CN112679458B - 一类含磺酸酯的杨梅素衍生物及其制备方法和应用 - Google Patents
一类含磺酸酯的杨梅素衍生物及其制备方法和应用 Download PDFInfo
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- CN112679458B CN112679458B CN202011478927.8A CN202011478927A CN112679458B CN 112679458 B CN112679458 B CN 112679458B CN 202011478927 A CN202011478927 A CN 202011478927A CN 112679458 B CN112679458 B CN 112679458B
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- trimethoxyphenyl
- dimethoxy
- chromen
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Abstract
Description
技术领域
本发明涉及化工技术领域,具体来说涉及一种含磺酸酯的杨梅素衍生物,同时还涉及该含磺酸酯的杨梅素衍生物的制备方法,及该含磺酸酯的杨梅素衍生物在抑制肿瘤细胞方面的应用。
背景技术
天然产物来自大自然,化学成分种类繁多、结构新颖,与环境的兼容性较好;同时,天然产物中的大多数化学物质如黄酮类、生物碱、萜类、萜烯类、酚类以及多糖等均具有杀虫、抑菌及抗肿瘤等生物活性。从天然产物的宝库中寻找高活性化合物,并对其进行结构优化,进而得到功能更优越的化合物,已成为研究和开发新型药物的热点之一,在具有高效、低毒等特点的新型农药研究方向极具潜力。
杨梅素是一种重要的天然产物,广泛地存在于多种植物中,如:日常食用的水果、蔬菜和饮料,有丰富的来源途径。药理研究表明,杨梅素在抗氧化、抗病毒、抗炎、抑菌以及抗肿瘤等生物活性方面表现突出,具有一定的研究和应用价值,近年来人们对它的研究也越来越多。但是,大多局限于医药方面的应用研究,在农药方面的应用研究较少。
2014年,赵等(赵洪菊.杨梅素衍生物的合成与生物活性研究[D].贵州大学,2014)报道了一系列含杂环烷基类杨梅素衍生物,利用MTT法,测试了所合成化合物对乳腺癌细胞MDA-MB-231的体外增殖抑制活性,其中,在浓度为1μmol/L时,部分化合物的抑制活性均高于对照药吉非替尼(9.73±8.04%)。
2015年,Xue等(Xue,W.;Song,B.A.;Zhao,H.J.;et al.Eur.J.Med.Chem.,2015,97,155-163.)报道了一系列含酰腙类杨梅素衍生物。利用MTT法,对所合成的化合物进行了人类乳腺癌细胞MDA-MB-231的体外增殖抑制活性测试,研究结果表明:杨梅素酰腙类衍生物对人类乳腺癌细胞MDA-MB-231都表现较好的抑制率。
2018年,阮等(阮祥辉,赵洪菊,张橙等.[J].高等学校化学学报,2018,39, 1197-1204.)设计合成了13含哌嗪酰胺的杨梅素衍生物,采用四甲基偶氮唑盐(MTT) 比色法测试了化合物对人类乳腺癌细胞(MDA-MB-231)的体外抗肿瘤活性。其中,部分化合物在浓度为1μmol/L时,对MDA-MB-231癌细胞的抑制率高于盐酸表阿霉素;少数化合物在浓度为10μmol/L时,对MDA-MB-231癌细胞的抑制活性与盐酸表阿霉素相当。此外,通过对目标肿瘤的形态学影响分析后得知,杨梅苷的细胞毒性虽然小,但是对肿瘤细胞的抑制作用不明显;而引入哌嗪酰胺后的杨梅素衍生物细胞毒性小,并能有效抑制肿瘤细胞的增殖,具有较好的抗肿瘤研究价值。
2019年,李等(李普,陈英,夏榕娇等.[J].高等学校化学学报,2019, 40(05):909-917.)利用活性拼接原理,将喹喔啉引入到杨梅素结构中,合成了一系列含喹喔啉基团的杨梅素新型衍生物,采用浊度法测试了目标化合物的体外抑菌活性,结果表明,目标化合物对柑橘溃疡病菌(Xac)和水稻白叶枯病菌(Xoo)均表现出较好的抑制活性,其对柑橘溃疡病菌的EC50为11.17μg/mL,明显优于对照药叶枯唑和噻菌铜EC50分别为45.85和61.13μg/mL;对水稻白叶枯病菌的抑制活性EC50为34.49μg/mL,优于对照药叶枯唑(148.20μg/mL)和噻菌铜(175.47μg/mL),采用半叶枯斑法测试了目标化合物的抗烟草花叶病毒(TMV)活性,结果表明,所有目标化合物在浓度为500mg/L时均有一定的抑制作用。
2019年,Chen等(Chen,Y.;Li,P.;Su,S.J.;et al.RSC Advances,2019,9, 23045-23052)计合成了一系列含有1,2,4-三唑类席夫碱的杨梅素衍生物,用浊度法测定目标化合物对对水稻白叶枯病菌(Xoo)、柑橘溃疡病菌(Xac)和烟草青枯病菌(Rs) 的生物活性。测定结果显示,化合物部分对柑橘溃疡病菌表现出良好的抑制作用,其EC50值为8.81μg/mL,优于对照药噻菌铜(61.12μg/mL)。对烟草青枯病菌的EC50值为15.52μg/mL,优于对照药噻唑铜(127.9μg/mL)。
2020年,Jiang等(Jiang,S.C.;Su,S,J.;Chen,M.;et al.J.Agric.FoodChem.2020, 68,5641-5647)设计合成了一系列含二硫代氨基甲酸酯的杨梅素衍生物,并采用浊度法测试了其对柑橘溃疡病菌、水稻白叶枯病菌和烟草青枯病菌的抑菌活性,结果显示部分化合物对柑橘溃疡病菌、水稻白叶枯病菌的活性最好,其EC50值分别为0.11 和1.58μg/mL,远优于对照药叶枯唑(48.93,56.05μg/mL)和噻菌铜(59.97,83.04 μg/mL).
磺酸酯是一类重要的具有广泛生物活性的活性基团。许多含有磺酰基的化合物具有抗癌、抑菌、抗病毒等活性。由于由于含磺酸酯衍生物在医药、农药等方面有着广泛的应用,所以其合成研究倍受关注。具有很大的开发前景。
2010年,Zeng等(Zeng,X.w.;Huang N.;Xu H.;et al.Chem.Pharm.Bull.2010,58,976-979)合成了十种5,5′-(对亚苯基双偶氮)-8-羟基喹啉磺酸盐,化合物5,5′-(对亚苯基双偶氮)-8-羟基喹啉对乙基苯磺酸盐和5,5′-(对亚苯基双偶氮)-8-羟基-喹啉对氯苯磺酸盐表现出较好的抗HIV-1活性,EC50值为2.59和4.01μg/mL,治疗指数(TI) 值为31.77和24.51。
2019年Kang等(Kang,G.Q.;Duan,W.G.;Lin,G.S.;et al.Molecules,2019,24,477-485)设计合成了系列(Z)和(E)-3-蒈烯-5-酮肟磺酸盐。初步评价了目标化合物在 50μg/mL的条件下对测试花生角孢、皮孢酸菌、番茄链孢、番茄根霉、霉双星和番茄红霉的体外抗真菌活性。生物测定结果表明,部分目标化合物对皮孢酸菌有良好的抑制活性,其抑制率均为100%,优于商业抗真菌剂氯乙腈。
2019年El-Gama等(El-Gamal,M.I.;Ullah,S.;Zaraei,S.O.;etal.Eur.J.Med.Chem. 2019,181,111560)设计合成了一系列雷洛昔芬磺酸/氨基磺酸衍生物。测试目标化合物对核苷酸焦磷酸酶/磷酸二酯酶-1和-3(NPP1和NPP3)酶的抑制作用。目标化合物对HT-29结肠癌细胞株(IC50=1.40μM)的疗效最高,对HT-29的选择性是F180成纤维细胞的8.43倍。对NPP1和NPP3的IC50分别为0.29μM和0.71μM。
综上所述,含磺酸酯的化合物和杨梅素衍生物都具有较好的生物活性,但是还未见有将磺酸酯引入到杨梅素中合成含磺酸酯的杨梅素衍生物在抗癌活性方面的相关报道。
发明内容
本发明的目的在于克服上述缺点而提供的含磺酸酯的杨梅素衍生物。
本发明的另一目的在提供了制备上述化合物中间体化合物及其制备方法。
本发明还有一目的是提供了一种含有上述化合物。
本发明还有一目的是提供了上述化合物的用途。
本发明另一目的是提供了利用上述化合物在抑制肿瘤细胞方面的应用。
为实现上述目的,本发明采用了下述技术方案:
一种含磺酸酯的杨梅素衍生物,该化合物具有如通式A所示的结构:
其中,
R独立地选自C1-C6烷基、C1-C6烯基、C1-C6炔基、卤素原子、C3-C6环烷基、任意取代或未取代的苯基、任意取代或未取代的芳杂环基中的一个或一个以上。
取代苯基为苯环上邻、间、对位含有的烷基、烷氧基、硝基、卤素原子或氢原子。
芳杂环基为噻吩基、呋喃基、吡咯基或吡啶基。
取代芳杂环基上的取代基为邻、间、对位含有C1-6的烷基、C1-6的烷氧基、硝基、卤素原子或氢原子。
本发明的磺酸酯杨梅素衍生物的制备方法,具体步骤如下:
(1)3-羟基-3’,4’,5’,5,7-五甲氧基杨梅素(中间体a)的制备:
以杨梅苷和碘甲烷为原料,以结晶碳酸钾为催化剂,N,N-二甲基甲酰胺(DMF)为溶剂调节制备5,7-二甲氧基-3-(((3,4,5-三甲氧基-6-甲基四氢-2H-吡喃-2-基)氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4–酮(中间体a):
(2)中间体a溶于无水乙醇,在盐酸的作用下回流脱苷,制备得到3-羟基-5,7- 二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(中间体b)
(3)中间体b及取代苯磺酰氯为原料,碳酸钾为催化剂,在乙腈中回流得到5,7- 二甲氧基-4-氧-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基-取代苯磺酸盐(目标化合物A)
本发明与现有技术要比,具有明显的有益效果,从以上技术方案可知:本发明制备是以杨梅苷和碘甲烷为原料进行取代得到5,7-二甲氧基-3-(((3,4,5-三甲氧基-6- 甲基四氢-2H-吡喃-2-基)氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4–酮再与盐酸进行脱苷得到3-羟基-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮,得到的化合物与取代磺酸盐进行反应得到目标化合物5,7-二甲氧基-4-氧-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基-取代苯磺酸盐。此制备方法以杨梅苷和取代磺酰氯为原料,以 DM、乙醇等溶剂,均为常见的有机试剂与溶剂,原料易得。并且此方法在常温或较低温度下就可反应,反应条件温和,后处理简单,产率高,可达70-96%之间。
本发明以3-羟基-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮与具有优良生物活性的含取代基的取代苯磺酰氯发生反应,生成含磺酸酯的杨梅素衍生物。在浓度为100和50μg/mL时,测定了目标化合物的抗植物细菌的活性。抑菌活性测试结果表明:在实验测试浓度下,对烟草青枯病菌拥有较好的抑制活性,可用于制备抗植物细菌药剂。
具体实施方式
实施例1
5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基苯磺酸盐(目标化合物A1)的制备方法,包括以下步骤:
(1)3-羟基-3’,4’,5’,5,7-五甲氧基杨梅素(中间体a)的制备:
在250mL圆底烧瓶中依次加入4.64g杨梅苷(10mmol)、22.09g K2CO3·1/2H2O(16mmol)和100mL DMF,常温下搅拌0.5h左右,缓慢滴加7.50mL碘甲烷(120 mmol),室温搅拌48h,TLC跟踪反应(甲醇:乙酸乙酯=1:4,V/V)。停止反应后,过滤沉淀,滤渣用二氯甲烷洗涤滤渣,合并滤液,用100mL水稀释,用二氯甲烷萃取三次,合并有机层,减压浓缩待用。
(2)3-羟基-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(中间体b)
将上述第一步(1)浓缩物溶于80mL无水乙醇中,升温至回流,待溶液澄清后,回流下加入10mL浓盐酸,随后有黄色固体析出,继续反应2-3h,冷却,过滤,得到粗产物3-羟基-5,7-二甲氧基-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮(中间体b),产率:56.4%。
(3)5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基苯磺酸盐(目标化合物A1)的制备
在100mL单口圆底烧瓶中加入中间体b 0.545g(1.4mmoL)、0.387g碳酸钾及 50mL乙腈,升温回流1h后缓慢滴加苯磺酰氯0.247g(1.4mmoL)的乙腈溶液,继续在此温度下反应3-4h,TLC跟踪反应(石油醚:乙酸乙酯=2:1,V/V),停止反应后,将混合物倒入100mL冰水中,过滤,用无水乙醇和DMF重结晶得到目标化合物 A1,产率:89.7%
实施例2
5,7-二甲氧基-4-氧-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基4-甲氧基苯磺酸盐合成(化合物编号为A2),包括以下步骤:
(1)3-羟基-3’,4’,5’,5,7-五甲氧基杨梅素(中间体a)的合成:
如实施例1第(1)步。
(2)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(中间体 b):
如实施例1第(2)步。
(3)5,7-二甲氧基-4-氧-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基4-甲基苯磺酸盐(化合物编号为A3)合成:
如实施例1第(3)步,区别在于以4-甲氧基苯磺酰氯为原料,产率:93.2%
实施例3
5,7-二甲氧基-4-氧-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基2-硝基苯磺酸盐(化合物编号为A3)制备,包括以下步骤:
(1)3-羟基-3’,4’,5’,5,7-五甲氧基杨梅素(中间体a)合成:
如实施例1第(1)步。
(2)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(中间体b) 合成:
如实施例1第(2)步。
(3)5,7-二甲氧基-4-氧-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基2-硝基苯磺酸盐(化合物编号为A3)制备:
如实施例1第(3)步区别在于2-硝基苯磺酰氯为原料,产率:95.4%。
实施例4
5,7-二甲氧基-4-氧-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基2-氟苯磺酸盐的合成 (化合物编号为A4),包括以下步骤:
(1)3-羟基-3’,4’,5’,5,7-五甲氧基杨梅素(中间体a)合成:
如实施例1第(1)步。
(2)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(中间体b) 合成:
如实施例1第(2)步。
(3)5,7-二甲氧基-4-氧-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基2-氟苯磺酸盐的合成(化合物编号为A4):
如实施例1第(3)步,区别在于2-氟苯磺酰氯为原料,产率:96.7%。
实施例5
5,7-二甲氧基-4-氧-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基4-氟苯磺酸盐的合成 (化合物编号为A5),包括以下步骤:
(1)3-羟基-3’,4’,5’,5,7-五甲氧基杨梅素(中间体a)合成:
如实施例1第(1)步。
(2)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(中间体b) 合成:
如实施例1第(2)步。
(3)5,7-二甲氧基-4-氧-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基4-氟苯磺酸盐的合成(化合物编号为A5):
如实施例1第(3)步,区别在于4-氟苯磺酰氯为原料,产率:93.0%。
实施例6
5,7-二甲氧基-4-氧-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基3-氟苯磺酸盐的合成 (化合物编号为A6),包括以下步骤:
(1)3-羟基-3’,4’,5’,5,7-五甲氧基杨梅素(中间体a)合成:
如实施例1第(1)步。
(2)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:
如实施例1第(2)步。
(3)5,7-二甲氧基-4-氧-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基3,4-二氟苯磺酸盐的合成:
如实施例1第(3)步,区别在于3,4-二氟苯磺酰氯为原料,产率:88.9%
实施例7
5,7-二甲氧基-4-氧-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基2-氯苯磺酸盐的合成 (化合物编号为A7),
包括以下步骤:
(1)3-羟基-3’,4’,5’,5,7-五甲氧基杨梅素(中间体a)合成:
如实施例1第(1)步。
(2)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:
如实施例1第(2)步。
(3)5,7-二甲氧基-4-氧-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基2-氯苯磺酸盐的合成(化合物编号为A7):
如实施例1第(3)步,区别在于2-氯苯磺酰氯为原料,产率:98.4%
实施例8
5,7-二甲氧基-4-氧-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基3-氯苯磺酸盐的合成 (化合物编号为A8),包括以下步骤:
(1)3-羟基-3’,4’,5’,5,7-五甲氧基杨梅素(中间体a)合成:
如实施例1第(1)步。
(2)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:
如实施例1第(2)步。
(3)5,7-二甲氧基-4-氧-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基3-氯苯磺酸盐的合成(化合物编号为A8):
如实施例1第(3)步,区别在于3-氯苯磺酰氯为原料,产率:93.5%.
实施例9
5,7-二甲氧基-4-氧-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基4-氯苯磺酸盐的合成 (化合物编号为A9),包括以下步骤:
(1)3-羟基-3’,4’,5’,5,7-五甲氧基杨梅素(中间体a)合成:
如实施例1第(1)步。
(2)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:
如实施例1第(2)步。
(3)5,7-二甲氧基-4-氧-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基4-氯苯磺酸盐的合成(化合物编号为A9):
如实施例1第(3)步,区别在于4-氯苯磺酰氯为原料,产率:98.5%.
实施例10
5,7-二甲氧基-4-氧-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基2-溴苯磺酸盐的合成 (化合物编号为A10),包括以下步骤:
(1)3-羟基-3’,4’,5’,5,7-五甲氧基杨梅素(中间体a)合成:
如实施例1第(1)步。
(2)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:
如实施例1第(2)步。
(3)5,7-二甲氧基-4-氧-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基4-氯苯磺酸盐的合成(化合物编号为A10):
如实施例1第(3)步,区别在于2-溴苯磺酰氯为原料,产率:96.1%.
实施例11
5,7-二甲氧基-4-氧-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基3-溴苯磺酸盐的合成 (化合物编号为A11),包括以下步骤:
(1)3-羟基-3’,4’,5’,5,7-五甲氧基杨梅素(中间体a)合成:
如实施例1第(1)步。
(2)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:
如实施例1第(2)步。
(3)5,7-二甲氧基-4-氧-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基3-溴苯磺酸盐的合成(化合物编号为A11);
如实施例1第(3)步,区别在于3-溴苯磺酰氯为原料,产率:98.1%。
实施例12
5,7-二甲氧基-4-氧-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基4-溴苯磺酸盐的合成 (化合物编号为A12),包括以下步骤:
(1)3-羟基-3’,4’,5’,5,7-五甲氧基杨梅素(中间体a)合成:
如实施例1第(1)步。
(2)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:
如实施例1第(2)步。
(3)5,7-二甲氧基-4-氧-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基4-溴苯磺酸盐的合成(化合物编号为A12):
如实施例1第(3)步,区别在于4-溴苯磺酰氯为原料,产率:93.6%.
实施例13
5,7-二甲氧基-4-氧-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基3-(三氟甲基)苯磺酸盐合成(化合物编号为A13),包括以下步骤:
(1)3-羟基-3’,4’,5’,5,7-五甲氧基杨梅素(中间体a)合成:
如实施例1第(1)步。
(2)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:
如实施例1第(2)步。
(3)5,7-二甲氧基-4-氧-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基3-(三氟甲基)苯磺酸盐合成(化合物编号为A13):
如实施例1第(3)步,区别在于3-三氟甲基苯磺酰氯为原料,产率:89.2%。
实施例14
5,7-二甲氧基-4-氧-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基3-(三氟甲氧基)苯磺酸盐合成(化合物编号为A14),包括以下步骤:
(1)3-羟基-3’,4’,5’,5,7-五甲氧基杨梅素(中间体a)合成:
如实施例1第(1)步。
(2)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:
如实施例1第(2)步。
(3)5,7-二甲氧基-4-氧-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基3-(三氟甲氧基)苯磺酸盐合成(化合物编号为A14):
如实施例1第(3)步,区别在于3-三氟甲氧基苯磺酰氯为原料,产率:87.2%。
实施例15
5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基4-(叔丁基)苯磺酸盐合成(化合物编号为A15),包括以下步骤:
(1)3-羟基-3’,4’,5’,5,7-五甲氧基杨梅素(中间体a)合成:
如实施例1第(1)步。
(2)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:
如实施例1第(2)步。
(3)5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基4-(叔丁基)苯磺酸盐合成(化合物编号为A15):
如实施例1第(3)步,区别在于4-叔丁基苯磺酰氯为原料,产率:96.5%。
实施例16
5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基4-氰基苯磺酸盐合成(化合物编号为A16),包括以下步骤:
(1)3-羟基-3’,4’,5’,5,7-五甲氧基杨梅素(中间体a)合成:
如实施例1第(1)步。
(2)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:
如实施例1第(2)步。
(3)5,7-二甲氧基-4-氧代-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基4-氰基苯磺酸盐合成(化合物编号为A16):
如实施例1第(3)步,区别在于4-氰基苯磺酰氯为原料,产率:92.7%。
实施例17
5,7-二甲氧基-4-氧-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基噻吩-2-磺酸盐合成(化合物编号为A17),包括以下步骤:
(1)3-羟基-3’,4’,5’,5,7-五甲氧基杨梅素(中间体a)合成:
如实施例1第(1)步。
(2)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:
如实施例1第(2)步。
(3)5,7-二甲氧基-4-氧-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基噻吩-2-磺酸盐合成 (化合物编号为A17):
如实施例1第(3)步,区别在于噻吩磺酰氯为原料,产率:96.3%。
实施例18
5,7-二甲氧基-4-氧-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基吡啶-2-磺酸盐合成(化合物编号为A18),包括以下步骤:
(1)3-羟基-3’,4’,5’,5,7-五甲氧基杨梅素(中间体a)合成:
如实施例1第(1)步。
(2)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:
如实施例1第(2)步。
(3)5,7-二甲氧基-4-氧-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基吡啶-2-磺酸盐合成 (化合物编号为A18):
如实施例1第(3)步,区别在于吡啶磺酰氯为原料,产率:88.1%。
实施例19
5,7-二甲氧基-4-氧-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基喹啉-2-磺酸盐合成(化合物编号为A19),包括以下步骤:
(1)3-羟基-3’,4’,5’,5,7-五甲氧基杨梅素(中间体a)合成:
如实施例1第(1)步。
(2)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:
如实施例1第(2)步。
(3)5,7-二甲氧基-4-氧-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基喹啉-2-磺酸盐合成(化合物编号为A19):
如实施例1第(3)步,区别在于喹啉磺酰氯为原料,产率87.9%。
实施例20
5,7-二甲氧基-4-氧-2-(3,4,5-三甲氧基苯基)-4H-色烯-3-基4-乙酰氨基苯磺酸盐 (化合物编号为A20),包括以下步骤:
(1)3-羟基-3’,4’,5’,5,7-五甲氧基杨梅素(中间体a)合成:
如实施例1第(1)步。
(2)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:
如实施例1第(2)步。
(3)5,7-二甲氧基-4-氧-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-乙酰氨基-2-磺酸盐合成(化合物编号为A20):
如实施例1第(3)步,区别在于乙酰氨基苯磺酰氯为原料,产率93.5%。
合成的含磺酸酯的杨梅素衍生物的理化性质和质谱数据见表1,核磁共振氢谱(1H NMR)和碳谱(13C NMR)数据见表2。
表1实施例1-20制得的化合物A理化性质
表2目标化合物核磁共振氢谱和碳谱数据
实施例21化合物抑制癌细胞活性测试(以A549细胞为例):
1测试方法
(1)细胞培养与药物作用
用含10%胎牛血清的DMEM高糖培养基在37℃、5%CO2的饱和湿度培养箱中培养A549细胞,每两天换一次培养液,3-4天传代一次。药物以DMSO为溶剂,配成1mmol/L、10mmol/L的贮存液,使用时用培养基稀释成1μmol/L和10μmol/L 的作用浓度,以DMSO作为阴性对照组,吉西他滨作为阳性对照,作用于对数生长期的细胞。
(2)MTT法
将对数生长期的A549细胞,用0.25%胰酶-EDTA消化后,配制成一定浓度的单细胞悬液,按4000个/孔接种于96孔板,每孔加入细胞悬液200μL。24h后,加入含不同浓度化合物及相应溶剂对照的新鲜培养基,每孔加200μL(DMSO终浓度<0.1%),每种受试化合物设5个剂量组,于37℃继续培养72h后,每孔加入5 mg/mL MTT溶液20μL,继续培养4h,弃上清后,每孔加入200μL DMSO溶解 MTT甲臜(Formazan)沉淀,微型振荡器振荡混匀后,酶标仪测定570nm光密度值 (OD),以溶剂对照处理的肿瘤细胞为对照组,用以下公式计算化合物对肿瘤细胞的抑制率,并用SPSS软件计算IC50:
2.抑制A549细胞活性测试结果
表3实施例1-20制得的化合物A对A549细胞作用72小时的体外抑制效果
化合物 | R | IC<sub>50</sub>/μM | 化合物 | R | IC<sub>50</sub>/μM |
A1 | Ph | 18.62 | A12 | 4-Br-Ph | 15.43 |
A2 | 4-OCH<sub>3</sub>-Ph | 17.05 | A13 | 3-CF<sub>3</sub>-Ph | 6.54 |
A3 | 2-NO<sub>2</sub>-Ph | 2.06 | A14 | 4-OCF<sub>3</sub>-Ph | 11.63 |
A4 | 2-F-Ph | 24.32 | A15 | 4-C(CH<sub>3</sub>)<sub>3</sub>-Ph | 5.09 |
A5 | 4-F-Ph | 25.66 | A16 | 4-CN-Ph | 23.34 |
A6 | 3,4-di-F-Ph | 28.34 | A17 | Thien-2-yl | 17.85 |
A7 | 2-Cl-Ph | 1.47 | A18 | Pyrid-3-yl | 24.66 |
A8 | 3-Cl-Ph | 15.33 | A19 | Quinol-8-yl | 17.34 |
A9 | 4-Cl-Ph | 17.58 | A20 | 4-Acetamido-Ph | 15.32 |
A10 | 2-Br-Ph | 1.64 | 吉非替尼 | - | 10.38 |
A11 | 3-Br-Ph | 14.32 |
经过初步测试,发现部分化合物对A549癌细胞的有明显的抑制作用,特别是化合物A3,A7,A10,A13和A15,其IC50值为2.06,1.47,1.64,6.54和5.09μM, 其抑制活性明显优于阳性对照药吉非替尼(10.38μM)。
如上实验活性数据表明含磺酸酯的杨梅素衍生物对A549癌细胞具有一定的抑制作用,其中部分目标化合物对A549癌细胞表现出优良的抑制活性,可作为潜在的抑A549癌细胞药物,具有较好应用的前景。
综合如上所述,仅是本发明的较佳实施例而已,并非对本发明作任何形式上的限制,任何未脱离本发明技术方案内容,依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与修饰,均仍属于本发明技术方案的范围内。
Claims (3)
3.如权利要求1所述的一种含磺酸酯的杨梅素衍生物在制备医用抑制A549癌细胞药剂方面的应用。
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