CN104292134B - 异羟肟酸类化合物及其制备方法和应用 - Google Patents
异羟肟酸类化合物及其制备方法和应用 Download PDFInfo
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- CN104292134B CN104292134B CN201410530422.XA CN201410530422A CN104292134B CN 104292134 B CN104292134 B CN 104292134B CN 201410530422 A CN201410530422 A CN 201410530422A CN 104292134 B CN104292134 B CN 104292134B
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Abstract
本发明涉及药物化学的技术领域，具体公开了异羟肟酸类化合物及其制备方法和应用，本发明还公开了所异羟肟酸类化合物在药学上可接受的盐和药学上可接受的溶剂合物。所述异羟肟酸类化合物的结构式为：
Description
技术领域
本发明涉及药物化学的技术领域，更具体的，涉及异羟肟酸类化合物及其制备方法和应用。
背景技术
近年来，组蛋白去乙酰化酶抑制剂(histonedeacetylaseinhibitors,HDACi)，已成为抗肿瘤药物的研究热点之一。目前，HDACi主要包括异羟肟酸类、环状四肽类、短链脂肪酸类、苯甲酰胺类、亲电酮类、三硫代碳酸等。其中，异羟肟酸类HDACi是最早发现且迄今研究最广泛的一类，其抑酶作用强，结构简单，合成容易。
异肟羟酸类HDACi的结构多由环、脂肪链和异羟肟酸三部分组成，分别对应HDACi的表面识别区、连接区和金属结合区(锌结合区)。其中：金属离子结合区能很好的与活性部位的锌离子直接作用是产生抑制活性所必须的，并与管道底部及周边的组氨酸和酪氨酸等残基形成氢键，通常能与锌离子配位的基团有羟肟酸、巯基、环氧酮或亲电酮等。连接区则恰好和狭窄的通道充分接触，通常为线性的饱和或不饱和碳链，或苯环、芳杂环。研究表明连接区的碳原子个数对酶的活性也有着重要影响，一般为5-6个较为合适，有利于金属结合区与管道底部的锌离子有效接触，增强抑酶的活性。表面识别区也与抑制剂的活性相关，并且在对HDACs亚型选择性抑制剂中发挥不可估量的作用，其应适宜地与通道的边缘残基紧密接触，一般是疏水性基团，大多数是取代的芳环、芳杂环、环肽等。
许多研究已表明HDAC异常导致的组蛋白乙酰化的状态失衡与肿瘤的发生和发展有着密切关系。HDACi主要是通过改变组蛋白的乙酰化程度来改变染色质结构，从而达到调控基因表达的目的。HDACi比传统的细胞毒性抗肿瘤药有明显的特点和优势：HDACi可引起肿瘤细胞的生长停滞，分化或凋亡；HDACi抑制肿瘤作用对多种肿瘤细胞都有明显的效果，对血液系统肿瘤和实体瘤的治疗作用在体内体外实验中均得到证实；对其他药物产生耐药性的肿瘤细胞，对其仍然有较好的反应性，并且它作用有一定的肿瘤特异性，对一些正常细胞并不引起生长停滞或凋亡。
异肟羟酸类HDACi较为成功的代表SAHA，作为首个HDACi于2006年10月被美国FDA批准上市，并用于治疗转移性皮肤T细胞淋巴瘤，但在近年的研究中，发现其存在生物利用度较差、对HDACs的亚型选择性不强的缺陷，以及出现一些严重的毒性反应，所以SAHA仍值得人们在已有的基础上探索寻求更优秀的化合物。
目前，对于进入临床研究阶段的HDACi，除了考察单独用药的疗效外，更多的研究是将HDACi与其他不同作用机制的抗肿瘤药物以及临床上常用的细胞毒药物联合使用。研究已发现，HDACi能够增加肿瘤细胞对化疗药物、干扰素和放射治疗的敏感度，所以联合用药成为了肿瘤治疗的新趋势。因此，通过筛选得到的候选HDACi，也将有希望运用于临床的研究与治疗中，这将有着一个广泛的应用前景。
发明内容
本发明要解决的技术问题在于克服现有异羟肟酸类化合物的不足，提供一种异羟肟酸类化合物及其药学上可接受的盐、药学上可接受的溶剂合物。
本发明要解决的另一技术问题在于提供一种所述异羟肟酸类化合物的制备方法。
本发明要解决的另一技术问题在于提供所述异羟肟酸类化合物及其药学上可接受的盐、药学上可接受的溶剂合物的应用。
本发明要解决的技术问题通过以下技术方案实现：
所述异羟肟酸类化合物，具有以下结构式：
所述异羟肟酸类化合物及其药学上可接受的盐由所述异羟肟酸类化合物与无机酸、有机酸、无机碱或有机碱进行化学反应得到。
进一步地，所述无机酸或有机酸选自：盐酸、氢溴酸、氢碘酸、硫酸、硝酸、碳酸、磷酸、高氯酸、醋酸、柠檬酸、草酸、乳酸、苹果酸、水杨酸、酒石酸、甲磺酸、乙磺酸、苯磺酸、取代的苯磺酸、异烟酸、油酸、鞣酸、泛酸、抗坏血酸、丁二酸、马来酸、龙胆酸、富马酸、葡萄糖酸、糖醛酸、葡萄糖二酸或蔗糖酸、甲酸、苯甲酸、谷氨酸、双羟萘酸、山梨酸。所述无机碱或有机碱选自：氢氧化钠、氢氧化钾、氢氧化锂、氢氧化铁、氢氧化钙、氢氧化钡、氢氧化铝、氢氧化镁、氢氧化锌、氨水、氢氧化有机季铵盐、碳酸钠、碳酸钾、碳酸锂、碳酸钙、碳酸钡、碳酸镁、碳酸化有机季铵盐、碳酸氢钠、碳酸氢钾、碳酸氢锂、碳酸氢钙、碳酸氢钡、碳酸氢镁、碳酸氢化有机季铵盐。
所述异羟肟酸类化合物及其药学上可接受的溶剂合物，具体地，所述溶剂合物为所述异羟肟酸类化合物与常用的溶剂以共价键、氢键、离子键、范德华力、络合、包合等形成的稳定物质。所述溶剂为水、乙醇、丙醇、丁醇、乙二醇、丙二醇、聚乙二醇或丙酮。
一种所述异羟肟酸类化合物的制备方法，
所述制备方法先将辛二酸酐在二氯甲烷中与苯胺类原料发生酰化反应得到辛二酸单酰苯胺化合物；然后在四氢呋喃、三乙胺催化下与氯甲酸异丁酯反应制成混合酸配；最后在甲醇中，室温下与羟胺发生氨解，得到所述异羟肟酸类化合物。具体地，所述制备方法包括以下步骤：
S1.将辛二酸酐溶解于CH2Cl2后，在冰浴条件下，加入苯胺类原料反应后，经过滤、提纯得到第一中间产物；
S2.将第一中间产物溶解于四氢呋喃，加入三乙胺，在冰浴条件下，加入氯甲酸异丁酯反应得到第二中间产物；
S3.在冰浴条件下，将羟胺溶液加入到第二中间产物中，反应后经旋蒸、提纯得到所述异羟肟酸类化合物；
S1中所述第一中间产物的结构式为：
S2中所述第二中间产物的结构式为：
具体地，所述制备方法的反应过程如下：
进一步地，S1中所述的辛二酸酐由辛二酸在醋酸酐的条件下加热反应得到。
进一步地，S1中第一中间产物的提纯步骤包括：将过滤得到的滤饼溶于碱性溶液后再过滤得到碱性滤液，再调节碱性滤液的pH为5～6后再次过滤得到第一中间产物。
进一步地，S3中所述异羟肟酸类化合物的提纯步骤包括：
S31.将旋蒸获得的残余物溶于pH为5～6的盐酸溶液中，过滤得到析出物，再将析出物置于饱和碳酸氢钠溶液中搅拌，过滤、洗涤、干燥得到粗产物；
S32.将S31中的粗产物置于水中，加热并加入乙醇，待粗产物溶解后过滤、滤液静置析出所述异羟肟酸类化合物。
一种所述异羟肟酸类化合物及其药学上可接受的盐、药学上可接受的溶剂合物在制备抗癌药物中的应用。
所述癌症为神经胶质瘤或肺癌。
所述神经胶质瘤的细胞株为U251、MGR2、U373，肺癌的细胞株为SPC、LTEP、H1650。
进一步地，所述抗癌药物为癌细胞增殖抑制剂、HDAC活性抑制剂、癌细胞凋亡促进剂、癌细胞自噬促进剂中的一种或几种。
与现有技术相比，本发明具有以下有益效果：
1.本发明所述异羟肟酸类化合物在抗神经胶质瘤(细胞株为U251、MGR2、U373)或肺癌(细胞株为SPC、LTEP、H1650)方面的效果比现有的SAHA和N25的更好。
2.本发明所述制备方法的优点在于：
在S1中合成辛二酸单酰苯胺类化合物时，采用二氯甲烷为溶剂，先将辛二酸酐溶于二氯甲烷，然后低温下滴加苯胺类化合物，生成辛二酸单酰苯胺类化合物，由于辛二酸单酰苯胺类化合物难溶于二氯甲烷，因此反应完成后可以将产品过滤出来，而母液可以继续使用，不会影响收率，大大减少了溶剂和原料的投入，减少了成本开支并且降低了对环境的影响。
由于N-单酰化物溶解于NaOH，S1中利用化合物之间溶解度不同进行碱提酸沉，此法可以除去反应中产生的副产物N-二酰化物。
在S2中使用氯甲酸异丁酯参与反应生成混合酸酐，较现有的合成路线中采用氯甲酸乙酯来说，反应活性并没有降低，但其毒性远远小于氯甲酸乙酯。
在S3中通过重结晶提纯可以使产物纯度达到96％以上。与现有方法相比，所述重结晶提纯操作简单、使用溶剂多为水溶剂，对实验人员和环境毒性较小，得到产物的纯度高。
附图说明
图1为N3F对U251细胞Caspase-3、Caspase-9、Belcin-1和Bcl-2表达的影响；
图2为N4I对SPC细胞Caspase-3、Caspase-9、Belcin-1和Bcl-2表达的影响。
具体实施方式
下面结合具体实施方式对本发明作进一步的说明。除非特别说明，本发明实施例中采用的原料和方法为本领域常规市购的原料和常规使用的方法。
异羟肟酸类化合物的制备与表征
以下各个实施例中使用的相同的仪器和药品如下：
质谱由WatersUPLC/Q-TOFmicroMS获得(美国Waters公司)。红外光谱使用Spectrum100傅立叶变换红外光谱仪PerkinElmer(KBr压片)。熔点测定使用北京泰克仪器有限公司的熔点仪。
原料、试剂及溶剂等一般从下列供应商购买：AladdinChemistryCo.Ltd；广州市齐云生物技术有限公司；广州化学试剂厂；天津市富宇精细化工有限公司；天津市永大化学试剂有限公司；国药集团化学试剂有限公司。
以下各实施例的异羟肟酸类化合物的简称、对应的中英文名称和原料的中英文名称如下表所示。
实施例1N-(4-正丁基苯基)-N`-羟基辛酰胺(N4B)的制备方法
一种N-(4-正丁基苯基)-N`-羟基辛酰胺的制备方法，包括以下步骤：
S1.辛二酸酐的合成
往烧瓶中加入30g辛二酸和36ml乙酸酐，加热回流4h后减压旋蒸去除乙酸和过量的乙酸酐，得白色蜡状固体；然后用20～30ml乙睛重结晶后，得到26.1～28.8克白色辛二酸酐，放入干燥皿中保存待用。辛二酸酐的收率为87％～96％，熔点为51.2～53.6℃。
S2.酰胺开环反应
往装有100ml二氯甲烷的500ml烧瓶中加入7.8克辛二酸酐，搅拌使辛二酸酐溶解；冰浴使溶液降至0℃左右，缓慢滴加9克4-正丁基苯胺(为保证辛二酸酐反应充分，4-正丁基苯胺稍微过量，剩余的4-正丁基苯胺会留在母液中供下次反应使用)，滴加完毕后继续搅拌1～2h，待有大量白色固体析出后，进行真空抽滤，然后用0℃左右的二氯甲烷洗涤滤饼；将滤饼干燥后加入2mol/L的NaOH溶液中溶解，然后再次抽滤，收集滤液，并往滤液中加入2mol/LHCl调节滤液的pH至5～6，得到第一中间产物(即辛二酸单酰苯胺类化合物)，烘干保存待用。
S3.混合酸酐的制备
500ml烧瓶加入10g的辛二酸单酰4-正丁基苯胺，3ml三乙胺(10mmol)和100ml无水四氢呋喃，冰浴搅拌下滴加8ml氯甲酸异丁酯，搅拌1～2h，得到第二中间产物(即混合酸酐)。
S4.异羟肟酸类化合物的粗产物制备
取6g盐酸羟胺溶于无水甲醇，加入8ml三乙胺，得到羟胺；将羟胺置于冰浴后缓慢滴到混合酸酐中，搅拌2～3h后旋干溶剂，然后用1mol/L的HCl溶液溶解残余物，调节pH至5～6，待析出固体后过滤；将析出固体置于饱和碳酸氢钠溶液中搅拌15min后，抽滤，滤饼用水洗涤，干燥后得粗产物。
S5.粗产物的提纯
利用重结晶提纯方法，将S4中的粗产物加入热水中水浴加热，在加热过程中加入无水乙醇，让粗产物充分溶解后趁热过滤除去杂质，静止缓慢析出晶体，得到纯度为96％的N-(4-正丁基苯基)-N`-羟基辛酰胺。
实施例2～6所述化合物的制备方法与实施例1的制备方法的区别仅使用的苯胺类原料不同，其余反应工艺与操作步骤均相同。
在上述各个实施例中粗产物的制备和提纯实验中发现，实施例1～6制备的异羟肟酸类化合物在水、乙醇等溶剂中的稳定性良好，非强酸或者强碱的条件下(即3<PH<10)可以保持化学结构的稳定性。
实施例1～实施例6制备的异羟肟酸类化合物的表征
实施例1N4B
1HNMR(500MHz,DMSO)δ10.32(s,1H),9.75(s,1H),8.64(s,1H),7.47(d,1H),7.08(d,2H),3.32(s,2H),2.51(d,4H),2.23(d,1H),1.94(t,2H),1.52(dd,4H),1.28(d,6H),0.94(dt,3H).MSm/z319.2(M-H)-.熔点:127.5-129.9℃.纯度:97.41％.Calcdfor摩尔质量.:320.43,C18H28N2O3:C,67.47；H,8.81；N,8.74；O,14.98
实施例2N4I
1HNMR(500MHz,DMSO)δ10.32(s,1H),9.75(s,1H),8.64(d,1H),7.48(d,1H),7.14(d,2H),3.32(s,1H),2.82(hept,1H),2.50(dt,2H),2.26(t,2H),1.52(d,4H),1.38–1.09(m,10H).MSm/z:307.2(M+H)+.熔点:139.4-141.8℃.纯度:98.15％.Calcdfor:摩尔质量.:306.4.C17H26N2O3:C,66.64；H,8.55；N,9.14；O,15.67
实施例3NS
1HNMR(500MHz,DMSO)δ11.80(s,1H),10.38(s,1H),8.23–6.75(m,8H),5.76(s,1H),3.33(s,1H),2.50(dt,4H),1.18(t,8H).MSm/z:385.17(M+H)+.熔点:136.5-137.8℃.纯度:98.98％.Calcdfor摩尔质量.:384.43.C21H24N2O5:C,65.61；H,6.29；N,7.29；O,20.81
实施例4N2E
1HNMR(500MHz,DMSO)δ10.32(s,1H),8.64(s,1H),7.88(d,1H),7.01-6.93(d,3H),4.07(d,2H),3.32(s,1H),2.47(dd,2H),1.94(s,2H),1.74–1.12(m,11H)MSm/z307.1(M-H)-.熔点:120.1-121.9℃.纯度:95.78％.Calcdfor摩尔质量.:308.37.C16H24N2O4:C,62.32；H,7.84；N,9.08；O,20.75
实施例5N3F
1HNMR(500MHz,DMSO)δ10.32(s,1H),8.65(s,1H),8.16(d,1H),7.74(d,1H),7.53(dd,1H),3.32(s,1H),2.48(ddd,2H),1.94(t,2H),1.67-1.53(ddd,4H),1.29(dd,4H).MSm/z365.1(M-H)-.熔点:127.9-129.2℃.纯度:97.59％.Calcdfor摩尔质量.:366.76.C15H18ClF3N2O3:C,49.12；H,4.95；Cl,9.67；F,15.54；N,7.64；O,13.09
实施例6N24
1HNMR(500MHz,Acetone)δ10.32(s,1H),8.65(d,1H),8.39(d,1H),7.93–7.65(m,2H),3.98(s,3H),3.33(s,1H),2.69–2.33(m,2H),1.93(d,2H),1.66–1.41(m,4H),1.27(dd,4H).MSm/z:304.15(M+H)+.熔点:145.8-146.9℃.纯度:95.16％.Calcdfor摩尔质量:339.34.C15H21N3O6:C,53.09；H,6.24；N,12.38；O,28.29
2.异羟肟酸类化合物的应用
以下实施例为实施例1～实施例6的异羟肟酸类化合物对癌细胞的体外药效学实验及结果。
以下实施例的对照药为：
SAHA：N-羟基-N’-苯基-辛二酰胺
N25：N-(2,5-二甲氧基苯基)-N'-羟基辛二酰胺，
实施例7对癌细胞的增殖抑制实验
选用3株胶质瘤细胞株：U251、MGR2、U373，3株肺癌细胞株：SPC、LTEP、H1650，以及正常人细胞LO2、MRC5，采用CCK-8法对细胞进行抗增殖实验考察。
分别取生长状态良好的细胞接种于96孔板，细胞密度为104个/孔，预将实施例1～实施6的异羟肟酸类化合物、对照药SAHA和N25均作用于同一细胞，每个药物的每组浓度分别设置3个复孔。所述每个药物的给药浓度均依次为：0.1umol/L、1.0umol/L、1.5umol/L、3umol/L、7.5umol/L、15umol/L、30.0umol/L。
具体步骤为：培养细胞，待细胞贴壁后，进行加药处理，给药处理48h后，各孔加入10uLCCK-8溶液，摇匀后放入细胞培养箱孵育1h，然后在酶标仪的450nm处测定吸光度值。结果见表1和表2。
结果表明：不同异羟肟酸类化合物对不同肿瘤细胞株的敏感性不同。在胶质瘤细胞株中，N3F和N2E对U251、MGR2胶质瘤细胞的抗增殖效果和对HDAC活性的抑制效果都比N25和SAHA强；同时N3F和N2E与SAHA和N25对比均对人正常细胞的毒性小。在肺癌细胞株中，N4I对SPC、LTEP、H1650肺癌细胞的抗增殖效果和对HDAC活性的抑制效果都比N25和SAHA强，表现出较强的敏感性，而对正常人细胞毒性较小。从中选择U251、SPC细胞株做后续实验。
表1抗胶质瘤细胞增殖、HDAC的抑制活性和毒性评价
表2抗肺癌细胞增殖、HDAC的抑制活性和毒性评价
实施例8对癌细胞凋亡蛋白或自噬蛋白表达的影响以及相互作用的应用取处于对数生长期的细胞，按3×106个/mL密度接种于直径10cm细胞培养皿中，每孔6ml，待细胞贴壁后，吸走孔内培养基，U251细胞中，N3F给药组浓度为：3umol/L、阳性对照SAHA组(3umol/L)，阴性对照组；而SPC细胞中，N4I给药组浓度为：1.50umol/L、阳性对照组SAHA组(1.50umol/L)，阴性对照组。最终培养基总体积为6ml，于37℃、5％CO2培养箱孵育。给药处理48h后，收集细胞。按蛋白提取试剂盒提取蛋白，并进行蛋白定量。进行ELISA试剂盒的实验。
结果如图1和图2所示，在U251、SPC细胞中，N3F和N4I能明显提升Caspase-3、Caspase-9、Belcin-1的蛋白表达，同时能降低Bcl-2的表达；抑制Caspase-3、Caspase-9后能明显提升Beclin-1的表达量。
Claims (9)
1.异羟肟酸类化合物及其药学上可接受的盐，其特征在于，所述异羟肟酸类化合物具有以下结构式：
2.根据权利要求1所述异羟肟酸类化合物及其药学上可接受的盐，其特征在于，所述药学上可接受的盐由异羟肟酸类化合物与无机酸、有机酸、无机碱或有机碱进行化学反应得到。
3.一种权利要求1所述异羟肟酸类化合物的制备方法，其特征在于，包括以下步骤：
S1.将辛二酸酐溶解于CH2Cl2后，在冰浴条件下，加入苯胺类原料反应后，经过滤、提纯得到第一中间产物；
S2.将第一中间产物溶解于四氢呋喃，加入三乙胺，在冰浴条件下，加入氯甲酸异丁酯反应得到第二中间产物；
S3.在冰浴条件下，将羟胺溶液加入到第二中间产物中，反应后经旋蒸、提纯得到所述异羟肟酸类化合物；
S1中所述第一中间产物的结构式为：
S2中所述第二中间产物的结构式为：
所述R选自2-氯-5-三氟甲基、2-乙氧基、4-异丙基、4-正丁基。
4.根据权利要求3所述异羟肟酸类化合物的制备方法，其特征在于，S1中所述的辛二酸酐由辛二酸在醋酸酐的条件下加热反应得到。
5.根据权利要求3所述异羟肟酸类化合物的制备方法，其特征在于，S1中第一中间产物的提纯步骤包括：将过滤得到的滤饼溶于碱性溶液后再过滤得到碱性滤液，再调节碱性滤液的pH为5～6后再次过滤得到第一中间产物。
6.根据权利要求3所述异羟肟酸类化合物的制备方法，其特征在于，S3中所述异羟肟酸类化合物的提纯步骤包括：
S31.将旋蒸获得的残余物溶于pH为5～6的盐酸溶液中，过滤得到析出物，再将析出物置于饱和碳酸氢钠溶液中搅拌，过滤、洗涤、干燥得到粗产物；
S32.将S31中的粗产物置于水中，加热并加入乙醇，待粗产物溶解后过滤、滤液静置析出所述异羟肟酸类化合物。
7.权利要求1所述异羟肟酸类化合物及其药学上可接受的盐在制备抗癌药物中的应用。
8.根据权利要求7所述应用，其特征在于，癌症为神经胶质瘤或肺癌。
9.根据权利要求8所述应用，其特征在于，神经胶质瘤的细胞株为U251、MGR2、U373，肺癌的细胞株为SPC、LTEP、H1650。
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