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N亚苄基橙皮素腙及类似物的合成与细胞活性

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N亚苄基橙皮素腙及类似物的合成与细胞活性

有机化学CHINESEJOURNALOFORGANICCHEMISTRYDOI10.6023/QOC201304028八『.亚苄基橙皮素腙及类似物的合成与细胞活性刘志平韦万兴甘春芳6黄燕敏6刘盛周敏崔建国6广西大学化学化工学院南宁530004广西师范学院化学与生命科学学院南宁530001NOTE摘要以天然橙皮素1为原料,与水合肼反应得到了橙皮素腙2,2分别与各种取代的芳香醛反应首次合成了8个苄基橙皮素腙3~10及6个类似物1116.所合成产物通过NMR,IR,HRESIMS方法进行了结构确证.MTT噻唑蓝蛋白染色法体外抑制肿瘤增值活性测试发现化合物5,7,10,L6对胃癌细胞SGC一7901有显著的抑制活性.关键词橙皮索;橙皮索腙;Ⅳ_苄基细胞活性SYNTHESISANDCYTOTOXICITYOFNBENZYLIDENEHESPERITINHYDRAZONESANDANALOGUESLIU,ZHIPING。,WEI,WANXING’。GAN,CHUNFANGHUANG,YANMINLIU,SHENG。ZHOU,MINCUI,JIANGUOCOLLEGEOFCHEMISTRYANDCHEMICALENGINEER,GUANGXIUNIVERSITY,NANNING530004COLLEGEOFCHEMISTRYANDLESCIENCE,GUANGXITEACHERSEDUCATIONUNIVERSITY,NANNING530001ABSTRACTHESPERITINHYDRAZONE2WASGENERATEDBYTHEREACTIONOFNATURALHESPERITINF11ASRAWMATERIALWITHHYDRAZINEHYDRATE.EIGHTNBENZYLIDENEHESPERITINHYDRAZONES3~10ANDSIXANALOGUES11~L6WERESYNTHESIZEDBYTHEREACTION0F2WITHVARIOUSALDEHYDES,RESPECTIVELY.THESTRUCTURESOFAL1REACTIONPRODUCTSWERECONFIRMEDBVNMR.IRANDHRMSTECH.NIQUES.ANDTHECYTOTOXITYAGAINSTHUMANCANCERCELLSGC一7901OFTHESYNTHESIZEDCOMPOUNDSWASALSOEVALUATED.THERESULTSSHOWED5.7.10AND16EXHIBITINGDISTINCTCYTOTOXITYAGAINSTSGC一7901.KEYWORDSHESPERITIN;HESPERITINHYDRAZONES;NBENZYLIDENE;CYTOTOXICITY橙皮素在芸香科植物柑橘、柑桔、柠檬等的果皮中广泛存在,具有降低胆固醇、提高免疫力、抑菌、抗病毒、抗氧化等多种功效L1~,但其开发利用率较低,未有高端的深加工产品上市.因此有必要探索增值化利用天然橙皮素的可行路径,提‘该产品的经济价值,而以天然农产品为原料经简单化学转化半合成具有高药用价值的药物具有原料多、步骤少、生态友好等特点,期以来一直是化学和药学工作者的研究热点之一一.如单杨等【4L、L哿橙皮苷通过水解、脱氢、选择性甲基化等步骤合成了具有多种生理活性的桃皮素、木犀草素、香叶木素等衍生物;汪秋安等【5J以橙皮苷为原料半合成了具有生物活性的山萘酚、黄酮醇、橙酮、香叶木素及其衍生物;BERNINI等【7L利用甲基三氧化铼作催化剂,合成了具有抑制人淋巴瘤细胞株增值活性的C环橙皮素内酯.腙及其衍生物是一类具有有抗茵L8、抗病毒_1、抗肿瘤I11以及除草I1】等多种生理活性的物质,而且具有较强的配位能力以及多样的配位形式,在农药、医药和分析试剂等方面有着广泛的应用13,141.近年来,有文献报道在黄酮母体上引入腙基含氮基团,可引起黄酮类化合物的生物活性发生显著变化.如HUSSAIN小组LJ5_合成了具有较好抗菌作用的2,4.二硝基苯腙黄酮类化合物BAK等【】6L在柚皮素母体上改造合成了5,7.二乙酰基柚皮素苯肼腙,具有显著的抑制肺癌NCI.H460和A549增殖活性,可以诱导肺癌肿瘤细胞在G前期凋亡.为EMAILCHEWXWEIYAHOO.CORN.CNRECEIVEDAPRIL18,2013;REVISEDMAY22,2013;PUBLISHEDONLINEMAY31,2013.PROJECTSUPPOSEDBYTHENATIONALNATURALSCIENCEFOUNDATIONOFCHINANO.81060261ANDTHENATURALSCIENCEFOUNDATIONOFGUANGXIPROVINCENO201IJJD20002.国家自然科学基金YO.8106026111广西科学自然科学基金重点NO.201LJJD20002资助项目.1988HTTP0C_JOURNALLCN/固2013CHINESECHEMICALS0C_ETYSIOC,CAS』ORGE,N20133319881993CHINESEJOURNALOFORGANICCHEMISTRY●此,我们将具有多种药效的腙基片段引入到橙皮素中,通过改变腙上取代基团的类型考察结构与细胞活性之问的构效关系,从而挖掘该产品潜在的应用价值.本研究以丰富易得的橙皮素为原料,以4.位羰基为改造位点,与水合肼作用合成橙皮素腙基,并在腙基础上与不同类型的醛缩合设计合成了一系列新型M亚苄基橙皮素腙3~L0及类似物11~16,MTT蛋白染色法体外抑制肿瘤细胞增殖活性测试发现化合物5,7,L0,16对SGC.7901细胞株具有显著的细胞活性.系列N亚苄基取代橙皮素腙类化合物的合成路线见SCHEME1,该合成路线步骤短、操作简捷、目标产物活性显著,可为进一步利用橙皮素资源、开发抗肿瘤药物提供依据.1结果与讨论在制备4.腙基橙皮素2时,先在醋酸催化下用2倍物质的量的水合肼回流反应,得到了黄色难溶性固体,点板成分较为复杂,柱层析也难以分离.主要原因为水合肼较少、反应温度较高时可能有双缩橙皮素腙等副产物生成.此外,橙皮素腙与原料点的风值基本相等,也为判别反应的进程造成了困难.通过多次条件优化得出橙皮素腙的合成最佳条件为过量的水合肼、60℃乙醇中反应4H,低温减压蒸干,加适量水溶解过量水合肼,并用乙酸乙酯萃取,有机层用饱和食盐水洗涤可得到纯的化合物2.鉴于化合物2的稳定性较弱,不宜长时间放置在后续实验中均从原料1开始制备化合物2,新制备的2直接参与下一步Ⅳ_亚苄基取代物的合成,化合物3~16的产率以原料1为基准计算.目标产物Ⅳ_亚苄基橙皮素腙及类似物3~L6中形成了ARCNNCHAR的长共轭结构而呈现黄色,分了结构趋于稳定.№OHO1NH2NH2’H20ETOH.REFLUXⅣ.亚苄基橙皮素腙3~L6中4一位碳原子FCN、亚苄基碳原子CHN及氧代芳香碳原子的化学位移相近,处于5145~168之间,碳原子的归属较为困难.为此,我们测定了多个化合物的CH远程相关,从HMBC的相关信号中归属了每个碳原子.其中4.位碳原子CN的化学位移位于163~168,亚苄基碳原子FCHN的化学位移位于153~159之间.化合物1中3.位CH2H和HH分别与2一位H分别呈反式SHJIL式图1,这可从值的大小加以判别.3一HA3.09,J_17.4,12.9HZ与H呈反式,值大;3一HH2.79,17.4,3.0HZ与H。呈顺式,值小;而当1转化成3时,3.H和3一HH的发生明显的不同变化,3一HH3.93,17.4,3.0HZ显著向低场移动,而3一H3.10,17.4,12.0HZ基本无变化.这是因为腙基上“ARCHN”结构上N原子与3HB距离较近,N原子对3.HB的吸电子作用使H明显向低场移动.所有Ⅳ_亚苄基腙及类似物3~16均存在相似的电子效应.3图1化合物1和3的结构FIGURE1STRUCTURESOFCOMPOUNDSOF1AND3OH、、,/ARCHOOHN\NH22ETOH.REFLUXO\㈤,~㈤,。,。,。㈣,,./.丫OCHH’,,,,1。4IOC,H3O,CHOCH,3CHINJORGCHEM2013,33,1988~19932013CHINESECHEMICALSOCIETYSIOC.CASHTTP//SIOCJOURNALCN/1989R6H3HO有机化学采用MTT噻唑蓝蛋白染色法,以胃癌细胞株SGC一7901作为筛查对象,并与顺铂为阳性对照,对化合物3~16进行了抗肿瘤活性评估表11.结果显示所合成的目标化合物比底物具有更好的抗肿瘤细胞增殖活性,化合物5,7,10,16对SGC.7901细胞株具有显著的抑制活性,IC50值分别位为10.6,6.9,9.8,9.6GMOLL~,活性比顺铂稍弱;4,6,15对SGC.7901细胞株有中等程度的抑制活性.初步的构效关系显示亚苄基结构上连有活泼的OH,NH有利于细胞活性的增强,而亚苄基结构为亲脂性萘、甲氧基苯结构时细胞活性明显减弱,这为设计合成新型的抗肿瘤药物以及此类化合物的构效关系研究提供有用参考.表1化合物3~L6对SGC.7901细胞株的半数抑制浓度IC50TABLE1HALFINHIBITORYCONCENTRATIONIC501OFCOMPOUNDS3~16AGAINSTSGC一7901CELLLINES2实验部分2.1试剂与仪器熔点在X4型显微熔点仪上测定,温度未校正;NMR用BRUKER.AV.III.300型核磁共振仪测定TMS为内标;高分辨率质谱用WATERSXEVOG2QT质谱仪;红外用NICOLETAVATERFT.IR360傅立叶红外光谱仪柱层析用硅胶青岛海洋化工厂产品.橙皮素购买白陕西锦泰生物工程有限公司.所用试剂为化学纯、溶剂为分析纯.2.24.腙基橙皮素2的合成在100ML烧瓶中将橙皮素302MG,1.00MMO1溶解于20ML95%乙醇中,在搅拌下加入过量的80%水合肼2.0ML48MMO1,油浴升温至60℃搅拌反应4H,旋转减压蒸干,加适量水,乙酸乙酯萃取3次,有机层依次用水、饱和食盐水洗涤,无水硫酸钠干燥,减压蒸干得浅棕色固体275MG.产率87.0%,M.P.216218℃;HNMRC2D60,300MHZ2.87DD,17.4,12.0HZ,1H,3AH,3.67DD,17.4,3.0HZ,1H,3BH,3.86S,3H,OCH3,5.1LDD,12.0,3.0HZ,1H,2一H,5.98D,J2.4HZ,1H,8一H,6.02D,J2.4HZ,1H,6H,6.96S,2H,5’,6’一H,7.03D,1.5HZ,1H,2H,7.84S,1H,3’OH,9.18S,1H,7OH,13.25S,1H,50H;IRKBRV3441,3018,2981,1620,1589,1522,1437,1351,L2711235,1154CM_。HRESIMSCALCDFORC16H17N20MHR317.1137,FOUND317.1115.2.3亚苄基橙皮素腙及类似物3~16的合成合成通法将新制备的橙皮素腙2溶解于装有15ML乙醇的100ML烧瓶中,加入各种取代的芳香醛1.O0MMO1,油浴升温至70℃搅拌反应2~6H,反应过程中原料点逐渐消失并伴有黄色固体生成.冷却减压抽滤、乙醇洗涤得黄色粉末状固体.部分反应冷却未出现沉淀,将反应液蒸干,硅胶柱层析分离『石油醚乙酸乙酯41~21,得黄色粉末状固体.N2氯亚苄基橙皮素腙3黄色粉末状固体328MG,产率75.0%.M.P.273275℃;HNMRC2D60,300MHZ3.10DD17.4,12.0HZ,1H,3BH13.88S,3H,OCH3,3.93DD,17.4,3.0HZ,1H,3AH,521DD,12.0,2.7HZ,1H,2H,6.02D,2.1HZ,1H,8H,6.05D,2.4HZ,IH,6H,7.00S,2H,5’,6L_H,7.08S,1H,2H,738~7.53M,3H,ARH,8.19DD,一8.7,1.5HZ,1H,ARH,8.93S,LH,NCH,12.97S,1H,SOH;IRKBR3424,2970,2901,1646,1434,1315,1L72CM;HRESIMSCALCDFORC23H2OC1N205MHI439.1061,FOUND439.1148.N2.羟基亚苄基橙皮素腙4淡黄色粉末状固体296MG.产率70.5%.M.P.249~251℃。HNMRDMSOD6,300MHZ3.58DD,17.1,12.0HZ,1H,3BH,4.04DD,17.1,3.0HZ,1H,3AH,4.33S,3H,OCH3,5.68DD,123,3.0HZ,1H,2H,13.22S,1H,5一OH,6.48D,J2.1HZ,1H,8H,6.52D,J2.4HZ,1H,6H,738~7.45M,5H,ARH,7.50S,2H,2H,7.81~7.87M,1H,ARH,8.00DD,7.8,1.5HZ,1H,ARH,9.28S,1H,NCH,13.22S,1H,50H;IRKBR3436,29492843,1638,1613,1577,1442,1356,1283,1241,1201,1148CM;HRESIMSCALCDFORC23H21N2O6『MH421.1400,FOUND421.1496.X3.羟基亚苄基橙皮索腙5黄色粉末状固体327MG产率77.8%.M.P.256~258。C;HNMRFC2D6O,300MHZ3.07DD,一17.4,12.0HZ,1H,L990HTTP//SIOCJOURNA1.CN/2013CHINESECHEMICALSOCIETY&SIOC,CASCHIN.ORG.CHEM.2013,33,1988~1993CHINESEJOURNALOFORGANICCHEMISTRY3B.H,3.91DD,L,一17.1,3.0HZ,1H,3AH,5.19DD,12.0,3.0HZ,1H,2H,6.01D,J2.4HZ,2H,6一H,6.04D,J2.4HZ,2H,6一H,6.95~6.99M,1H,ARH,7.01S,2H,5’,6’H,7.09S,1H,2F_H,7.317.42M,2H,ARH,8.53S,1H,NCH,13.08S,1H,5OH;IRKBRV3440,3023,2971,2933,1622,1589,L520,1437,1364,1279,1237,1155,113LCMHRESI.MSCALCDFORC23H21N206MH】十421.1400,FOUND421.1490.4.羟基亚苄基橙皮素腙6黄色粉末状固体304MG.产率72.4%.M.P.249~251℃HNMRC2D60,300MHZ3.05DD,17.4,12.0HZ,1H,3BH,3.87S,3H,OCH3,3.91DD,17.4,3.0HZ,1H,3AH,5.17DD,一12.0,3.0HZ,1H,2H,6.00D,J2.4HZ,2H,6一H,6.04D,J2.4HZ,2H,6H,6.93D,8.7HZ,2H,ARH,7.00S,2H,5’,6H,7.08S,1H,2’一H,7.76D,8.7HZ,2H,ARH,8.50S,1H,NCH,13.17S,1H,50H;IRKBRV3432,3281,2966,2945,1597,L515,1450,1374,1307,1286,L】56CMHRESIMSCALCDFORC23H21N206MH421.1400,FOUND421.1494.X3一甲氧基一4.羟基亚苄基橙皮素腙7黄色粉末状固体297MG,产率65.8%.M.P.262264℃;。HNMRDMSO一,300MHZ3.09DD,17.4,11.7HZ,1H,3BH,3.74DD,一17.1,2.7HZ,1H,3AH,3.79S,3H,OCH3,3.79S,3H,OCH3,5.17DD,L1.7,2.7HZ,1H,2H,5.89D,一2.4HZ,LH,8一H,5.93D,2.4HZ,1H,6H,6.84~6.96M,4H,ARH,7_30DD,L,一8.1,1.5HZ,1H,ARH,7.41D,1.8HZ,1H,ARH,8.50S,1H,NCH,9.09S,1H,OH,9.73S,1H,3’OH,10.15S,1H,7一OH,13.24S,1H,50H;IRKBRV3444,2909,1659,1642,1626,1454,1430,1270,1160CMHRESI.MSCALCDFORC24H23N207MH十451.1505,FOUND451.1546.N3,4一二甲氧基亚苄基橙皮素腙8浅黄色粉末状固体372MG,产率80.2%.M.P.263265℃HNMRC2D60,300MHZ3.IIDD,一L7.4,11.70HZ,1H,3BH,3.74DD,L7.4,3.0HZ,1H,3AH,3.78S,3H,OCH3,3.78S,3H,OCH3,3.8S,3H,0CH3,5.18DD,L1.7,3.0HZ,1H,2H,5.89D,J2.4HZ,1H,8一H,5.93D,J2.1HZ,1H,6一H,6.886.92M,3H,ARH,7.04D,8.4HZ,LH,5H,7.40DD,,8.4,1.5HZ,1H,ARH,7.44D,1.5HZ,1H,ARH,8.55S,1H,NCH,9.09S,1H,5OH,10.18S,1H,5一OH,13.23S,1H,5一OH;IRKBRV3436,2970,2917,2848,1650,1634,1601,1511,1438,1377。12741152.1123CMHRESIMSCALCDFORC25H25N207MH465.1662,FOUND465.1648.N3,4,5一三甲氧基亚苄基橙皮素腙9浅黄色粉末状固体393MG,产率78.9%.M.P.247249OC。HNMRC2060,300MHZ3.09DD,17.4,12.0HZ,1H,3BH,3.79S,3H,OCH3,3.87S,3H,OCH3,3.87S,3H,OCH3,3.90S,3H,OCH3,3.91DD,L,17.4,3.0HZ,LH,3AH,5.17DD,一12.0,3.0HZ,1H,2H,5.99D,J2.4HZ,1H,8H,6.04D,J2.1HZ,1H,6H,6.99S,2H,5’,6’H,7.07S,1H,2’H,7.22D,8.4HZ,2H,ARH,8.51S,1H,NCH,13.15S,1H,50H;IRKBRV3456,2994,2929,2835,1646,1621,1593,1503,1458,1409,1315,1278,1237,LL55,1131CMHRESI.MSCALCDFORC26H27N2OSMH495.1767,FOUND495.1881.4一Ⅳ,Ⅳ_二甲基亚苄基橙皮素腙10腙色粉末状固体252MG,产率56.5%.M.P.160~162℃HNMRC2D60,300MHZ3.02DD,17.1,L2.3HZ,1H,3BH,3.07S,6H,NCH32,3.87S,3H,OCH3,3.92DD,17.1,3.0HZ,1H,3AH,5.15DD,L,12.0,3.0HZ,1H,2H,5.99D,J2.1HZ,1H,8一H,6.03D,J2.1HZ,1H,6H,6.77D,8.7HZ,2H,ARH,6.99S,2H,5’,6H,7.08S,1H,2H,7.71D,J8.7HZ,2H,ARH,8.43S,1H,NCH,13.27S,1H,50H;IRKBRV3444,2974,2917,2852,1642,1626,1556,1434,1409,1360,1290,1180,1155CM;HRESI.MSCALCDFORC25H26N305MH448.1872,FOUND448.1968.N3.吡啶亚甲基橙皮素腙11黄色粉末状固体222MG,产率54.8%.M.P.119~121℃HNMRDMSO,300MHZ3.12DD,一17.4,12.0HZ,1H,3BH,3.88S,3H,OCH3,3.95DD,17.4,3.0HZ,1H,3AH,5.22DD,12.0,3.0HZ,1H,2H,6.01D,J2.1HZ,1H,8H,6.04D,2.4HZ,1H,6一H,7.00S,2H,5’,6H,7.08S,1H,2H,7.48DD,L,7.8,4.8HZ,1H,ARH,8.30DD,7.8,1.5HZ,1H,ARH,8.66DD,一4.8,1.5HZ,IH,ARH,8.69S,1H,NCH,9.03D,1.8HZ,1H,ARH,13.00S,1H,5一OH;IRKBRV3456,2962,913,2847,1654,1642,1454,1429,1368,13431278,1160CM_。;HRESIMSCALCDFORC22H20N3O5MHR406.1403.FOUND406.1479.X3.噻吩亚甲基橙皮素腙12黄色粉末状固体323MG,产率78.8%.M.P.200~202℃HNMRC2D60,300MHZ3.06DD,17.4,12.0HZ,1H,3BH,3.88S,3H,OCH3,3.89DD,L,17,4,3.0HZ,1H,3AH,5.18DD,12.0,3.0HZ,1H,2H,6.00D,J2.1CHIN.JORG.CHEM.2013,33,198819932013CHINESECHEMICALSOCIETY&SIOC,CASHTTP//SIOCJOURNALCN/1991有机化学HZ,1H,8一H,6.03D,J2.1HZ,1H,6一H,7.00S,2H,5’,6’一H,7.08S,LH,2’H,7.55DD,7.8,2.7HZ,1H,ARH,7.64D,.,5.1HZ,1H,ARH,7.75S,1H,3OH,8.02D,3.0HZ,1H,ARH,8.64S,1H,NCH,9.12S,1H,7OH,13.08S,1H,50H;IRKBR3456,2970,2917,2852,1642,1614,1561,1462,1434,1373,1279,L151CLTI一HR.ESIMSCALCDFORC21H1IN2OS『MHR4L1.1015,FOUND4L1.1082.N1.萘亚甲基橙皮素腙13黄色针状固体307MG,产率67.6%.M.P.195~197℃;HNMRC2D60,300MHZ13.2LDD,17.4,12.0HZ,1H3B.H,3.95S,3H,OCH3,3.97DD,L7.4,3.0HZ,1H,3AH,5.26DD,11.7,2.7HZ,1H,2H,6.03D,1.5HZ,1H,8一H,6.07D,_,1.5HZ,1H,6一H,7.02S,2H,5’,6’一H,7.1LS,1H,2’H,7.57~7.66M,3H,ARH,7.77S,1H,ARH,8.01D,7.5HZ,1H,ARH,8.07D,J2.1HZ,1H,ARH,8.16D,J7.2HZ,1H,ARH,9.03D,8.1HZ,1H,ARH,9.18S,1H,OH,930S,1H,NCH,L3.15S,1H,50H;IRKBRV3432,2974,2917,2848,1626,L6051544,1520,1442,1356,1287,1254,L156,LL31CM;HRESIMSCALCDFORC27H23N205MHR455.1607.FOUND455.1721.N6.甲氧基一3.萘亚甲基橙皮素腙14黄色粉末状固体340MG,产率70_3%.M.P.294~296℃;HNMRDMSO一,300MHZ3.14DD,17.4,12.0HZ,1H,3BH,3.79S,3H,OCH3,3.90S,3H,OCH3,3.82DD,17.4,3.0HZ,1H,3AH,5.20DD,T,11.7,2.7HZ,1H,2H,5.91D,J2.4HZ,1H

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