CN105037191A - 一种脱氢枞胺咪唑有机盐及其制备方法、应用 - Google Patents
一种脱氢枞胺咪唑有机盐及其制备方法、应用 Download PDFInfo
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Abstract
本发明公开了一种脱氢枞胺咪唑有机盐及其制备方法、应用，属于脱氢枞胺基化合物。该脱氢枞胺咪唑有机盐为4,5-咪唑二甲酸单脱氢枞胺有机盐，制备方法为脱氢枞胺和4,5-咪唑二羧酸在甲苯介质下反应8-12h，其中，脱氢枞胺与4,5-咪唑二羧酸摩尔比1:1.0－1:1.5，反应结束后过滤，将甲苯减压旋蒸，得到该化合物。该化合物还可应用在抗肿瘤药物。该化合物表现出良好的抗宫颈癌活性，制备方法易操作，实验中所需物品毒性小。
Description
技术领域：
本发明涉及脱氢枞胺基化合物，具体涉及脱氢枞胺咪唑有机盐及其制备方法、应用。
背景技术：
随着石油等一次性资源的逐渐枯竭以及人类环境保护意识的普遍提高，利用松香等可再生的天然资源代替石油来发展精细化工已成为国内外的一种趋势。我国和美国是松香出产量最大的两个国家，全世界每年生产120万吨松香，我国和美国就约占总产量的50％，是世界松香市场主要的供应国。改性过的松香在美国被使用和出口，而在我国则恰恰相反，原料松香被大量使用及出口，这与我国松香产业的发展趋势并不相符，这一国情更不能适应我国化工、材料、制药等产业对松香产品的需求。对我国的资源保护和经济发展也十分不利。基于此，《国家中长期科学和技术发展规划纲要(2006-2020年)》要求我国主要林化产品深加工率要提高到60％以上，林业高技术产业总产值占林业总产值10％-15％以上。因此，急需开辟松香深加工利用研究，改变我国松香资源深度加工落后的不利局面。现在，先天的资源优势以及政策上的倾斜，使得松香改性产品在中国的发展具有得天独厚的优势。
脱氢枞胺(如式I所示)是松香重要的改性产品之一，原料丰富，价格相对便宜，松香经过一系列结构改性得到歧化松香胺，脱氢枞胺具有一些独特理化性质，如有稳定的性质，良好的光学活性，较大的比旋光度等。近年来，随着脱氢枞胺的提取和纯化技术的不断增强，其性能得到了提高，同时进一步扩大了应用范围。脱氢枞胺可作为良好的光学拆分剂是因为结构中天然手性碳的存在。脱氢枞胺也可用作特效的杀虫剂、杀菌剂和防霉剂，这是因为脱氢枞胺本身有一定的生物活性。另外，在金属缓蚀剂、润滑油添加剂、原油破乳剂、木材防腐剂、抗静电剂、表面活性剂、染料和涂料助剂、水处理剂等领域，脱氢枞胺及其衍生物也被广泛使用，在光化学拆分、造纸、金属加工、选矿、纺织印染、涂料、石油开采、医药、农药等领域的应用前景同样不可小觑。随着脱氢枞胺提取和纯化技术的进步，产品质量的提高，预计脱氢枞胺在医药、农药、金属加工、选矿、表面活性剂、染料、涂料、光化学拆分领域将得到更广泛的应用，
许多希夫碱化合物是具有生物活性的,例如具有抗疟疾活性[BohachGA,FastDJ,NelsonRD,SchlievertPM.Malaria.In:RodesJ,BenhamouJP,BleiA,ReichenJ,RizzettoM,editors.Thetextbookofhepatology:frombasicsciencetoclinicalpractice.Oxford(UK):WileyBlackwell；2007.p.1029-34]、抗菌活性[AlekshunMN,LevySB.Molecularmechanismsofantibacterialmultidrugresistance.Cell2007；128(6):1037-50]、抗真菌活性[KarthikeyanMS,PrasadDJ,PoojaryB,BhatKS,HollaBS,KumariNS.SynthesisandbiologicalactivityofSchiffandMannichbasesbearing2,4-dichloro-5-uorophenylmoiety.BioorgMedChem2006；14(22):7482-9]及抗病毒活性[SriramD,YogeeswariP,MyneeduNS,SaraswatV.Abacavirprodrugs:microwave-assistedsynthesisandtheirevaluationofanti-HIVactivities.BioorgMedChemLett2006；16(8):2127-9]等。据报道某些氢枞胺基衍生物具有抗癌等活性[陈泳，林中祥.树脂酸及其衍生物的抗肿瘤和抗微生物活性研究新进展[J].林产化学与工业，2008，28(5)：113－119]。
咪唑是含氮的芳香体系，具有一个闭合的大π键，在形成相应有机金属配合物的过程中易形成π…π堆积以及C-H…π相互作用，且其中一个氮原子未成键的sp2轨道上有一对孤对电子，易于组装出许多具有新颖结构和特殊功能的超分子配合物。这些配合物不但结构多姿多彩，还具有不寻常的光、电、磁、催化、吸附分离、生物活性等性质，具有良好的应用前景，故受到人们的极大关注和研究。咪唑羧酸类配体同时含有N和O原子，他们与金属离子配位时配位能力和选择性不同，往往可以得到许多不同的、新颖的配合物，所以咪唑羧酸为配体的配合物的合成和性质研究引起了科学研究者的极大兴趣。特别是4,5-咪唑二羧酸及其衍生物可以通过调节PH值以及其他方式和金属形成不同的配位方式。
咪唑羧酸及其衍生物是一类重要的医药中间体，同时本身就具有显著的生物活性,如2-[1-咪唑基]乙酸可用于体外1H-NMR探针来测定体内血红细胞的pH及细胞空间大小[Gil.MS,Paula.Z,Cruz.P,etal.Imidazol-1-ylalkanoicacidasextrinsicH-NMRprobesforthedeterminationofintracellularpH.extracellularpHandcellvolum.BioorgMedChem.1994.2.305-314]。而其C取代衍生物广泛地用作化学疗法试剂,如[1-(4-硝基咪唑)]羧酸是一类很好的免疫抑制剂、放射疗法的协助剂[Bhujanga.Rao.A.K.S,Rao.CG,Singh.B.B.N-Substitutionof2-Methyl-4(5)-nitro-1H-imidazole:anewhigh-yieldingmethodforPreparationof4-NitroIsomers.J.Org.Chem.1990.55.3702-3704.],[1-(5-硝基咪唑)]羧酸系列化合物可治疗原生虫传染病。并且由它合成的双膦酸类新药如唑来膦酸等[Weinheim.E.B,Hirschberg.R.G.Certain1-hydroxy-eihane,1,1-diphosphonicacidderivativesusefulintreatingcalciummetabosdisturbances.US:4687767.1987.]，在临床上已用于治疗高钙血症和骨痛症等疾病,均取得了显著疗效。马天亮研究了2-位上不同取代基的咪唑羧酸衍生物配体合成金属有机配位聚合物,制备了一系列具有光学、磁学和手性结构等性质的多功能晶体材料[马天亮.咪唑羧酸衍生物为配体的金属有机配位聚合物的合成、结构及性质研究[D].吉林大学.2011.]。景学敏利用两种不同吡啶基-4,5-咪唑二羧酸与稀土和过渡金属中心组装，通过π-π和氢键等分子间相互作用构筑了一系列结构新颖的三维超分子化合物，发现其具有明显的反铁磁性质[景学敏.金属—吡啶基咪唑羧酸化合物的合成、结构及性质研究[D].吉林大学.2011.]。王爽利用4,5-咪唑二羧酸及其衍生物作为有机配体，得到了一系列配位聚合物，发现其在气体储存、磁性和发光方面有很好的性质[王爽.咪唑羧酸及其衍生物为配体的配位聚合物的合成、表征及性质研究[D].吉林大学.2011.]。宋漫漫研究2-(4-吡啶)-4,5-咪唑二羧酸与金属配位，得到一系列配合物，发现其具有超灵敏荧光性质和较好的热稳定性,这就使其在发光及其他方面具有潜在的应用价值[宋漫漫.咪唑羧酸类配体与稀土配合物的合成、结构及性质研究[D].郑州大学.2013.]。胡凡研究发现苯并咪唑衍生物与过渡金属形成的配合物中,有些具有生物分子的模拟酶作用,部分还具有催化活性[胡凡.苯并咪唑羧酸的合成及其金属配合物催化作用研究[D].西北大学.2008.]。因而有关其合成方法的研究具有重要的学术意义和应用价值。
自由基是人体各种疾病和衰老的根源，能将细胞和组织分解，影响代谢功能，并会引起不同的健康问题。越来越多的研究显示抗氧化是预防衰老的重要步骤。例如，氧自由基负离子(·O2-)是引起肿瘤及癌变的重要成分。如果能够消除过多的氧化自由基，对于许多自由基引起的及老化相关疾病都能够预防，如癌症、动脉硬化、糖尿病、白内障、心血管病、老年痴呆、关节炎等。肿瘤严重危害人类的生命健康。脱氢枞胺类化合物可以抑制肿瘤增殖，表现出一定的抗肿瘤活性。陈泳将所合成的脱氢枞胺衍生物进行筛选[陈泳.脱氢枞胺衍生物的合成及其生物活性研究[D].南京林业大学.2012.]，测试其抗癌活性、抗菌活性等，并对构效关系进行分析。发现脱氢枞胺衍生物对前列腺癌细胞、卵巢癌细胞、肝癌细胞有抑制作用；脱氢枞胺衍生物的雄激素受体结合活性为前列腺癌的治疗提供新的思路和参考；对金黄色葡萄球菌、大肠杆菌以及枯草芽孢杆菌具有显著的抑制活性。
发明内容：
本发明的目的是提供一种具体的脱氢枞胺咪唑化合物，即4,5-咪唑二甲酸单脱氢枞胺有机盐，该化合物具有良好的抗癌活性。
进一步公开该化合物的合成方法，该制备方法易操作，实验中所需物品毒性小，结合天然产物与药物中间体，富有创新性。
进一步公开了该化合物的应用，脱氢枞胺咪唑有机盐为4,5-咪唑二甲酸单脱氢枞胺有机盐在制备抗肿瘤药物的应用。
本化合物结构新颖，具有独特的抗癌活性，为研究化合物的生物活性与结构的关系创造条件，为新药开发奠定基础。同时，该4,5-咪唑二甲酸单脱氢枞胺有机盐中拥有氮、氧活性配位中心，说明这类化合物本身就是潜在的良好配体，可以进一步进行配位组装，为进一步的研究创造条件。
4,5-咪唑二甲酸单脱氢枞胺有机盐(L1)，它有如下结构式：
4,5-咪唑二甲酸单脱氢枞胺有机盐的制备方法，其步骤如下：
脱氢枞胺和4,5-咪唑二羧酸在甲苯介质下反应8-12h，其中，脱氢枞胺与4,5-咪唑二羧酸摩尔比1:1.0－1:1.5，反应结束后过滤，将甲苯减压旋蒸，得到白色粉末，即4,5-咪唑二甲酸单脱氢枞胺有机盐(L1)。
所述的步骤脱氢枞胺与4,5-咪唑二羧酸摩尔比1:1.2。
4,5-咪唑二甲酸单脱氢枞胺有机盐在抗肿瘤药物的应用。
4,5-咪唑二甲酸单脱氢枞胺有机盐抗肿瘤活性的测定
采用MTT法研究L1对宫颈癌细胞(Hela)的抑制作用。具体操作如下：取对数生长期的Hela细胞，配制成1×105个/mL的单细胞悬液，接种于96孔培养板，每孔100μL，于体积分数为5％的CO2、饱和湿度、37℃培养箱中培养24h后，在96孔培养板加入100μL不同浓度的样品，每种浓度均为2个复孔。分别继续培养细胞24h后，每孔加20μL的MTT染色液，37℃、5％CO2培养箱中继续培养4h，小心去除上层清液，然后每孔加200μLTHF，充分震荡30min后，在酶标仪上595nm波长处测定OD样值，实验的空白组是用100μL无血清的DMEM培养液代替样品，测出的吸光度值为OD空白值，通过公式(1)计算样品对Hela细胞抑制率。
有益效果：
本发明保护的化合物L1将脱氢枞胺与4,5-咪唑二羧酸结合起来，脱氢枞胺和咪唑羧酸都具有良好的生物活性，本发明将二者结合起来，构筑结构新颖的化合物，研究化合物的生物活性与结构的关系，开发出具有独特抗肿瘤活性的新化合物，为新药开发奠定基础。化合物L1增强了生物活性，当其浓度大于等于10μg/mL时，抑制率可达100％，IC50为1.06μg/mL，表现出良好的抗宫颈癌活性，为抗宫颈癌细胞新药物的开发提供依据。
化合物L1的制备方法易操作，实验中所需物品毒性小，结合天然产物与药物中间体，富有创新性。
这一研究表明了脱氢枞胺和咪唑羧酸生成的化合物是一类具有优良前景的抗癌剂。本项目主要采用MTT噻唑蓝比色法研究其对宫颈癌细胞(Hela)的抑制作用。
附图说明：
图1为本发明化合物L1的核磁氢谱图
图2为本发明化合物L1的晶体结构图
图3为本发明化合物L1对宫颈癌细胞(Hela)的抑制作用
具体实施方式：
1H-NMR光谱在瑞士布鲁克拜厄斯宾公司AVANCEⅢ600MHz型核磁共振光谱仪上测定；单晶在德国Bruker公司APEXDUO型X射线单晶衍射仪上测定。
实施例1
4,5-咪唑二甲酸单脱氢枞胺有机盐(L1)的制备
合成方法如下：在100mL的单口烧瓶中加入2.85g(10mmol)脱氢枞胺、1.56g(10mmol)4,5-咪唑二羧酸(摩尔比1:1.0)和50mL的甲苯，110℃冷凝回流反应8h。反应结束后热过滤，旋蒸得白色固体，质量为1.9537g，产率为44.3％。m.p.142.4℃～143.3℃；元素分析:C25H35O4N3，计算值(％):C68.03，H7.94，N9.52；实验值(％):C67.81，H7.58，N9.43。
b、改用CH2Cl2做溶剂，设置反应温度为35℃，其他条件不变，得到相似结果。
L1的1H-NMR(DMSO，δ/ppm，600MHz)：0.95(3H，s，H-8)；1.13～1.15(9H，t，J＝7.2Hz,H-12，24,25)；1.26(2H，m，H-9)；1.38～1.41(2H，t，J＝4.2Hz，H-10)；1.63～1.64(2H，m，H-11)；1.68～1.71(2H，m，H-16)；2.28(1H，d，J＝13.2Hz，H-14)；2.60(1H，s，H-23)；2.73～2.78(1H，m，H-15)；2.79～2.88(2H，m，H-6)；6.86(1H，s，H-20)；6.95～6.97(1H，d，J＝1.8Hz，H-22)；7.15～7.16(1H，d，J＝8.4Hz，H-19)；7.56(1H，s，H-1)；7.56～7.58(2H，s，H-c)；12.72(1H，s，H-a)。
L1的单晶如图2所示。
以上核磁、单晶表征结果表明：脱氢枞胺与4,5-咪唑二羧酸合成得到4,5-咪唑二甲酸单脱氢枞胺有机盐。
本实验采用MTT法研究L1对宫颈癌细胞(Hela)的抑制作用，结果如图3所示。从图中可以明显地看出，宫颈癌细胞(Hela)的抑制率随化合物浓度的增加而上升，当其浓度大于等于10μg/mL时，抑制率可达100％，IC50为1.06μg/mL，说明了L1具有良好的抗宫颈癌活性。
实施例2
4,5-咪唑二甲酸单脱氢枞胺有机盐(L1)的制备
合成方法如下：在100mL的单口烧瓶中加入2.85g(10mmol)脱氢枞胺、1.87g(12mmol)4,5-咪唑二羧酸(摩尔比1:1.2)和50mL的甲苯，110℃冷凝回流反应8h。反应结束后热过滤，旋蒸得白色固体，质量为2.0329g，产率为46.1％。m.p.142.4℃～143.3℃；元素分析:C25H35O4N3，计算值(％):C68.03，H7.94，N9.52；实验值(％):C67.81，H7.58，N9.43。
b、改用CH2Cl2做溶剂，设置反应温度为35℃，其他条件不变，得到相似结果。
实施例3
4,5-咪唑二甲酸单脱氢枞胺有机盐(L1)的制备
合成方法如下：在100mL的单口烧瓶中加入2.85g(10mmol)脱氢枞胺、2.34g(15mmol)4,5-咪唑二羧酸(摩尔比1:1.5)和50mL的甲苯，110℃冷凝回流反应12h。反应结束后热过滤，旋蒸得白色固体，质量为1.7261g，产率为39.4％。m.p.142.4℃～143.3℃；元素分析:C25H35O4N3，计算值(％):C68.03，H7.94，N9.52；实验值(％):C67.81，H7.58，N9.43。
b、改用CH2Cl2做溶剂，设置反应温度为35℃，其他条件不变，得到相似结果。
实施例4
4,5-咪唑二甲酸单脱氢枞胺有机盐(L1)的制备
合成方法如下：在100mL的单口烧瓶中加入2.85g(10mmol)脱氢枞胺、1.87g(12mmol)4,5-咪唑二羧酸(摩尔比1:1.2)和50mL的甲醇，70℃冷凝回流反应12h。反应结束后热过滤，旋蒸得白色固体，质量为1.5941g，产率为36.1％。m.p.142.4℃～143.3℃；元素分析:C25H35O4N3，计算值(％):C68.03，H7.94，N9.52；实验值(％):C67.81，H7.58，N9.43。
b、改用CH2Cl2做溶剂，设置反应温度为35℃，其他条件不变，得到相似结果。
Claims (4)
1.一种脱氢枞胺咪唑有机盐，其特征在于：所述的脱氢枞胺咪唑有机盐为4,5-咪唑二甲酸单脱氢枞胺有机盐，结构式如下
2.一种4,5-咪唑二甲酸单脱氢枞胺有机盐的制备方法，其步骤如下：
脱氢枞胺和4,5-咪唑二羧酸在甲苯介质下反应8-12h，其中，脱氢枞胺与4,5-咪唑二羧酸摩尔比1:1.0－1:1.5，反应结束后过滤，将甲苯减压旋蒸，得到4,5-咪唑二甲酸单脱氢枞胺有机盐。
3.根据权利要求2所述的制备方法，其特征在于：所述的步骤脱氢枞胺与4,5-咪唑二羧酸摩尔比1:1.2。
4.一种根据权利要求1所述的脱氢枞胺咪唑有机盐在抗肿瘤药物的应用。
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