CN103664689A - 对癌细胞微管蛋白聚合有抑制作用的一类查尔酮肟衍生物及其制备方法 - Google Patents
对癌细胞微管蛋白聚合有抑制作用的一类查尔酮肟衍生物及其制备方法 Download PDFInfo
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Abstract
Description
技术领域
本发明涉及一类查尔酮肟类衍生物及其制备方法与抑制肿瘤细胞微管蛋白聚合的功能。
背景技术
查尔酮类化合物广泛存在于甘草、啤酒花、镰形棘豆等植物中。查尔酮的基本结构式是1,3-二苯基丙烯酮,由于查尔酮类化合物分子具有较大的柔性,如抗癌、抗炎症、抗菌、抗寄生虫、抗病毒、治疗糖尿病、神经保护、抑制电压门控制假通道、抗胃溃疡。查尔酮类药物能抑制肿瘤细胞微管蛋白的解聚和聚合,即通过破坏微管在体内和体外的形态和功能来抑制癌细胞的活性,从而发挥抗癌作用。有些查尔酮类药物可以促进和稳定微管蛋白的聚合形式(最近的研究表明,药物对微管解聚的抑制作用是由于它们对微管动力学的干扰,而不是微管蛋白聚合物量的改变。);而有些查尔酮类药物通过与秋水仙碱结合位点强烈的结合来抑制微管的聚合。
近年来,含肟化合物在药物研究和生物学等方面显示出越来越重要的作用,其肟结构经常作为配合物而使药物发挥抗癌活性,为了寻找更好的抗癌类药物,我们将肟结构和查尔酮结构作为药物的主要结构进行化合物的合成和活性测试研究表明,肿瘤细胞对于此类查尔酮肟药物具有很高的敏感性,因此查尔酮肟类药物开发成为抗肿瘤药物研究开发的一个热点。开发它具有一定的理论意义和实际的价值,因此,我们设计合成了一系列以(1E,2E)-查尔酮肟为母环的查尔酮肟衍生物。
发明内容
本发明的目的在于提供一类查尔酮肟类衍生物及其制备方法。
本发明的技术方案如下:
1.一类查尔酮肟类衍生物,其特征是它们有如下通式:
式中,R1、R2、R3、R4、R5、R6、R7、R8、R9、R10选自H、C1-5烷基、C1-5烷氧基、卤素、卤素取代的C1-5烷基、硝基、氨基。
2.一种制备权利要求1所述的一类查尔酮肟类衍生物制法,它们由下列步骤成:
步骤1.低温条件下,100ml烧瓶中加入化合物1用有机溶剂溶解,搅拌一段时间后,将溶于相同体积有机溶剂的化合物2加入到上述烧瓶中,搅拌反应一段时间后将一定量的10%NaOH溶液缓慢滴加到上述反应中。经TLC跟踪反应,待反应完全后,有固体析出,过滤烘干得到黄色粉末3。
步骤2.将上面得到的化合物3和盐酸羟胺混合,加入一定量的有机溶剂溶解,然后加入一定量的NaSO4和K2CO3在乙酸乙酯中回流搅拌反应,TLC跟踪 反应,反应完全后,旋干,萃取,用硅胶柱层析进行分离纯化得到化合物4。
3.实验结果表明,本发明的新型查尔酮肟类衍生物对癌细胞微管的聚合具有明显的抑制作用。因此本发明的查尔酮肟类衍生物可以应用于制备抗癌药物。
具体实施方式:
实施例一:(1Z,2E)-1-(4-乙氧基苯基)-3-(3,4-二甲氧基苯基)-2-烯-1-肟的制备
低温条件下,100ml烧瓶中加入3,4-二甲氧基苯甲醛(1.66g,10mmol)用20ml乙醇溶解,搅拌一段时间后,将溶于20ml乙醇的对甲氧基苯乙酮(1.50g,10mmol)加入到上述烧瓶中,搅拌反应一段时间后将8ml的10%NaOH溶液缓慢滴加到上述反应中。经TLC跟踪反应,待反应完全后,有固体析出,过滤烘干得到黄色粉末。取上述得到的固体(0.33g,1mmol)和盐酸羟胺(0.21g,3mmol)混合,20ml乙酸乙酯溶解,然后加入无水NaSO4(0.22g,1.5mmol)和K2CO3(0.21g,1.5mmol)在乙酸乙酯中回流搅拌反应,TLC跟踪反应,反应完全后,旋干,用二氯甲烷萃取,用硅胶柱层析进行分离纯化得到黄色粉末状目标化合物。产率81%,m.p:85~87℃,1H NMR(DMSO-d6,400MHz):3.63~3.70(m,6H);4.00~4.06(m,2H);6.69~6.77(m,2H);6.79~6.81(m,1H);6.86~6.89(m,2H);7.10~7.24(m,2H);7.43~7.46(m,2H);10.88(s,1H).ESI-MS:327.37(C19H21NO4,[M+H]+).Anal.Calcd for C19H21NO4:C,69.71;H,6.47;N,4.28;O,19.55%;Found:C,69.70;H,6.48;N,4.29;O,19.54%.
实施例二:(1Z,2E)-1-(4-甲氧基苯基)-3-(2,4,5-三甲氧基苯基)-2-烯-1- 肟的制备
制备方法同实施例一,以2,4,5-三甲氧基苯甲醛代替3,4-二甲氧基苯甲醛,得到黄色粉末状目标化合物。产率62%,m.p:95℃,1H NMR(DMSO-d6,400MHz):3.66(s,3H);3.68(s,3H);3.74(s,3H);3.78(s,3H);6.57(s,1H);6.91~6.93(m,3H);7.05(s,1H);7.27(s,1H);7.56(d,J=8.8,2H);11.02(s,1H).ESI-MS:343.37(C19H21NO5,[M+H]+).Anal.Calcd for C19H2lNO5:C,66.46;H,6.16;N,4.08;O,23.30%;Found:C,66.48;H,6.47;N,4.28;O,19.54%.
实施例三:(1E,2E)-1-(4-乙氧基苯基)-3-(2,4,5-三甲氧基苯基)-2-烯-1-肟的制备
制备方法同实施例一,以2,4,5-三甲氧基苯甲醛代替3,4-二甲氧基苯甲醛,对乙氧基苯乙酮代替对甲氧基苯乙酮得到黄色粉末状目标化合物。产率73%,m.p:156~157℃,1H NMR(DMSO-d6,400MHz):1.31(s,3H);3.58~3.59(m,3H);3.75(s,3H);3.79~3.90(m,3H);3.99~4.01(m,2H);6.28(s,1H);6.54(s,1H);6.83~6.93(m,2H);7.05~7.18(m,1H);7.34~7.38(m,2H);7.58~7.87(m,1H);10.98(s,1H).ESI-MS:357.4(C20H23NO5,[M+H]+).Anal.Calcd for C20H23NO5:C,67.21;H,6.49;N,3.92;O,22.38%;Found:C,67.19;H,6.50;N,3.92;O,22.39%.
实施例四:(1E,2E)-1-(3,4-二氯苯基)-3-(2,4,5-三甲氧苯基)-2-烯-1-肟的制备
制备方法同实施例一,以2,4,5-三甲氧基苯甲醛代替3,4-二甲氧基苯甲醛,3,4-二氯苯乙酮代替对甲氧基苯乙酮得到黄色粉末状目标化合物。产率46%,m.p:152~153℃,1H NMR(DMSO-d6,400MHz):3.72(s,3H);3.75(s,3H);3.80(s,3H);6.55(d,J=12.42,1H);6.65(s,1H);7.04~7.09(m,1H);7.17(s,1H);7.24~7.27(m,1H);7.53(s,1H);7.75~7.77(m,1H);11.29(s,1H).ESI-MS:343.37(C19H21NO5,[M+H]+).Anal.Calcd for C19H21NO5:C,66.46;H,6.16;N,4.08;O,23.30%;Found:C,66.50;H,6.14;N,4.07;O,23.29%.
实施例五:(1E,2E)-1-(3-溴)-3-(2,4,6-三甲氧苯基)-2-烯-1-肟的制备
制备方法同实施例一,以2,4,6-三甲氧基苯甲醛代替3,4-二甲氧基苯甲醛,3-溴苯乙酮对替对甲氧基苯乙酮得到黄色粉末状目标化合物。产率53%,m.p:138~139℃,1H NMR(DMSO-d6,400MHz):3.80(s,6H);3.82(s,3H);6.27(s,2H);6.93(d,J=17.04,1H);7.39~7.46(m,2H);7.59~7.65(m,2H);7.74~7.78(m,1H);10.38(s,1H).ESI-MS:392.24(C18H18BrNO4,[M+H]+).Anal.Calcd for C18H18BrNO4:C,55.12;H,4.63;Br,20.37;N,3.57;O,16.32%;Found:C,55.10;H,4.62;Br,20.38;N,3.57;O,16.34%.
实施例六:(1E,2E)-1-(3,4-二氯苯基)-3-(2,4,6-三甲氧苯基)-2-烯-1-肟的制备
制备方法同实施例一,以2,4,6-三甲氧基苯甲醛代替3,4-二甲氧基苯甲醛,3,4-二氯苯乙酮代替对甲氧基苯乙酮得到黄色粉末状目标化合物。产率72%,m.p:151~152℃,1H NMR(DMSO-d6,400MHz):3.77(s,6H);3.80(s,3H);6.24(s,2H);6.56~6.60(m,1H);7.22~7.30(m,2H);7.50(s,1H);7.73~7.75(m,1H);11.1(s,1H).ESI-MS:382.24(C18H17Cl2NO4,[M+H]+).Anal.Calcd for C18H17Cl2NO4:C,56.56;H,4.48;Cl,18.55;N,3.66;O,16.74%;Found:C,56.60;H,4.46;Cl,18.55;N,3.65;O,16.73%.
实施例七:(1E,2E)-1-(3-氨基苯)-3-(2,4,6-三甲氧苯基)-2-烯-1-肟的制备
制备方法同实施例一,以2,4,6-三甲氧基苯甲醛代替3,4-二甲氧基苯甲醛,3-氨基苯乙酮代替对甲氧基苯乙酮得到黄色粉末状目标化合物。产率80%,m.p:161~162℃,1H NMR(DMSO-d6,400MHz):3.79(s,6H);3.82(s,3H);5.14(s,1H);6.27(s,1H);6.56~6.63(m,2H);6.66~6.68(m,1H);6.93~6.98(m,1H);7.03~7.07(m,1H);7.71~7.75(m,1H);11.00(s,1H).ESI-MS:328.36(C18H20N2O4,[M+H]+).Anal.Calcd for C18H20N2O4:C,65.84;H,6.14;N,8.53;O,19.49%;Found:C,65.80;H,6.12;N,8.54;O,19.50%.
实施例八:3-(1Z,2E)-1-(3-硝基苯)-3-(2,4,6-三甲氧苯基)-2-烯-1-肟的制备
制备方法同实施例一,以2,4,6-三甲氧基苯甲醛代替3,4-二甲氧基苯甲醛,3-硝基苯乙酮代替对甲氧基苯乙酮得到黄色粉末状目标化合物。产率43%,m.p:167~168℃,1H NMR(DMSO-d6,400MHz):3.66(s,9H);7.58(t,J=16,1H);7.88(d,J=7.92,1H);8.06~8.12(m,3H);11.54(s,1H).ESI-MS:374.34(C18H18N2O7,[M+H]+).Anal.Calcd for C18H18N2O7:C,57.75;H,4.85;N,7.48;O,29.92%;Found:C,57.73;H,4.86;N,7.48;O,29.93%.
实施例九:(1Z,2E)-1-(4-溴苯基)-3-(2,4,6-三甲氧苯基)-2-烯-1-肟的制备
制备方法同实施例一,以2,4,6-三甲氧基苯甲醛代替3,4-二甲氧基苯甲醛,对溴苯乙酮代替对甲氧基苯乙酮,得到黄色粉末状目标化合物。产率67%,m.p:182~183℃,1H NMR(DMSO-d6,400MHz):3.66(s,3H);3.72(s,6H);6.02~6.13(m,2H);6.20~6.27(m,1H);7.27(s,1H);7.39~7.41(m,2H);7.49~7.51(m,2H);11.03(s,1H).ESI-MS:392.24(C18H18BrNO4,[M+H]+).Anal.Calcd for C18H18BrNO4:C,55.12;H,4.63;Br,20.37;N,3.57;O,16.32%;Found:C,55.10;H,4.66;Br,20.38;N,3.56;O,16.31%.
实施例十:(1Z,2E)-1-(4-乙氧苯基)-3-(3,4,5-三甲氧苯基)-2-烯-1-肟的 制备
制备方法同实施例一,以3,4,5-三甲氧基苯甲醛代替3,4-二甲氧基苯甲醛,对乙氧基苯乙酮代替对甲氧基苯乙酮,得到黄色粉末状目标化合物。产率68%,m.p:152~153℃,1H NMR(DMSO-d6,400MHz):3.58(s,3H);3.62~3.63(m,2H);3.69(s,6H);6.53(s,2H);6.84~6.88(m,3H);7.28(s,1H);7.41~7.44(m,2H);11.03(s,1H).ESI-MS:357.40(C20H23NO5,[M+H]+).Anal.Calcd for C20H23NO5:C,67.21;H,6.49;N,3.92;O,22.38%;Found:C,67.23;H,6.48;N,3.92;O,22.37%.
实施例十一:(1Z,2E)-1-(4-乙氧苯基)-3-(4-甲氧苯基)-2-烯-1-肟的制备
制备方法同实施例一,以对甲氧基苯甲醛代替3,4-二甲氧基苯甲醛,对乙氧基苯乙酮代替对甲氧基苯乙酮,得到黄色粉末状目标化合物。产率82%,m.p:146~147℃,1H NMR(DMSO-d6,400MHz):1.36(t,J=6.96,3H);3.78(s,3H);4.08(dd,J1=13.88,J2=13.92,2H);6.68(d,J=16,1H);6.70~6.93(m,4H);7.37~7.51(m,5H);11.31(s,1H).ESI-MS:297.35(C18H19NO3,[M+H]+).Anal.Calcd for C18H19NO3:C,72.71;H,6.44;N,4.71;O,16.14%;Found:C,72.73;H,6.45;N,4.70;O,16.12%.
实施例十二:(1E,2E)-1-(3,4-二氯苯基)-3-(4-甲氧苯基)-2-烯-1-肟的制
制备方法同实施例一,以对甲氧基苯甲醛代替3,4-二甲氧基苯甲醛,得到黄色粉末状目标化合物。产率48%,m.p:137~138℃,1H NMR(DMSO-d6,400MHz):3.70(S,3H);5.90(s,1H);6.77~6.79(m,2H);7.15(d,J=8.64,2H);7.28(S,1H);7.46~7.50(m,1H);7.56~7.58(m,2H);11.47(s,1H).ESI-MS:322.19(C16H13Cl2NO2,[M+H]+).Anal.Calcd for C16H13Cl2NO2:C,59.65;H,4.07;Cl,22.01;N,4.35;O,9.93%;Found:C,59.63;H,4.08;Cl,22.02;N,4.34;O,9.94%.
实施例十三:(1Z,2E)-1-(4-乙氧苯基)-3-(2-甲氧苯基)-2-烯-1-肟的制备
制备方法同实施例一,以邻甲氧基苯甲醛代替3,4-二甲氧基苯甲醛,得到黄色粉末状目标化合物。产率67%,m.p:156~158℃,1H NMR(DMSO-d6,400MHz):1.34~1.38(s,3H);3.72~3.76(m,3H);4.06~4.08(m,2H);6.70~6.75(m,1H);6.92~7.10(m,5H);7.21~7.40(m,3H);7.55~7.66(m,1H);11.3(s,1H).ESI-MS:297.35(C18H19NO3,[M+H]+).Anal.Calcd for C18H19NO3:C,72.71;H,6.44;N,4.71;O,16.14%;Found:C,72.73;H,6.45;N,4.70;O,16.12%.
实施例十四:(1Z,2E)-3-(3-甲氧苯基)-1-(4-甲氧苯基)-2-烯-1-肟的制备
制备方法同实施例一,以间甲氧基苯甲醛代替3,4-二甲氧基苯甲醛,得到黄色粉末状目标化合物。产率58%,m.p:30℃,1H NMR(DMSO-d6,400MHz):3.76(s,3H);3.79(s,3H);6.71~6.77(m,1H);6.81~6.91(m,1H);6.99~7.04(m,3H);7.10~7.19(m,2H);7.22~7.30(m,1H);7.43(d,J=8.76,1H);7.59~7.65(m,1H);11.52(s,1H).ESI-MS:283.32(C17H17NO3,[M+H]+).Anal.Calcd for C17H17NO3:C,72.07;H,6.05;N,4.94;O,16.94%;Found:C,72.03;H,6.04;N,4.97;O,16.96%.
实施例十五:查尔酮肟类衍生物体外抗肿瘤活性研究
采用MTT[3-(4,5)-双甲基-2-噻唑-(2,5)-苯基溴化四氮唑蓝]法来测定查尔酮肟类衍生物对人乳腺癌细胞株(MCF-7)和人体肺癌细胞株(A549)的半数抑制浓度(IC50)。
(1)培养液(每升)的配制:①悬浮细胞:RPMI-1640培养粉一袋(10.4g),新生牛血清100ml,青霉素溶液(20万U/ml)0.5ml,链霉素溶液(20万U/ml)0.5ml,加三蒸水溶解后,用5.6%的NaHCO3溶液调PH值至7.2-7.4,最后定容至1000ml。过滤灭菌。②贴壁细胞:同上,再加入NaHCO32.00g,HEPES2.38g。
(2)PBS缓冲液(每升)的配制:NaCl8.00g,KCl0.40g,Na2HPO4·12H2O0.06g,KH2PO40.06g,NaHCO30.35g。高压灭菌。
(3)胰蛋白酶液的配制:利用PBS缓冲液配成浓度为0.5%胰蛋白酶液。过滤除菌。
(4)实验药液的配制:将测试样品用少量的三蒸水溶解配成储备液,一般按实验最高浓度的10倍配制储备液。根据化合物溶解性不同,可用三蒸水直接溶解,或用少量DMSO助溶,再加三蒸水溶解。DMSO在培养液中的浓度不宜过大,加药后的每孔细胞悬液中DMSO的终浓度一般不超过0.05%-0.1%。储备液保存于-20℃冰箱中备用。
(5)人乳腺癌细胞MCF-7的培养:为贴壁生长细胞,常规培养于RPMI-1640培养液内(含10%小牛血清、100U/ml链霉素),置37℃、5%CO2培养箱中培养,每隔3-4天传代一次。传代时先弃去原培养液,再用PBS缓冲液洗涤;然后用0.5%胰蛋白酶消化30秒左右,加入少量新鲜培养液终止消化;吹打,使贴壁细胞从培养瓶壁上脱落下来;移取适量至新鲜培养瓶中,再补充新鲜培养液至原体积(培养液体积约为培养瓶容量的1/10)。
(6)人肺癌细胞A549的培养:为贴壁生长细胞,常规培养于RPMI-1640培养液内(含10%小牛血清、100U/ml链霉素),置37℃、5%CO2培养箱中培养,每隔3-4天传代一次。传代时先弃去原培养液,再用PBS缓冲液洗涤;然后用0.5%胰蛋白酶消化30秒左右,加入少量新鲜培养液终止消化;吹打,使贴壁细胞从培养瓶壁上脱落下来;移取适量至新鲜培养瓶中,再补充新鲜培养液至原体积(培养液体积约为培养瓶容量的1/10)。
(7)细胞孵育:取对数生长期的肿瘤细胞,调细胞悬液浓度为1-1.5×105个ml-1。在96孔培养板中每孔加细胞悬液100μl,置37℃,5%CO2培养箱中培养24h。培养24h后,分别按设计加入药液。
(8)加药:将测试药液按照最终浓度的浓度梯度分别加入到各个孔中,每个浓度设6个平行孔。实验分为药物试验组(分别加入不同浓度的测试药)、对照组(只加培养液和细胞,不加测试药)和空白组(只加培养液,不加细胞和测试药)。将加药后的96孔板置于37℃,5%CO2培养箱中培养48h。阳性对照药物的活性按照测试样品的方法测定。
(9)存活细胞的测定:在培养了48h后的96孔板中,每孔加MTT40μl(用PBS缓冲液配成4mg/ml)。在37℃放置4h后,移去上清液。每孔加150μl DMSO,振荡5min,使formazan结晶溶解。最后,利用自动酶标仪在570nm波长处检测各孔的光密度(OD值)。
抑制率的计算:细胞生长的抑制率按照下列公式计算:
生长抑制率=(1-存活率)×100%=[1-(OD实验-OD空白)/(OD对照-OD空白)]×100%(OD实验表示测试药物组的平均光密度,OD对照表示对照组的平均光密度,OD空白表示对照组的平均光密度)。
半数抑制浓度(IC50)定义为当50%的肿瘤细胞存活时的药物浓度。根据测 定的光密度(OD值),制作细胞生长抑制率的标准曲线,在标准曲线上求得其对应的药物浓度。
测得的IC50见表1所示。
表格1本发明所列查尔酮肟类衍生物对肿瘤细胞的抑制IC50值
Claims (3)
3.实验结果表明,本发明的新型查尔酮肟类衍生物对癌细胞微管的聚合具有明显的抑制作用。因此本发明的查尔酮肟类衍生物可以应用于制备抗癌药物。
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PL424479A1 (pl) * | 2018-02-02 | 2019-08-12 | Uniwersytet Przyrodniczy we Wrocławiu | (E)-oksym 4'fenylo-2-metylochalkonu i (Z)-oksym 4'-fenylo-2-metylochalkonu oraz sposób ich jednoczesnego otrzymywania |
PL424477A1 (pl) * | 2018-02-02 | 2019-08-12 | Uniwersytet Przyrodniczy we Wrocławiu | (E)-oksym 4-chloro-4'-fenylochalkonu i (Z)-oksym 4-chloro-4'-fenylochalkonu oraz sposób ich jednoczesnego otrzymywania |
PL424480A1 (pl) * | 2018-02-02 | 2019-08-12 | Uniwersytet Przyrodniczy we Wrocławiu | (E)-oksym 4'-fenylo-2-metoksychalkonu i (Z)-oksym 4'-fenylo-2-metoksychalkonu oraz sposób ich jednoczesnego otrzymywania |
PL424475A1 (pl) * | 2018-02-02 | 2019-08-12 | Uniwersytet Przyrodniczy we Wrocławiu | (E)-oksym 4-etylo-4'fenylochalkonu i (Z)-oksym 4-etylo-4'-fenylochalkonu oraz sposób ich jednoczesnego otrzymywania |
PL424471A1 (pl) * | 2018-02-02 | 2019-08-12 | Uniwersytet Przyrodniczy we Wrocławiu | (E)-oksym 4-etoksy-4'-fenylochalkonu i (Z)-oksym 4-etoksy-4'-fenylochalkonu oraz sposób ich jednoczesnego otrzymywania |
PL424478A1 (pl) * | 2018-02-02 | 2019-08-12 | Uniwersytet Przyrodniczy we Wrocławiu | (E)-oksym 4-bromo-4'-fenylochalkonu i (Z)-oksym 4-bromo-4'-fenylochalkonu oraz sposób ich jednoczesnego otrzymywania |
PL424481A1 (pl) * | 2018-02-02 | 2019-08-12 | Uniwersytet Przyrodniczy we Wrocławiu | (E)-oksym 4'-fenylochalkonu i (Z)-oksym 4'-fenylochalkonu oraz sposób ich jednoczesnego otrzymywania |
PL424474A1 (pl) * | 2018-02-02 | 2019-08-12 | Uniwersytet Przyrodniczy we Wrocławiu | (E)-oksym 4'-fenylo-4-fluorochalkonu i (Z)-oksym 4'-fenylo-4-fluorochalkonu oraz sposób ich jednoczesnego otrzymywania |
PL424469A1 (pl) * | 2018-02-02 | 2019-08-12 | Uniwersytet Przyrodniczy we Wrocławiu | (E)-oksym 2,4-dimetoksy-4'-fenylochalkonu i (Z)-oksym 2,4-dimetoksy-4'-fenylochalkonu oraz sposób ich jednoczesnego otrzymywania |
PL424472A1 (pl) * | 2018-02-02 | 2019-08-12 | Uniwersytet Przyrodniczy we Wrocławiu | (E)-oksym 4'-fenylo-4-nitrochalkonu i (Z)-oksym 4'-fenylo-4-nitrochalkonu oraz sposób ich jednoczesnego otrzymywania |
PL424476A1 (pl) * | 2018-02-02 | 2019-08-12 | Uniwersytet Przyrodniczy we Wrocławiu | (E)-oksym 4'-fenylo-4-karboksychalkonu i (Z)-oksym 4'-fenylo-4-karboksychalkonu oraz sposób ich jednoczesnego otrzymywania |
PL424473A1 (pl) * | 2018-02-02 | 2019-08-12 | Uniwersytet Przyrodniczy we Wrocławiu | (E)-oksym 4'-fenylo-4-metylochalkonu i (Z)-oksym 4'-fenylo-4-metylochalkonu oraz sposób ich jednoczesnego otrzymywania |
PL424695A1 (pl) * | 2018-02-27 | 2019-09-09 | Uniwersytet Przyrodniczy we Wrocławiu | (E)-oksym 4'-fenylo-4-metoksychalkonu i (Z)-oksym 4'-fenylo-4-metoksychalkonu oraz sposób ich jednoczesnego otrzymywania |
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