试验结果(图1)：与对照组(Ctrl)相比，已报道的HDACs抑制剂4MS和本发明的化合物6a都能上调细胞内Ac-HH4(class I亚族HDACs的底物)和Ac-Tub(HDAC6的底物)的水平，而本发明的化合物6b只能上调Ac-Tub的蛋白水平，对Ac-HH4无影响。这进一步验证了表1的体外HDACs抑制活性结果，即本发明的化合物6a是广谱HDACs抑制剂，6b是HDAC6亚型选择性抑制剂。
实施例4.目标化合物免疫荧光染色(Immunofluorescence staining)评价试验
用Immunofluorescence staining试验评价已报道的具有荧光的HDACs抑制剂4MS和本发明的具有荧光的HDACs抑制剂6a、6b在细胞内的成像情况。由于化合物6b具有很强的HDAC6选择性，我们重点考察该化合物能否对细胞内的HDAC6进行标记成像，从而用于HDAC6相关疾病的诊断和治疗。
试验原理：蛋白酶体功能缺陷或被抑制会使其水解清除错误折叠蛋白的能力降低，从而导致错误折叠蛋白形成蛋白聚集体(aggresome)，它是多种神经退行性疾病，如帕金森病(Parkinson’s disease；PD)和路易体痴呆(Dementia with Lewy body；DLB)的重要标志物。HDAC6是蛋白聚集体的组成成分，因此可以用HDAC6特异性抗体对aggresome进行标记成像。如果具有荧光的HDACs抑制剂4MS、6a和6b能与细胞内的HDAC6特异性结合，则可与抗体标记的HDAC6形成共定位(co-localization)，从而实现对aggresome的标记成像。
试验材料和方法：A549细胞被5μM蛋白酶体抑制剂MG-132处理24小时后用多聚甲醛固定，然后分别用HDAC6特异性一抗孵育，再用相应荧光二抗孵育，之后用2μM具有荧光的HDACs抑制剂孵育，封片后用荧光共聚焦显微镜观察成像。
试验结果(图2)：图2A结果显示HDAC6(红色荧光)在细胞质中分布较均匀，表明A549经二甲基亚砜(dmso)处理后无aggresome形成，具有荧光的HDACs抑制剂4MS、6a和6b(绿色荧光)在细胞内成像无明显区别；图2B结果显示HDAC6(红色荧光)在细胞核周围形成圆形亮点(图中白框所示)，表明A549经蛋白酶体抑制剂MG-132处理后形成aggresome，值得注意的是，本发明的具有荧光的HDAC6选择性抑制剂6b(绿色荧光)能与HDAC6(红色荧光)共定位，而具有荧光的广谱HDACs抑制剂4MS和6a则未观察到这种共定位现象。上述结果表明本发明的具有荧光的HDAC6选择性抑制剂6b可用于细胞内HDAC6的标记成像。
Claims (7)
1.具有荧光的选择性组蛋白去乙酰化酶抑制剂，其特征在于，具有如下结构通式(I)或(II)所示的结构：
其中，n是0-10；R1是氢或烷基；R2是氢或烷基。
2.如权利要求1所述的具有荧光的选择性组蛋白去乙酰化酶抑制剂，其特征在于结构通式(I)或(II)中，n是1或2；R1是氢或甲基或乙基；R2是氢或甲基或乙基。
3.如权利要求1或2所述的具有荧光的选择性组蛋白去乙酰化酶抑制剂，其特征在于是下述化合物之一：
4.如权利要求1或2所述具有荧光的选择性组蛋白去乙酰化酶抑制剂的制备方法，包括以下步骤：起始原料1和2在乙醇中通过微波反应得到中间体化合物3；在4,5-双二苯基膦-9,9-二甲基氧杂蒽、双(二亚苄基丙酮)钯和碳酸铯存在条件下，中间体化合物3与吗啉或各种胺在甲苯中反应分别得到中间体化合物4或4’；中间体化合物4或4’水解分别得到羧酸中间体化合物5或5’；最后，中间体化合物5或5’分别与羟胺缩合得到目标化合物(I)或(II)；
式(I)化合物合成路线如下：
其中，n同权利要求1或2中通式(I)或(II)中所述；
上述合成路线中的试剂及反应条件：
a：三乙胺，乙醇，微波加热，100℃；
b：吗啉，4,5-双二苯基膦-9,9-二甲基氧杂蒽，双(二亚苄基丙酮)钯，碳酸铯，甲苯，65℃；
c：氢氧化锂，水/四氢呋喃；
d：草酰氯，N,N-二甲基甲酰胺，二氯甲烷，盐酸羟胺，三乙胺，水/四氢呋喃；
式(II)化合物合成路线如下：
其中，n、R1、R2同权利要求1或2中通式(I)或(II)中所述；
上述合成路线中的试剂及反应条件：
a：三乙胺，乙醇，微波加热，100℃；
b：各种胺，4,5-双二苯基膦-9,9-二甲基氧杂蒽，双(二亚苄基丙酮)钯，碳酸铯，甲苯，65℃；
c：氢氧化锂，水/四氢呋喃；
d：草酰氯，N,N-二甲基甲酰胺，二氯甲烷，盐酸羟胺，三乙胺，水/四氢呋喃。
5.如权利要求1-3任一所述的化合物在制备治疗或诊断与组蛋白去乙酰化酶功能异常相关疾病的药物中的应用，所述的与组蛋白去乙酰化酶功能异常相关疾病为：肿瘤、神经退行性疾病、炎症和自身免疫性疾病。
6.一种治疗或诊断与组蛋白去乙酰化酶功能异常相关疾病的药物组合物，包含权利要求1-3任一所述的化合物和一种或多种药学上可接受的载体或赋形剂。
7.如权利要求1-3任一所述的化合物在制备检测组蛋白去乙酰化酶组织分布、细胞及组织成像药物中的应用。
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