CN105237504B - 杨梅素含氮类衍生物及其制备方法和用途 - Google Patents
杨梅素含氮类衍生物及其制备方法和用途 Download PDFInfo
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- CN105237504B CN105237504B CN201510621302.5A CN201510621302A CN105237504B CN 105237504 B CN105237504 B CN 105237504B CN 201510621302 A CN201510621302 A CN 201510621302A CN 105237504 B CN105237504 B CN 105237504B
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- myricetin
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- chromene
- trimethoxyphenyls
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- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
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- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
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- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
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- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
本发明涉及一种杨梅素含氮类衍生物及其制备方法和用途,其化合物结构有下列通式(III)表示。本发明介绍了以杨梅苷、卤代烷烃、仲胺、六水合哌嗪、芳香酸、取代芳香酸、溴乙酸乙酯、水合肼、芳香醛以及取代芳香醛为原料,经取代、水解和缩合反应合成一系列杨梅素含氮类衍生物。该类化合物对癌细胞有较好的抑制作用,且毒性较小,可用于制备抗癌药物。
Description
技术领域
本发明涉及具有抗癌作用的含杨梅素氮类衍生物及制备方法和用途。
背景技术
杨梅素(3',4',5',3,5,7-六羟基黄酮醇,Myricetin),杨梅素广泛的存在于壳斗科(Fagaceae)、豆科(Leguminosae)、报春(Pfimulaceae)、葡萄科(Vitaceae)、菊科(Compositae)等植物中,杨梅素通常存在于我们日常食用的水果,蔬菜和和饮料中,例如:茶和红酒等。有研究表明:杨梅素具有抗癌、抗氧化(Ong,K.C.;Khoo,H.E.Biologicaleffectsofmyricetin[J].GeneralPharmacology:TheVascularSystem,1997,29(2):121-126)、抗病毒(Ono,K.;Nakane,H.;Fukushima,M.;etal.DifferentialinhibitoryeffectsofvariousflavonoidsontheactivitiesofreversetranscriptaseandcellularDNAandRNApolymerases[J].EuropeanJournalofBiochemistry,1990,190(3):469-476)、抗炎(Lee,Y.S.;Choi,E.M.MyricetininhibitsIL-1β-inducedinflammatorymediatorsinSW982humansynovialsarcomacells[J].InternationalImmunopharmacology,2010,10(7):812-814)、抑菌(El-Gammal,A.A.;Mansour,R.Antimicrobialactivitiesofsomeflavonoidcompounds[J].ZentralblattfürMikrobiologie,1986,141(7):561-565)等多种药理活性。
目前其在抗癌活性方面的研究较多,对人类多种肿瘤细胞有明显的抑制作用(张秀娟,黄清玲,季宇彬.杨梅素的药理活性研究进展[J].天津药学,2008,20(5):57-60)。现代医学证明杨梅素在肿瘤发生发展的多个阶段均有作用,包括肿瘤细胞的增殖、诱导肿瘤细胞的分化和凋亡,以及抑制肿瘤的发生和转移。由于杨梅素具有抗肿瘤谱广泛,对正常细胞毒性低,同时能增强免疫力的作用,因此在开发新型的抗肿瘤药物领域,杨梅素以及杨梅素的衍生物得到了越来越多的关注。
2007年,Lee(K.W.;Kang,N.J.;Rogozin,E.A.;etal.MyricetinisanovelnaturalinhibitorofneoplasticcelltransformationandMEK1[J].Carcinogenesis,2007,28(9):1918-1927)发现杨梅素在浓度为10μmol/L下对JP6P+小鼠表皮细胞的恶性肿瘤转化及增殖具有明显抑制作用,其机制是阻断MEK/ERK/AP-1信号路径;杨梅素还可抑制蛋氨酸及Akt的活性,影响成髓细胞瘤肌动蛋白细胞骨架重组,遏制成髓瘤细胞在转移过程中由肝细胞生长因子导致的形态学变化,从而抑制其转移,其IC50值为6μmol/L(Labbé,D.;Provencal,M.;Lamy,S.;etal.Theflavonolsquercetin,kaempferol,andmyricetininhibithepatocytegrowthfactor-inducedmedulloblastomacellmigration[J].TheJournalofnutrition,2009,139(4):646-652)。
2009年,张莉静等(张莉静,刘志国,孟大利,夏明钰.杨梅树皮提取物及杨梅素抗肿瘤活性[J].沈阳药科大学学报,2009,26(4):307-311)对杨梅素单体化合物进行体外抗肿瘤研究,研究表明:杨梅素对人***HeLa细胞、人黑色素瘤A375-S2细胞、人乳腺癌MCF-7细胞和人肝癌HepG2细胞均具有明显的细胞毒作用,杨梅素明显抑制HeLa细胞的增殖,诱导HeLa细胞调亡。
2010年,张秀娟等(张秀娟,凌云,于华,季宇彬.杨梅树皮素诱导人肝癌HepG-2细胞凋亡机制的研究[J].中国中药杂志,2010,35(8):1046-1050)探讨了杨梅素对人肝癌HepG-2抑制生长和诱导凋亡作用及其机制,研究表明:杨梅素对人肝癌HepG-2细胞生长具有明显的抑制作用,并具有剂量依赖性,IC50为58.6617mg/L;杨梅素作用72h后,HepG-2细胞呈现典型细胞凋亡特征,细胞周期阻滞于G2/M期,凋亡率最高为64.73%。2011年,Zhang等(Zhang,X.;Zou,Z.;Xu,C.;etal.MyricetininducesG2/MphasearrestinHepG2cellsbyinhibitingtheactivityofthecyclinB/Cdc2complex[J].MolMedReport,2011,4:273-277)进一步研究了杨梅素对肝癌细胞的作用机制,发现杨梅素是通过降低肝癌细胞中Cdc2和周期蛋白B1的水平,从而抑制肝癌细胞的生长繁殖。
2010年,韦伟等(Wei,W.,EffectsofmyricetinontheapoptosisofbladdercancercellBIU-87[J].JournalofChongqingMedicalUniversity,2010,35(12):1791-1793)研究了杨梅素诱导膀胱癌细胞株BIU-87凋亡的机制,通过培养人膀胱癌细胞株BIU-87,加入不同浓度杨梅素干扰,在倒置显微镜下观察细胞形态学变化;并利用MTT及Hoechst33258染色法检测杨梅素对膀胱癌细胞株BIU-87凋亡的影响;后用RT-PCR检测细胞凋亡相关基因survivin及caspase-3转录水平的改变,免疫印迹法检测survivin和caspase-3的表达情况,结果表明:杨梅素能诱导膀胱癌细胞BIU-87细胞凋亡,并明显抑制survivin的转录和表达,同时对caspase-3有上调作用。
2011年,Phillips等(Phillips,P.;Sangwan,V.;Borja-Cacho,D.;etal.Myricetininducespancreaticcancercelldeathviatheinductionofapoptosisandinhibitionofthephosphatidylinositol3-kinase(PI3K)signalingpathway[J].Cancerletters,2011,308(2):181-188)研究了杨梅素对胰腺癌细胞在体内与体外的作用。研究发现,杨梅素在25μmol/L~200μmol/L呈剂量依耐性地抑制AktL磷酸化,能降低PI3激酶的活性,诱导体外胰腺癌细胞凋亡死亡;在体内,杨梅素通过对肿瘤的消减和癌细胞的转移来治疗胰腺肿瘤。
2011年,Kang等(Kang,N.J.;Jung,S.K.;Lee,K.W.;etal.Myricetinisapotentchemopreventivephytochemicalinskincarcinogenesis[J].AnnalsoftheNewYorkAcademyofSciences,2011,1229(1):124-132)研究了杨梅素对小鼠皮肤癌细胞的抑制作用,研究发现:杨梅素是通过减弱紫外线B,诱导COX-2的表达,从而抑制皮肤癌凋亡;通过作用靶标抑菌作用PI3-K诱导的血管生成,因此,杨梅素是一个有前途的抑制癌细胞生长的化学预防剂。
发明内容
本发明的目的在于设计合成一系列结构新颖的杨梅素含氮类衍生物,该类化合物以天然产物杨梅苷为先导,通过结构修饰合成了一系列杨梅素衍生物,经抗癌活性测试表明,杨梅素衍生物和杨梅素及现有商品化药剂EpirubicinHydrochloride相比抗癌活性明显提高,并且杨梅素衍生物对乳腺癌细胞(MDA-MB-231)的细胞毒性较小,该类化合物可作为抑制癌细胞的药物。所制备的杨梅素含氮类衍生物结构由下列通式(III)表示:
R3为(1)苯基或取代苯基;(2)杂环基包括吡啶基、呋喃基、噻吩基、吡咯基;
取代苯基为苯环上含有一个或多个甲基、乙基、甲氧基、乙氧基、正丙基、异丙基、三氟甲基、硝基、胺基。
本发明内容中,取代苯基可为苯环上含有一个或多个甲基、乙基、甲氧基、乙氧基、
正丙基、异丙基、三氟甲基、硝基、胺基。
本发明内容中,化合物具有抗肿瘤活性,特征是对人乳腺癌细胞(MDA-MB-231)有着良好的活性,用途是在制备抗癌药物中的应用。
本发明通式(III)化合物的制备方法是以杨梅苷、卤代烷烃、溴乙酸乙酯、水合肼、芳香醛以及取代芳香醛为原料,经取代、水解和缩合反应合成目标产物,其合成路线为:
合成方法如下:
第一步:3-羟基-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的制备
在圆底烧瓶中加入杨梅苷和K2CO3溶于DMF中,搅拌均匀后,缓慢的滴加碘甲烷,
室温搅拌数小时,停止反应后,用水分散,用乙酸乙酯萃取,合并滤液,合并有机相,减压浓缩,然后将浓缩物溶于无水乙醇,升温至回流,溶液澄清后,回流下加入浓盐酸,慢慢的有黄色固体析出,继续反应2h,冷却,冰箱放置过夜,过滤,得到粗产物,不需要纯化,直接用于下一步的反应,
第二步:3-氧乙酸乙酯-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的制备
在三口瓶中依次加入第一步的产物,K2CO3和无水丙酮,室温搅拌均匀后,滴加溴乙酸乙酯,滴毕,回流反应数小时,停止反应后,冷却至室温,浓缩后倒入冰水中,析晶,抽滤,滤饼用氯仿/水重结晶得到目标产物,
第三步:2-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基)氧基)乙酰肼的制备
在三口瓶中依次加入第二步的产物,80%水合肼和无水乙醇,回流反应,TCL点板跟踪,直至反应完全,减压浓缩除去大量溶剂后,冷却,有沉淀产生析出,抽滤,滤饼用无水乙醇重结晶得到目标产物,
第四步:杨梅素酰腙类衍生物的制备
在三口瓶中依次加入第三步的产物和芳香醛,用无水乙醇溶解,滴入催化量的醋酸,搅拌加热回流,TLC点板跟踪,直至反应完全,浓缩反应液,冷却,有大量的沉淀析出,抽滤,滤饼用无水乙醇重结晶得到目标产物。
本步骤适用于所有上述目标化合物杨梅素含氮类衍生物的合成。
本发明路线和制备方法已合成并证明有抗癌作用的化合物如下:
化合物22:2-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基)氧基)-N'-(2-氟亚苄基)乙酰肼
化合物23:2-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基)氧基)-N'-(4-甲基亚苄基)乙酰肼
化合物24:2-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基)氧基)-N'-(吡啶-2-基亚甲基)乙酰肼
化合物25:2-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基)氧基)-N'-(呋喃-2-基亚甲基)乙酰肼
化合物26:2-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基)氧基)-N'-((3-甲基噻吩-2-基)亚甲基)乙酰肼
化合物27:N'-((1H-吡咯-2-基)亚甲基)-2-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基)氧基)乙酰肼
本发明合成的杨梅素含氮类衍生物具有较好的抗癌活性,可用于制备抗癌药物。
附图说明
图1:化合物(9-18)在设定浓度下对乳腺癌细胞MDA-MB-231作用24、48、72小时的形态学影响。
图2:化合物(19-27)在设定浓度下对乳腺癌细胞MDA-MB-231作用24、48、72小时的形态学影响。
本发明涉及到的27个杨梅素含氮类衍生物都对目标肿瘤有良好的抑制活性,阳性药对肿瘤细胞的毒性明显太大(使得细胞全部破碎裂解),而本实验合成的化合物基本对目标细胞损伤很小,这种抑制活性主要体现在抑制细胞的增殖(细胞数量与对照相比明显变少),或者诱导细胞分化(从形态学观察得出,细胞在数目减少的同时,细胞发生了变形,但是损伤不是很明显),所以这些药对目标肿瘤有非常的抑制活性,值得进一步进行深入研究。
具体实施方式
本具体实施实例仅仅是对本发明的解释,但不限制本发明,本领域及时人员在阅读完本说明书后可以根据需要对本实施实例做出没有创造性贡献的修改,但只要在本发明的权利要求范围内的都受到专利法的保护。
实施实例一、3-(3-(二乙基氨-1-基)丙氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(化合物1)
(1)3-羟基-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的合成
在圆底烧瓶中加入杨梅苷2.32g(5mmol)溶于60mLDMF中11.06g(16mmol)K2CO3
搅拌10min后,缓慢的加入10mL(32mmol)碘甲烷,室温搅拌60h,过滤沉淀,并用乙酸乙酯洗涤,合并滤液,将滤液倒入100mL水中,用乙酸乙酯萃取三次,合并有机相,减压浓缩,然后将浓缩物溶于30mL的无水乙醇,升温至回流,溶液澄清后,回流下加入8mL浓盐酸,慢慢的有黄色固体析出,继续反应2h,冷却,冰箱放置过夜,过滤,得到粗产物A,粗产物A不需要纯化,直接用于下一步的反应。
(2)3-(3-溴丙氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的合成
在圆底烧瓶中加入上一步的产物A1.17g(3mmol)和1.66g(12mmol)K2CO3,用30mL的DMF溶解后,加入2.42g(12mmol)1,3-二溴丙烷,在室温下反应12h,乙酸乙酯为展开剂点板跟踪反应,停止反应后,用50mL的水分散,以乙酸乙酯萃取3次,每次25ml,得到有机相依次用1N的HCl,饱和NaHCO3,饱和NaCl水溶液分别洗涤2次后,合并乙酸乙酯层,用无水硫酸钠干燥后蒸去溶剂,用减压柱层析(石油醚:乙酸乙酯=2:1,V/V),得到中间体B1。
(3)目标化合物3-(3-(二乙基氨-1-基)丙氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的合成:
在圆底烧瓶中加入上一步的产物B10.25g(0.5mmol),无水K2CO30.14g(1mmol),和25mLDMF,搅拌10min后加入0.70g(1mmol)二乙胺,在室温下反应24h,以(氯仿:甲醇=5:1,V/V)为展开剂点板跟踪反应,停止反应后,加入50mL水分散,用乙酸乙酯萃取三次,每次25ml,合并有机相1N的HCl,饱和NaHCO3,饱和NaCl水溶液分别洗涤2次后,合并乙酸乙酯层,用无水硫酸钠干燥后蒸去溶剂,用减压柱层析(氯仿:甲醇=10:1,V/V),得到目标产物。
实施实例二、5,7-二甲氧基-3-(4-(吡咯烷-1-基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(化合物7)
(1)3-羟基-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的合成
如实施实例一(1)条件和方法合成。
(2)3-(4-溴丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的合成
如实施实例一(2)条件和方法合成,区别在于加入2.56g的1,4-二溴丁烷。
(3)5,7-二甲氧基-3-(4-(吡咯烷-1-基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的合成:
如实施实例一(3)条件和方法合成,区别在于加入0.68g的吡咯烷。
利用类似的合成方法,已合成的部分含杂环烷基类杨梅素衍生物的结构如下所示:
实施实例三、5,7-二甲氧基-3-(4-(哌嗪-1-基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-
(1)3-羟基-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的合成
如实施实例一(1)条件和方法合成。
(2)3-(4-溴丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的合成
如实施实例二(2)条件和方法合成。
(3)5,7-二甲氧基-3-(4-(哌嗪-1-基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的合成:
在圆底烧瓶中加入上一步的产物1.05g(2mmol),无水K2CO31.38g(10mmol),和50mLDMF,搅拌10min后加入1.94g(10mmol)六水合哌嗪哌嗪,在室温下反应24h,以(氯仿:甲醇=5:1,V/V)为展开剂点板跟踪反应,停止反应后,加入50mL水分散,用乙酸乙酯萃取三次,合并有机相1N的HCl,饱和NaHCO3,饱和NaCl水溶液分别洗涤2次后,合并乙酸乙酯层,用无水硫酸钠干燥后蒸去溶剂,用减压柱层析(氯仿:甲醇=15:1,V/V),得到目标产物。
实施实例四、3-(4-(4-(4-氟苯甲酰基)哌嗪-1-基)丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(化合物12)
(1)3-羟基-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的合成
如实施实例一(1)条件和方法合成。
(2)3-(4-溴丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的制备
如实施实例二(2)条件和方法合成。
(3)5,7-二甲氧基-3-(4-(哌嗪-1-基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的合成
如实施实例三(3)条件和方法合成。
(4)3-(4-(4-(4-氟苯甲酰基)哌嗪-1-基)丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的合成:
在圆底烧瓶中,在冰浴条件下,加入对氟苯甲酸0.046g(0.33mmoL)以及HATU0.137g(0.36mmoL),以10mL的干燥DCM溶解后加入1mL的三乙胺一起在冰浴下搅拌30min,然后除去冰浴,加入第三步的产物0.159g(0.3mmoL)在室温下反应12h,TLC跟踪反应至无明显变化(展开剂:氯仿:甲醇=5:1,V/V),停止反应后,用水洗涤反应液3次,每次20mL,无水硫酸钠干燥后减压除去DCM,然后减压柱层析分离(氯仿:甲醇=10:1,V/V),得到目标产物。
实施实例五、3-(4-(4-(4-氯苯甲酰基)哌嗪-1-基)丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(化合物13)
(1)3-羟基-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的合成
如实施实例一(1)条件和方法合成。
(2)3-氧(4-溴代丁基)-3’,4’,5,5’,7-五甲氧基杨梅素的制备
如实施实例二(2)条件和方法合成。
(3)5,7-二甲氧基-3-(4-(哌嗪-1-基)丁氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的合成
如实施实例三(3)条件和方法合成。
(4)3-(4-(4-(4-氯苯甲酰基)哌嗪-1-基)丁氧基)-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的合成:
如实施实例三(4)条件和方法合成,区别在于加入0.052g的对氯苯甲酸。
利用类似的合成方法,已合成的部分哌嗪酰胺类杨梅素的衍生物的结构如下所示:
实施实例六、2-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基)氧基)-N'-(2-氟亚苄基)乙酰肼(化合物22)
(1)3-羟基-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的合成
如实施实例一(1)条件和方法合成。
(2)3-氧乙酸乙酯-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的制备
在三口瓶中依次加入第一步的产物1.17g(3mmol),无水K2CO30.5g(3.6mmol)和无水丙酮30mL,室温搅拌30min后,滴加溴乙酸乙酯0.4mL(3.6mmol),滴毕,回流反应24h,冷却至室温,减压浓缩后倒入冰水中,析晶,抽滤,滤饼用氯仿/水重结晶得到目标产物。
(3)2-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基)氧基)乙酰肼的制备
在三口瓶中依次加入第二步的产物1.42g(3mmol),80%水合肼0.66mL(10mmol)和无水乙醇30mL,搅拌下回流反应2h,TCL点板跟踪,直至反应完全,减压除去大量溶剂,冷却,析晶,抽滤,滤饼用无水乙醇重结晶得到目标产物。
(4)2-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基)氧基)-N'-(2-氟亚苄基)乙酰肼的合成:
在三口瓶中依次加入第三步的产物0.15g(0.33mmol),邻氟苯甲醛0.045g(0.36mmol),25mL无水乙醇及催化量醋酸,搅拌加热回流2h,TLC点板跟踪,直至反应完全,浓缩反应液,冷却,析晶,抽滤,滤饼用无水乙醇重结晶得到目标产物。
实施实例七、2-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基)氧基)-N'-(4-甲基亚苄基)乙酰肼(化合物23)
(1)3-羟基-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的合成
如实施实例一(1)条件和方法合成。
(2)3-氧乙酸乙酯-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的制备
如实施实例六(2)条件和方法合成。
(3)2-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基)氧基)乙酰肼的制备
如实施实例六(3)条件和方法合成。
(4)2-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基)氧基)-N'-(4-甲基亚苄基)乙酰肼的合成:
如实施实例六(4)条件和方法合成,区别在于加入加入0.044g的对甲基苯甲醛。
利用类似的合成方法,已合成的部分杨梅素酰腙类衍生物的结构如下所示:
合成的杨梅素含氮类衍生物的波谱数据如下:
2-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基)氧基)-N'-(2-氟苄基)乙酰肼(化合物22)
黄色固体,产率:78.4%,m.p.136~138℃;IR(KBr,cm-1):νmax1699,1683,1620,1604,1558,1417,1361,1246,1207,1124,1109,1012,819;1HNMR(500MHz,CDCl3)δ:3.92-3.99(m,15H,5×OCH3),4.35(s,2H,CH2),6.40(d,J=2.3Hz,1H,H-6),6.54(d,J=2.3Hz,1H,H-8),7.07(J=18.9Hz,1H),7.16(t,J=14.9Hz,1H),7.22(overlappings,2H,H-2’,H-6’),7.35(q,J=20.6Hz,1H),8.15(t,J=13.7Hz,1H),9.65(s,1H,NH),12.35(s,1H,N=CH);13CNMR(125MHz,CDCl3)δ:174.7(C-4),165.6(C=O),164.7(C-7),161.1(C-9),160.6(C),159.1(C-2),154.2(C-5),153.6(C-3’,C-5’),142.6(CH),141.3(C-4’),140.8(C-3),132.0(CH),127.6(CH),124.8(C-1’),124.4(CH),121.8(C),115.7(CH),108.8(C-10),105.7(C-6’,C-2’),96.5(C-6),92.7(C-8),73.2(OCH2),61.2(4’-OCH3),56.6(7-OCH3),56.5(3’,5’-OCH3),56.0(8-OCH3);MS(ESI,m/z):567.3[M+H]+,589.2[M+Na]+.
2-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基)氧基)-N'-(4-甲基亚苄基)乙酰肼(化合物23)
灰白色固体,产率:82.3%,m.p.152~154℃;IR(KBr,cm-1):νmax1699,1683,1620,1604,1558,1506,1417,1354,1247,1219,1124,1109,1011,819;1HNMR(500MHz,CDCl3)δ:2.36(s,3H,CH3),3.92-3.99(m,15H,5×OCH3),4.35(s,2H,CH2),6.40(d,J=2.3Hz,1H,H-6),6.54(d,J=2.3Hz,1H,H-8),7.19(d,J=8Hz,2H,2CH),7.21(overlappings,2H,H-2’,H-6’),7.71(d,J=8Hz,2H,CH),8.35(s,1H,NH),12.10(s,1H,N=CH);13CNMR(125MHz,CDCl3)δ:174.7(C-4),165.2(C=O),164.9(C-7),161.1(C-9),159.1(C-2),154.2(C-5),153.6(C-3’,C-5’),149.5(C),141.5(C-4’),140.8(C-3),131.1(C),129.6(CH),129.4(CH),128.5(CH),127.9(CH),124.8(C-1’),108.8(C-10),105.7(C-6’,C-2’),96.5(C-6),92.8(C-8),73.3(OCH2),61.2(4’-OCH3),56.7(7-OCH3),56.5(3’,5’-OCH3),56.0(8-OCH3),21.7(CH3);MS(ESI,m/z):563.3[M+H]+,585.3[M+Na]+.
2-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基)氧基)-N'-(吡啶-2-基甲基)乙酰肼(化合物24)
淡黄色固体,产率:55.6%,m.p.176~178℃;IR(KBr,cm-1):νmax1699,1683,1602,1588,1506,1417,1361,1244,1211,1126,1012,819;1HNMR(500MHz,CDCl3)δ:3.92-3.99(m,15H,5×OCH3),4.36(s,2H,CH2),6.40(d,J=2.3Hz,1H,H-6),6.53(d,J=2.3Hz,1H,H-8),7.22(overlappings,2H,H-2’,H-6’),7.27(t,J=13.3Hz,1H),7.71(t,J=15.4Hz,1H),8.20(d,J=8Hz,1H),8.53(s,1H,NH),8.62(d,J=4.6Hz,1H),12.53(s,1H,N=CH);13CNMR(125MHz,CDCl3)δ:174.7(C-4),165.9(C=O),164.8(C-7),161.2(C-9),159.1(C-2),154.1(C-5),153.6(C-3’,C-5’),153.3(C),149.6(CH),149.4(CH),141.4(C-4’),140.8(C-3),136.4(CH),127.6(CH),124.8(C-1’),121.3(CH),108.8(C-10),105.7(C-6’,C-2’),96.5(C-6),92.7(C-8),73.2(OCH2),61.2(4’-OCH3),56.6(7-OCH3),56.5(3’,5’-OCH3),56.0(8-OCH3);MS(ESI,m/z):550.3[M+H]+,572.2[M+Na]+.
2-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基)氧基)-N'-(呋喃-2-基亚甲基)乙酰肼(化合物25)
灰白色固体,产率:73.2%,m.p.172~174℃;IR(KBr,cm-1):νmax1699,1683,1608,1558,1506,1417,1359,1246,1217,1126,1066,1014,819;1HNMR(500MHz,CDCl3)δ:3.92-3.99(m,15H,5×OCH3),4.32(s,2H,CH2),6.41(d,J=2.3Hz,1H,H-6),6.48(q,J=5.1Hz,1H,CH),6.54(d,J=2.3Hz,1H,H-8),6.86(d,J=3.4Hz,1H,CH),7.20(overlappings,2H,H-2’,H-6’),7.51(d,J=1.15Hz,1H,CH),8.30(s,1H,NH),12.25(s,1H,N=CH);13CNMR(125MHz,CDCl3)δ:174.8(C-4),165.2(C=O),164.9(C-7),161.1(C-9),159.1(C-2),154.2(C-5),153.6(C-3’,C-5’),149.5(C),144.7(CH),141.5(C-4’),140.8(C-3),138.8(CH),124.8(C-1’),113.3(CH),111.9(CH),108.8(C-10),105.7(C-6’,C-2’),96.6(C-6),92.8(C-8),73.3(OCH2),61.2(4’-OCH3),56.7(7-OCH3),56.5(3’,5’-OCH3),56.0(8-OCH3);MS(ESI,m/z):539.3[M+H]+,561.2[M+Na]+.
2-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基)氧基)-N'-((3-甲基噻吩-2-基)亚甲基)乙酰肼(化合物26)
灰白色固体,产率:65.9%,m.p.132~134℃;IR(KBr,cm-1):νmax1699,1681,1620,1606,1558,1506,1417,1354,1246,1217,1126,1107,1064,1010,816;1HNMR(500MHz,CDCl3)δ:2.42(s,3H,CH3),3.92-3.99(m,15H,5×OCH3),4.32(s,2H,CH2),6.41(d,J=2.3Hz,1H,H-6),6.54(d,J=2.3Hz,1H,H-8),6.84(d,J=5.15Hz,1H,CH),7.21(overlappings,2H,H-2’,H-6’),7.28(d,J=5.15Hz,1H,CH),8.63(s,1H,NH),12.08(s,1H,N=CH);13CNMR(125MHz,CDCl3)δ:174.7(C-4),164.9(C=O),164.9(C-7),161.1(C-9),159.1(C-2),154.1(C-5),153.6(C-3’,C-5’),144.1(C),141.4(C-4’),140.8(C-3),140.5(C),132.5(CH),130.5(CH),128.0(CH),124.8(C-1’),108.8(C-10),105.7(C-6’,C-2’),96.5(C-6),92.8(C-8),73.3(OCH2),61.2(4’-OCH3),56.7(7-OCH3),56.5(3’,5’-OCH3),56.0(8-OCH3),14.2(CH3);MS(ESI,m/z):569.2[M+H]+,591.2[M+Na]+
N'-((1H-吡咯-2-基)亚甲基)-2-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基)氧基)乙酰肼(化合物27)
灰白色固体,产率:72.4%,m.p.135~137℃;IR(KBr,cm-1):νmax1699,1681,1620,1602,1558,1506,1417,1354,1244,1213,1126,1107,1039,1006,815;1HNMR(500MHz,CDCl3)δ:3.92-4.00(m,15H,5×OCH3),4.32(s,2H,CH2),6.25(d,J=2.3Hz,1H,H-6),6.41(d,J=2.3Hz,1H,H-8),6.54(m,2H,2CH),6.91(s,1H,CH),7.21(overlappings,2H,H-2’,H-6’),8.23(s,1H,NH),9.54(s,1H,NH),12.11(s,1H,N=CH);13CNMR(125MHz,CDCl3)δ:174.8(C-4),165.2(C=O),164.9(C-7),161.0(C-9),159.1(C-2),154.1(C-5),153.6(C-3’,C-5’),141.4(C-4’),140.8(C-3),140.8(CH),127.2(C),124.8(C-1’),124.3(CH),114.8(CH),109.8(CH),108.8(C-10),105.7(C-6’,C-2’),96.5(C-6),92.8(C-8),73.2(OCH2),61.2(4’-OCH3),56.7(7-OCH3),56.5(3’,5’-OCH3),56.0(8-OCH3);MS(ESI,m/z):538.3[M+H]+,560.2[M+Na]+.实施实例八、化合物对癌细胞MDA-MB-231、A549、PC-3、HeLa和SiHa的体外增殖抑制活性测试
人乳腺癌细胞MDA-MB-231用10%FBS的DMEM培养,人肺癌细胞A549、人***癌PC-3、增殖表皮癌细胞HeLa和人子宫颈鳞癌细胞SiHa用10%FBS的RPMI1640培养,37℃、5%CO2的饱和湿度培养箱中培养,2天换一次培养液,4-6天传一次代。取对数生长期细胞为实验对象。细胞用0.025%胰蛋白酶(含0.5mMEDTA)消化处理。20mM化合物溶解于DMSO作为储备液。在使用前,直接用培养基将其稀释到所需浓度。阴性对照组加入与药物同体积的DMSO,阳性对照组加入与被测药物同浓度的盐酸表阿霉素和吉非替尼。处理药剂中的DMSO最终浓度不超过0.1%(v/v)。
取对数生长期细胞,用0.025%胰蛋白酶消化后,重悬于含10%FBS的DMEM或RPMI1640培养基中,以4.5×104个/mL的终浓度接种于96孔培养板上,每孔100μL,最右侧一列为空白对照组,加无细胞的有血清DMEM或RPMI1640培养基,置于37℃、5%CO2的饱和湿度培养箱中培养。24h后吸掉培养基,加入含不同浓度药物的有血清培养基,每孔200μL,空白对照组每孔加200μL完全培养基分别处理实验要求时间,去除上清,加100μL/well浓度0.5mg/mL的MTT。培养4h后再补加100μL/well的10%的SDS。37℃下10h使结晶物充分溶解后取出,微震荡5min,放置室温下30min,在A595波长下测OD值,并计算细胞活性、抑制率和P值。
以药物的浓度或处理时间为横轴,OD值或者抑制率为纵轴,绘制曲线。每样本浓度重复六个孔,每个实验重复三次,取平均值为最终结果。
实验结果以SPSS软件进行方差分析,P<0.05时为差异显著,p<0.01时为差异极显著。细胞增殖的抑制率计算公式如下:
表1杨梅素含氮衍生物对乳腺癌细胞MDA-MB-231的体外增殖抑制活性
注:*化合物在设定浓度下对MDA-MB-231抑制率与阴性对照组(DMSO)抑制率差异性分析有显著性差异(P<0.05)。
表2杨梅素含氮衍生物对A549、PC-3、HeLa和SiHa癌细胞的体外增殖抑制活性(10μM)
注:*化合物在浓度为10μM下对癌细胞A549、PC-3、HeLa和SiHa抑制率与阴性对照组(DMSO)抑制率差异性分析有显著性差异(P<0.05)。
从表1的数据和附图表明,以上化合物都对目标肿瘤细胞MDA-MB-231有良好的抑制活性,其中化合物25的抑制活性与阳性药盐酸表阿霉素相比,在同样的剂量和作用时间要高于阳性药,最值得一提的是阳性药对肿瘤细胞的毒性明显太大(使得细胞全部破碎裂解),本专利所合成的新化合物基本对目标细胞损伤很小,这种抑制活性主要体现在抑制细胞的增殖(细胞数量与对照相比明显变少),或者诱导细胞分化(从形态学观察我们不难发现,细胞在数目减少的同时,细胞发生了变形,但是损伤不是很明显);从表2的数据可看出,所合成的杨梅素含氮类衍生物对A549、PC-3、HeLa和SiHa等癌细胞也具有良好的抑制效果,部分化合物的抑制效果优于阳性对照药剂,表明这一系列化合物可作为抗癌药物进行进一步的研究。
Claims (4)
1.杨梅素含氮类衍生物,其特征是结构由下列通式(III)表示:
R3为呋喃基。
2.权利要求1所述的杨梅素含氮类衍生物在制备抗癌药物中的应用。
3.按照权利要求1所述杨梅素含氮类衍生物的制备方法,其特征在于通式(III)化合物的制备方法是以杨梅苷、碘甲烷、溴乙酸乙酯、水合肼、醛R-CHO为原料,经取代和缩合反应合成目标产物,其合成反应路线为:
其中R、R3为呋喃基。
4.根据权利要求3所述的杨梅素含氮类衍生物的制备方法,其特征是经取代和缩合合成,通式(III)的合成方法为:
第一步:3-羟基-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的制备
在圆底烧瓶中加入杨梅苷和K2CO3溶于DMF中,搅拌均匀后,缓慢的滴加碘甲烷,
室温搅拌60小时,停止反应后,用水分散,用乙酸乙酯萃取,合并有机相,减压浓缩,然后将浓缩物溶于无水乙醇,升温至回流,溶液澄清后,回流下加入浓盐酸,慢慢的有黄色固体析出,继续反应2h,冷却,冰箱放置过夜,过滤,得到粗产物,不需要纯化,直接用于下一步的反应,
第二步:3-氧乙酸乙酯-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮的制备
在三口瓶中依次加入第一步的产物,K2CO3和无水丙酮,室温搅拌均匀后,滴加溴乙酸乙酯,滴毕,回流反应24小时,停止反应后,冷却至室温,浓缩后倒入冰水中,析晶,抽滤,滤饼用氯仿/水重结晶得到目标产物,
第三步:2-((5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基)氧基)乙酰肼的制备在三口瓶中依次加入第二步的产物,80%水合肼和无水乙醇,回流反应2h,TCL点板跟踪,直至反应完全,减压浓缩除去大量溶剂后,冷却,有沉淀产生析出,抽滤,滤饼用无水乙醇重结晶得到目标产物,
第四步:杨梅素含氮类衍生物的制备
在三口瓶中依次加入第三步的产物和醛R-CHO,用无水乙醇溶解,滴入催化量的醋酸,搅拌加热回流2h,TLC点板跟踪,直至反应完全,浓缩反应液,冷却,有大量的沉淀析出,抽滤,滤饼用无水乙醇重结晶得到式(III)化合物
其中,R、R3为呋喃基。
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