CN114539098A - 一种双功能hdac6抑制剂、合成方法及应用 - Google Patents
一种双功能hdac6抑制剂、合成方法及应用 Download PDFInfo
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- CN114539098A CN114539098A CN202210180109.2A CN202210180109A CN114539098A CN 114539098 A CN114539098 A CN 114539098A CN 202210180109 A CN202210180109 A CN 202210180109A CN 114539098 A CN114539098 A CN 114539098A
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Abstract
本发明属于医药学技术领域，公开了一种双功能HDAC6抑制剂、合成方法及应用。双功能HDAC6抑制剂对HDAC6显示出了强的选择性，且能够有效抑制HSP90的活性，抑制多种肿瘤细胞的增殖，对成纤维细胞的增值展现出了较好的抑制活性。本发明同时还提供了一种含有HDAC6抑制剂的吉西他滨前药，能够有效抑制多种癌细胞的增殖，活性强于吉西他滨本身。本发明每个化合物中所有的碳原子、氢原子包含了所有的同位素，例如C12，C14，H1，H2，H3。保护的适应症包括癌症，例如肺癌、乳腺癌、肝癌、软巢癌、前列腺癌、胰腺癌。还包括器官纤维化，如肺纤维化、心脏纤维化、肝纤维化、囊性纤维化和肾纤维化。
Description
技术领域
本发明属于医药学技术领域，尤其涉及一种双功能HDAC6抑制剂、合成方法及应用。
背景技术
目前，表观遗传研究正成为人类攻克肿瘤的希望。表观遗传改变多发生在肿瘤发生的早期，此时肿瘤细胞尚未对人体造成实质性伤害，此时进行干预，很有可能将其扼杀在摇篮里。另外，相比遗传修饰几乎是不可逆转而言，表观遗传修饰异常可以逆转，是肿瘤细胞恢复为正常状态。因而，表观遗传研究具有更为广阔的应用前景。组蛋白修饰是表观遗传修饰的一种重要方式，人类绝大多数肿瘤细胞都存在组蛋白修饰异常，这种异常能引起抑癌基因沉默致使肿瘤形成。组蛋白去乙酰化酶(Histone deacetylase,HDAC)是一个包含多个成员的酶家族，目前已知有18种亚型，按其种系及与酵母同源性不同分为以下四类：与酵母Rpd3，HoS1，HoSt2同源的Ⅰ类，包括HDAC1、HDAC2、HDAC3、HDAC8；与酵母Hda1，HoS3同源的Ⅱa类，包括HDAC4、HDAC5、HDAC7、HDAC9，Ⅱb类包括HDAC6、HDAC10；与酵母Sir2同源的Ⅲ类，包括SIRT1～SIRT7；与Ⅰ和Ⅱ类HDAC都有部分同源性，但其种系不同的Ⅳ类，包括HDAC11。其中Ⅰ、Ⅱ、Ⅳ类为经典的Zn2+依赖的HDACs，而第Ⅲ类属于Sirtuin家族，为NAD+依赖的HDACs。研究表明，第Ⅰ和Ⅱ类HDACs能够抑制肿瘤细胞分化和凋亡、促进肿瘤细胞增殖等，其与肿瘤的发生、发展密切相关，以HDACs为靶点的抑制剂研究已经成为抗肿瘤药物研究的热点之一。
组蛋白的共价修饰与基因的表达调控密切关联，其末端会发生多种共价修饰，主要包括磷酸化、乙酰化、甲基化、腺苷酸化、泛素化修饰等。在正常生理状态下，组蛋白乙酰化与去乙酰化的动态平衡是由组蛋白乙酰化酶(HAT)与组蛋白去乙酰化酶(HDAC)调控。HDAC与多种疾病的发生和发展关系密切，已成为抗肿瘤药物、神经系统疾病等药物研究有效的靶点之一。其中，HDAC6具有独特的结构及底物特异性，它的表达与功能的改变与癌症，神经退行性疾病，炎症、自身免疫应答等诸多疾病的病理生理进程密切相关。HDAC6抑制剂已经在癌症、神经退行性疾病、免疫性疾病以及器官纤维化等治疗方面极具前景。
但无论是癌症还是器官纤维化，都是机制极其复杂的疾病，仅通过单靶点药物治疗，很难达到持久的疗效，且易产生耐药性。而双靶点药物能够抑制疾病发生发展的多条通路，能够有效解决药效和耐药性的问题。此外，多项实验证明，HDAC6抑制剂与其它靶点的抑制剂联合使用，能够发挥协同作用，如与HSP90抑制剂联用，能够展现出更强的抗肿瘤活性。这为双靶点HDAC6抑制剂的设计提供了理论基础。
本发明设计并合成了两个系列的双靶点HDAC6抑制，分别是HSP90与HDAC6双靶点抑制剂以及含有HDAC6抑制剂的吉西他滨前药。这两个系列化合物对HDAC6展现出了强的选择性，且能够抑制双靶点，能够有效抑制多种肿瘤细胞的增殖，且对成纤维细胞也具有较好的增殖抑制活性。这为治疗癌症和器官纤维化提供了新的潜在方法。
发明内容
为克服相关技术中存在的问题，本发明公开实施例提供了一种双功能HDAC6抑制剂、合成方法及应用。
所述技术方案如下：一种双功能HDAC6抑制剂，所述双功能HDAC6抑制剂的分子结构通式为：
所述双功能HDAC6抑制剂对Hsp90抑制活性剂量为98nM～821nM，对HDAC6的抑制活性剂量为15.7nM～140.8nM。
进一步，R为下列分子式中的一种：
进一步，所述双功能HDAC6抑制剂的分子结构通式中碳原子包括12C以及14C，氢原子包括1H、2H以及3H。
本发明另一目的在于提供一种所述双功能HDAC6抑制剂的合成方法所述双功能HDAC6抑制剂合成路线包括：
进一步，所述双功能HDAC6抑制剂的合成方法具体包括：
将化合物2,4二羟基苯甲酸甲酯、溴代烷、三氯化铝溶于装有100毫升无水二氯甲烷的玻璃耐压瓶中，在氩气保护条件下50℃搅拌反应。反应2小时后，再补加溴代烷；继续50℃搅拌反应12小时后，将反应液冰浴冷却至0℃，加入2M氢氧化钠中和至pH为7，乙酸乙酯(EA)萃取3次，饱和氯化钠水溶液洗涤3次，无水硫酸钠干燥。真空浓缩溶剂，柱层析纯化粗产物，得到第二中间体；
将第二中间体，溶于20毫升无水DMF，加入无水碳酸钾，氩气保护状态下，加入溴苄，120℃搅拌反应12小时；反应结束后，冷却至室温，加水，乙酸乙酯萃取，饱和氯化钠洗涤3次，无水硫酸钠干燥；干燥完成后，真空浓缩溶剂，柱层析纯化粗产物，得到第三中间体；
将第三中间体溶于四氢呋喃(THF,40毫升)，加入20毫升1M氢氧化锂水溶液和20毫升水，50℃搅拌反应12h。反应结束后，冷却至室温，加入1M盐酸水溶液中和至PH≈2，乙酸乙酯萃取3次，饱和氯化钠洗涤3次，无水硫酸钠干燥。干燥完成后，真空浓缩溶剂，得到第四中间体；
将第四中间体，溶于无水二氯甲烷30毫升，加入1-羟基苯并三唑，第五中间体，冰浴冷却至0℃后，加入三乙胺，冰浴搅拌30分钟后转至室温，反应12小时；反应结束后，真空浓缩溶剂，柱层析纯化粗产物，得到第六中间体；
将第六中间体，溶于无水二氯甲烷20毫升，冷却至-78℃后，加入1M三氯化硼二氯甲烷溶液，-78℃反应1小时，转入室温反应2小时；反应结束后，真空浓缩蒸干溶剂，加入甲醇洗涤，真空浓缩蒸干甲醇，反复3次，柱层析纯化粗产物(二氯甲烷:甲醇＝40:1)，得到第七中间体；
将第七中间体，加入1M羟胺钾甲醇溶液20毫升，室温搅拌，反应3小时，反应结束后，真空浓缩蒸干溶剂，加水，加入1M盐酸中和至PH≈2，过滤得到粗产物，HPLC纯化，得到终产物。
本发明另一目的在于提供一种利用所述双功能HDAC6抑制剂在制备用于治疗肺癌、乳腺癌、肝癌、软巢癌、前列腺癌、胰腺癌药物、肺纤维化、心脏纤维化、肝纤维化、囊性纤维化和肾纤维化药物中的应用。
本发明另一目的在于提供一种利用所述双功能HDAC6抑制剂制备的吉西他滨前药，所述吉西他滨前药结构式为：
所述吉西他滨前药给药剂量为5毫克/千克和10毫克/千克。
本发明的另一目的在于提供一种利用所述双功能HDAC6抑制剂在制备用于治疗肺癌、乳腺癌、肝癌、软巢癌、前列腺癌、胰腺癌药物、肺纤维化、心脏纤维化、肝纤维化、囊性纤维化和肾纤维化药物中的应用。
结合上述的所有技术方案，本发明所具备的优点及积极效果为：
本发明提供的第一个系列化合物对HDAC6显示出了强的选择性，且能够有效抑制HSP90蛋白的活性，能够有效抑制多种肿瘤细胞的增殖，且对器官纤维化展现出了极好的抑制活性。
本发明提供的第二个系列中的吉西他滨前药，能够有效抑制多种癌细胞的增殖，活性强于吉西他滨。
本发明每个化合物中所有的碳原子、氢原子包含了所有的同位素，例如12C，14C，1H，2H，3H。保护的适应症包括癌症，例如肺癌、乳腺癌、肝癌、软巢癌、前列腺癌、胰腺癌等等。还包括器官纤维化，其中包括肺纤维化、心脏纤维化、肝纤维化、囊性纤维化和肾纤维化。
当理解的是，以上的一般描述和后文的细节描述仅是示例性和解释性的，并不能限制本发明的公开。
附图说明
此处的附图被并入说明书中并构成本说明书的一部分，示出了符合本公开的实施例，并与说明书一起用于解释本公开的原理。
图1是本发明实施例提供的双功能HDAC6抑制剂制备方法流程图。
图2是本发明实施例提供的吉西他滨前药GZ在5毫克/千克和10毫克/千克两个给药剂量下，都能够有效抑制4T1肿瘤的增殖示意图。
具体实施方式
为使本发明的上述目的、特征和优点能够更加明显易懂，下面结合附图对本发明的具体实施方式做详细的说明。在下面的描述中阐述了很多具体细节以便于充分理解本发明。但是本发明能够以很多不同于在此描述的其他方式来实施，本领域技术人员可以在不违背本发明内涵的情况下做类似改进，因此本发明不受下面公开的具体实施的限制。
本发明提供的双功能HDAC6抑制剂中，双功能是指具备HDAC6与HSP90双功能，分子结构通式为：
在本发明一优选实施例中，R为下列分子式中的一种：
每个化合物中所有的碳原子、氢原子包含了所有的同位素，例如12C，14C，1H，2H，3H。保护的适应症包括癌症，例如肺癌、乳腺癌、肝癌、软巢癌、前列腺癌、胰腺癌等等。还包括器官纤维化，其中包括肺纤维化、心脏纤维化、肝纤维化、囊性纤维化和肾纤维化。
在本发明一优选实施例中提供一种含有HDAC6抑制剂的吉西他滨前药，结构式为：
每个化合物中所有的碳原子、氢原子包含了所有的同位素，例如12C，14C，1H，2H，3H。保护的适应症包括癌症，例如肺癌、乳腺癌、肝癌、软巢癌、前列腺癌、胰腺癌等等。还包括器官纤维化，其中包括肺纤维化、心脏纤维化、肝纤维化、囊性纤维化和肾纤维化。
下面结合具体实施例对本发明的技术方案作进一步描述。
实施例1
本发明提供的合成路线1：
如图1所示，双功能HDAC6抑制剂制备方法的步骤如下：
S101，将化合物2,4二羟基苯甲酸甲酯(化合物1，3.87克,23毫摩尔,1倍量)、溴代烷(2.0倍量)、三氯化铝(6.1克,46毫摩尔,2.0倍量)溶于装有100毫升无水二氯甲烷(DCM)的玻璃耐压瓶中，在氩气保护条件下50℃搅拌反应。反应2小时后，再补加溴代烷(46毫摩尔,2倍量)。继续50℃搅拌反应12小时后，将反应液冰浴冷却至0℃，加入2M氢氧化钠(NaOH)中和至pH≈7，乙酸乙酯(EA)萃取3次，饱和氯化钠水溶液洗涤3次，无水硫酸钠干燥。真空浓缩溶剂，柱层析纯化粗产物(石油醚:乙酸乙酯＝10:1)，得到第二中间体(化合物2)(黄色固体，产率72％)。
S102，将第二中间体(化合物2)(9.5毫摩尔,1倍量)，溶于20毫升无水DMF，加入无水碳酸钾(3.94克,28.5毫摩尔,3倍量)，氩气保护状态下，加入溴苄(2.82毫升,23.8毫摩尔,2.5倍量)，120℃搅拌反应12小时。反应结束后，冷却至室温，加水，乙酸乙酯萃取，饱和氯化钠洗涤3次，无水硫酸钠干燥。干燥完成后，真空浓缩溶剂，柱层析纯化粗产物(石油醚:乙酸乙酯＝20:1)，得到第三中间体(化合物4)(白色固体，产率96％)。
S103，将第三中间体(化合物3)(2克,1.0倍量)溶于四氢呋喃(THF,40毫升)，加入20毫升1M氢氧化锂水溶液和20毫升水，50℃搅拌反应12h。反应结束后，冷却至室温，加入1M盐酸水溶液中和至pH≈2，乙酸乙酯萃取3次，饱和氯化钠洗涤3次，无水硫酸钠干燥。干燥完成后，真空浓缩溶剂，得到第四中间体(化合物4)(白色固体，产率99％)。
S104，将第四中间体(化合物4)(1.6毫摩尔,1.0倍量)，溶于无水二氯甲烷30毫升，加入1-羟基苯并三唑(HOBT,0.86克,6.3毫摩尔,1.5倍量)，(1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐)(EDCI,1.63克,8.5毫摩尔,2倍量)，第五中间体(化合物5)(4-甲氨基甲基苯甲酸甲酯,1,52克,8.5毫摩尔,2倍量)，冰浴冷却至0℃后，加入三乙胺(TEA,1.18毫升,8.5毫摩尔,2倍量)，冰浴搅拌30分钟后转至室温，反应12小时。反应结束后，真空浓缩溶剂，柱层析纯化粗产物(石油醚:乙酸乙酯＝5:1)，得到第六中间体(化合物6)(白色固体，产率87％)。
S105，将第六中间体(化合物6)(2.7毫摩尔,1倍量)，溶于无水二氯甲烷20毫升，冷却至-78℃后，加入1M三氯化硼二氯甲烷溶液(7.2毫升,8.1毫摩尔,3倍量)，-78℃反应1小时，转入室温反应2小时。反应结束后，真空浓缩蒸干溶剂，加入甲醇洗涤，真空浓缩蒸干甲醇，反复3次，柱层析纯化粗产物(二氯甲烷:甲醇＝40:1)，得到第七中间体(化合物7)(无色固体，产率74％)。
S106，将第七中间体(化合物7)(0.5克,1倍量)，加入1M羟胺钾甲醇溶液20毫升，室温搅拌，反应3小时，反应结束后，真空浓缩蒸干溶剂，加水，加入1M盐酸中和至pH≈2，过滤得到粗产物，HPLC(MeOH:H2O＝60:40)纯化，得到终产物(化合物8)(橙色固体，产率42％)。
实施例2
将化合物9(12克,52毫摩尔)溶于无水甲醇(MeOH,80毫升)中，缓慢滴加浓硫酸(12M,1.2毫升)，90℃回流，反应16小时。反应结束后，真空浓缩蒸干溶剂，加水，乙酸乙酯萃取，氯化钠(NaCl)洗涤3次，无水硫酸钠干燥。干燥完成后，真空浓缩溶剂，柱层析纯化粗产物(石油醚:乙酸乙酯＝4:1)，得到中间体10(白色固体，产率72％)。
化合物10反应生成中间体11步骤同第二中间体反应生成第三中间体(实施例1)。
将化合物11(0.5克,1.2毫摩尔,1倍量)与不同取代基硼酸酯(1.8毫摩尔,1.5倍量)、碳酸氢钠(NaHCO3,0.37克,3.5毫摩尔,3倍量)、二氯二(三苯基磷)合钯(Pd(PPh3)2Cl2,0.6毫摩尔,0.5倍量)混合加入两颈瓶，氮气保护状态下，加入DMF与水的混合溶剂(5:1)，90℃，反应12小时。反应结束后，加水，乙酸乙酯萃取，饱和氯化钠洗涤3次，无水硫酸钠干燥。干燥完成后，真空浓缩溶剂，柱层析纯化粗产物(石油醚:乙酸乙酯＝5:1)，得到中间体12(白色固体，产率76％)。
化合物12反应至终产物16步骤同化合物3反应至终产物8。
实施例3
合成路线3：
反应步骤：
化合物17反应至中间体19步骤同化合物9反应至中间体11。
将化合物19(3克,7毫摩尔,1.0倍量)与化合物20(3.54克,13.9毫摩尔,2倍量)、乙酸钾(2.06克,21毫摩尔,3.0倍量)、[1,1‘-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(PdCl2(dppf)CH2Cl2,0.57克,0.7毫摩尔,0.1倍量)，混合加入两颈瓶，氮气保护状态下，加入除过氧气的1，4-二氧六环50毫升，90℃反应12小时。反应结束后，用藻土过滤反应液，乙酸乙酯洗涤，滤液用饱和氯化钠洗涤3次，无水硫酸钠干燥。干燥完成后，真空浓缩溶剂，柱层析纯化粗产物(石油醚:乙酸乙酯＝15:1)，得到中间体21(白色固体，产率83％)。
将化合物21(0.5克,1毫摩尔,1.0倍量)与不同取代基溴苄(1.2毫摩尔,1.2倍量)，碳酸氢钠(NaHCO3,0.265克,3.1毫摩尔,3倍量)、二氯二(三苯基磷)合钯(Pd(PPh3)2Cl2,0.04克,0.05毫摩尔,0.05倍量)混合加入两颈瓶，氮气保护状态下，加入除过氧气的DMF与水的混合溶剂(5:1)，90℃搅拌反应12小时。反应结束后，加水，乙酸乙酯萃取3次，饱和氯化钠洗涤3次，无水硫酸钠干燥。干燥完成后，真空浓缩溶剂，柱层析纯化粗产物(石油醚:乙酸乙酯＝10:1)，得到中间体22。
将化合物22(0.6毫摩尔,1.0倍量)，固体氢氧化钠(1.8毫摩尔,3.0倍量)溶于甲醇与水的混合溶剂(3:1)，90℃回流，反应12小时，反应结束后加入1M盐酸水溶液中和至pH≈2，乙酸乙酯萃取，饱和氯化钠洗涤3次，无水硫酸钠干燥。干燥完成后，真空浓缩溶剂，得到中间体23(白色固体，产率99％)。
化合物23反应至终产物26步骤同化合物4反应至终产物(实施例1)。
实施例4
合成路线4：
将吉西他滨盐酸盐(0.5克,1.6毫摩尔,1倍量)，溶于12毫升的无水DMF和无水二甲亚砜(DMSO)混合溶液中(v/v,DMF:DMSO＝3:1)，加入N-甲基吗啡啉(NMM,0.16克,1.6毫摩尔,1倍量)，1-羟基苯并三氮唑(HOBT,0.22克,1.6毫摩尔,1倍量)，(1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐)(EDCI,0.42克,2.1毫摩尔,1.3倍量)，十五烷酸(0.44克,1.8毫摩尔,1.1倍量)，55℃条件下搅拌反应17小时，反应结束后，加水，乙酸乙酯萃取3次，饱和氯化钠水溶液洗涤3次，无水硫酸钠干燥。干燥完成后，真空浓缩溶剂，柱层析纯化粗产物(PE:EA＝1:1)，得到终产物纯品GZ。
所有的化合物的高分辨质谱结果如下表1所示，结构正确。
表1：终产物的结构与高分辨质谱结果
下面结合具体实验以及实验数据对本发明的积极效果作进一步描述。
实验
1、对第一个系列的化合物测试了对Hsp90和HDAC6的抑制活性，结果如下表2所示：
表2：
从表2的结果中可以看出，第一个系列的所有化合物都对HSP90和HDAC6显示出了较强的抑制活性，且IC50值都在纳摩尔范围内，说明该系列化合物皆为HSP90与HDAC6的双靶点抑制剂。
3、针对所有化合物，本发明又测试了对三种癌细胞和一种肺成纤维细胞的增值抑制活性，药物处理时间为72小时，结果如下表3所示：
表3：
从表3的结果中可以看出，所有的化合物对三种癌细A549、MDA-MB-231和4T1都展现出了较强的增殖抑制活性。IC50值都在微摩尔范围内。同时，所有化合物对人肺成纤维细胞HLF-1也展现出了较强的增殖抑制活性，IC50值都在微摩尔范围内。该结果证明这两个系列化合物在癌症和器官纤维化领域展现出了成药潜力。
4、由于化合物GZ对所有的细胞都显示出了最好的增值抑制活性，本发明同时还对其进行了体内抗肿瘤增殖实验，所用细胞为4T1，老鼠为昆明白鼠，腹腔注射给药，溶剂为PEG400：乙醇：水＝6:2:2。结果如图2所示：
从图2结果中可以看出，本发明所设计的吉西他滨前药GZ在5毫克/千克和10毫克/千克两个给药剂量下，都能够有效抑制4T1肿瘤的增殖，且活性优于其母体药物吉西他滨。
本申请旨在涵盖本公开的任何变型、用途或者适应性变化，这些变型、用途或者适应性变化遵循本公开的一般性原理并包括本公开未公开的本技术领域中的公知常识或惯用技术手段。说明书和实施例仅被视为示例性的，本公开的真正范围和精神由所附的权利要求指出。应当理解的是，本公开并不局限于上面已经描述并在附图中示出的精确结构，并且可以在不脱离其范围进行各种修改和改变。
Claims (10)
1.一种双功能HDAC6抑制剂，其特征在于，所述双功能HDAC6抑制剂的分子结构通式为：
2.根据权利要求1所述的双功能HDAC6抑制剂，其特征在于，所述双功能HDAC6抑制剂对Hsp90抑制活性剂量为98nM～821nM，对HDAC6的抑制活性剂量为15.7nM～140.8nM。
3.根据权利要求1所述的双功能HDAC6抑制剂，其特征在于，R为下列分子式中的一种：
4.根据权利要求1所述的双功能HDAC6抑制剂，其特征在于，所述双功能HDAC6抑制剂的分子结构通式中碳原子包括12C以及14C，氢原子包括1H、2H以及3H。
5.一种根据权利要求1所述双功能HDAC6抑制剂的合成方法，其特征在于，所述双功能HDAC6抑制剂合成路线为：
6.根据权利要求5所述双功能HDAC6抑制剂的合成方法，其特征在于，所述双功能HDAC6抑制剂的合成方法具体包括：
将化合物2,4二羟基苯甲酸甲酯、溴代烷、三氯化铝溶于装有100毫升无水二氯甲烷的玻璃耐压瓶中，在氩气保护条件下50℃搅拌反应；反应2小时后，再补加溴代烷；继续50℃搅拌反应12小时后，将反应液冰浴冷却至0℃，加入2M氢氧化钠中和至pH为7，乙酸乙酯萃取3次，饱和氯化钠水溶液洗涤3次，无水硫酸钠干燥；真空浓缩溶剂，柱层析纯化粗产物，得到第二中间体；
将第二中间体，溶于20毫升无水DMF，加入无水碳酸钾，氩气保护状态下，加入溴苄，120℃搅拌反应12小时；反应结束后，冷却至室温，加水，乙酸乙酯萃取，饱和氯化钠洗涤3次，无水硫酸钠干燥；干燥完成后，真空浓缩溶剂，柱层析纯化粗产物，得到第三中间体；
将第三中间体溶于四氢呋喃，加入20毫升1M氢氧化锂水溶液和20毫升水，50℃搅拌反应12h；反应结束后，冷却至室温，加入1M盐酸水溶液中和至pH≈2，乙酸乙酯萃取3次，饱和氯化钠洗涤3次，无水硫酸钠干燥；干燥完成后，真空浓缩溶剂，得到第四中间体；
将第四中间体，溶于无水二氯甲烷30毫升，加入1-羟基苯并三唑，第五中间体，冰浴冷却至0℃后，加入三乙胺，冰浴搅拌30分钟后转至室温，反应12小时；反应结束后，真空浓缩溶剂，柱层析纯化粗产物，得到第六中间体；
将第六中间体，溶于无水二氯甲烷20毫升，冷却至-78℃后，加入1M三氯化硼二氯甲烷溶液，-78℃反应1小时，转入室温反应2小时；反应结束后，真空浓缩蒸干溶剂，加入甲醇洗涤，真空浓缩蒸干甲醇，反复3次，柱层析纯化粗产物(二氯甲烷:甲醇＝40:1)，得到第七中间体；
将第七中间体，加入1M羟胺钾甲醇溶液20毫升，室温搅拌，反应3小时，反应结束后，真空浓缩蒸干溶剂，加水，加入1M盐酸中和至pH≈2，过滤得到粗产物，HPLC纯化，得到终产物。
7.根据权利要求5所述双功能HDAC6抑制剂的合成方法，其特征在于，所述双功能HDAC6抑制剂合成路线还包括：
所述双功能HDAC6抑制剂合成路线还包括：
8.一种利用权利要求1～7任意一项所述双功能HDAC6抑制剂制备吉西他滨前药，其特征在于，所述吉西他滨前药结构式为：
9.根据权利要求8所述双功能HDAC6抑制剂制备吉西他滨前药，其特征在于，所述吉西他滨前药给药剂量为5毫克/千克和10毫克/千克。
10.一种利用权利要求8～9任意一项所述双功能HDAC6抑制剂在制备用于治疗肺癌、乳腺癌、肝癌、软巢癌、前列腺癌、胰腺癌、肺纤维化、心脏纤维化、肝纤维化、囊性纤维化和肾纤维化药物中的应用。
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