CN105523961A - 一类含肉桂酰腙骨架的多甲氧基的抗肿瘤化合物的设计、合成及生物活性评价 - Google Patents
一类含肉桂酰腙骨架的多甲氧基的抗肿瘤化合物的设计、合成及生物活性评价 Download PDFInfo
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Abstract
本发明公开了一类含肉桂酰腙骨架的多甲氧基的衍生物、其制备方法及应用,所述由甲硝唑合成的衍生物的结构如式所示:其中,R1选自:-H、-OCH3;R2选自:-H、-Br;R3选自:3,4,5-OCH3、3,4-OCH3、2-OH、2-OCH3、3-OCH3、4-OCH3、2,4,5-OCH3、3-OH、4-OH、2-F、3-F、4-F、2-Br、3-Br、4-Br、4-Cl、4-NO2。本发明对人肝癌细胞(HEPG2),人乳腺癌细胞(MCF-7),人肺癌细胞(A549)有明显的抑制作用,因此本发明的含肉桂酰腙骨架的多甲氧基的衍生物可以应用于制备抗肿瘤药物。
Description
技术领域
本发明属于药物化学领域,尤其涉及一类含肉桂酰腙骨架的多甲氧基的衍生物、其制备方法及应用。
发明简介
恶性肿瘤是严重威胁人类健康的常见疾病。寻找有效的抗肿瘤药物与方法,彻底攻克癌症,是一项世界性的难题。虽然抗肿瘤药物化学结构和作用机制是各种各样,但是目前临床上常用的抗肿瘤药物普遍存在对实体瘤疗效较差、毒副作用大以及容易产生多药耐药性等诸多缺点。因此发现高效低毒的新型抗肿瘤药物,仍是一项极其重要的研究课题。
微管是细胞骨架的主要组成部分,由α微管蛋白(α-tubulin)和β微管蛋白(β-tubulin)异二聚体组成,具有维持细胞形态、细胞分裂、信号转导及物质输送等过程中起着重要作用。抗微管药物已经成为一种主要的化疗药物,广泛应用于临床各类肿瘤治疗中。微管蛋白抑制剂通过与微管蛋白特定位点结合,影响和干扰微管蛋白的聚合和解聚的动力学,进而阻断M期纺锤体的形成。使肿瘤细胞生长停滞于G2/M期。临床上应用的微管蛋白抑制剂主要有以紫杉醇为代表的抑制微管蛋白解聚药物和以长春碱类为代表的抑制微管聚合药物。然而,上述药物毒副作用大、易产生耐药性、结构复杂、合成难度大等问题。寻找新型、高效、低毒的微管抑制剂已成为当今抗肿瘤药物研究的一个热点。直到1987年美国国家癌症研究所从南非矮生柳树中发现了天然活性产物CA-4。CA-4是一类结构简单的顺式二苯乙烯类化合物,它是目前已知的微管蛋白抑制剂中活性最强的化合物之一。然而CA-4水溶性差、生物利用度低,而且给药后CA-4很容易转变为无药理活性的结构相对稳定的反式结构。因此为了克服这一缺点,国际上近年来围绕CA-4的结构进行了改造,作了大量的工作,已合成了数百个CA-4衍生物,我们这发明就是根据CA-4进行结构改造。
发明内容
本发明的目的在于提供一类肉桂酰腙骨架的多甲氧基的抗肿瘤化合物的制备方法及其在抗肿瘤药物中的应用。
技术方案:
一类肉桂酰腙骨架的多甲氧基的衍生物,其结构如式所示:
其中,R1选自:-H、-OCH3;R2选自:-H、-Br;R3选自:3,4,5-OCH3、3,4-OCH3、2-OH、2-OCH3、3-OCH3、4-OCH3、2,4,5-OCH3、3-OH、4-OH、2-F、3-F、4-F、2-Br、3-Br、4-Br、4-Cl、4-NO2。
制备方法包括如下步骤:
步骤1.室温条件下,向反应容器中依次加入结构A化合物、HOBt和EDC·HCl,在乙腈中反应2小时。然后把反应物移至0~10℃加入水合肼。TLC跟踪反应,充分反应后,得到结构如式B所示的化合物。
步骤2.向反应容器中依次加入结构如式B所示的化合物以及结构如式C所示的化合物,乙酸作催化,在无水乙醇体系中回流,TLC跟踪反应。充分反应后,得到结构如式D所示的化合物。
式A~D中,R1选自:-H、-OCH3;R2选自:-H、-Br;R3选自:3,4,5-OCH3、3,4-OCH3、2-OH、2-OCH3、3-OCH3、4-OCH3、2,4,5-OCH3、3-OH、4-OH、2-F、3-F、4-F、2-Br、3-Br、4-Br、4-Cl、4-NO2。
本发明对人肝癌细胞(HEPG2),人乳腺癌细胞(MCF-7),人肺癌细胞(A549)有明显的抑制作用,因此本发明的含肉桂酰腙骨架的多甲氧基的衍生物可以应用于制备抗肿瘤药物。
具体实施方式
在某个具体的实施例中,本发明的制备过程和相关产物的结构式如下所述:
一种制备上述含肉桂酰腙骨架的多甲氧基的抗肿瘤化合物的方法,它包括以下步骤:
步骤a.将多羟基取代的肉桂酸(10mmol)溶于15mL乙腈溶剂中,再加入HOBt(12mmol)和EDC·HCl(12mmol),室温搅拌2小时。将反应液移至0~10℃,逐滴滴加水合肼(36mmol)。TLC跟踪反应,反应结束后,将反应液真空旋干,用乙酸乙酯和饱和食盐水萃取,得到有机层真空旋干等到4a-c。
步骤b.将化合物4a-c(1.0mmol)和不同取代的苯甲醛(1.1mmol)溶于20mL的无水甲醇中,搅拌条件下滴加2滴乙酸催化,回流条件下搅拌反应2小时,直至有明显的沉淀产生。将反应物倒入冰饱和食盐水中,产生沉淀,过滤,将得到的沉淀水洗和在无水乙醇中重结晶得到5a-7g。
实施例一:
(E)-N’-((E)-3,4,5-三甲氧基苄基)-3-(3,4,5-三甲氧基苯基)乙酰肼(5a)的制备
将(E)-3-(3,4,5-三甲氧基苯基)-丙烯酸(10mmol)溶于15mL乙腈溶剂中,再加入HOBt(12mmol)和EDC·HCl(12mmol),室温搅拌2小时。将反应液移至0~10℃,逐滴滴加水合肼(36mmol),TLC跟踪反应,反应结束后,将反应液真空旋干,用乙酸乙酯和饱和食盐水萃取,得到有机层真空旋干等到4a。再将化合物4a(1.0mmol)和3,4,5-三甲氧基苯甲醛(1.1mmol)溶于20mL的无水甲醇中,搅拌条件下滴加2滴乙酸催化,回流条件下搅拌反应2小时,直至有明显的沉淀产生。将反应物倒入冰饱和食盐水中,产生沉淀,过滤,将得到的沉淀水洗和在无水乙醇中重结晶得到5a。得淡黄色的粉末,产率:89.1%.m.p.219-221℃.1HNMR(400MHz,DMSO-d6)δ:11.68(s,0.58H),11.55(s,0.42H),8.16(s,0.56H),7.98(s,0.44H),7.61(dd,J=18.5,9.3Hz,1.49H),7.11(d,J=3.8Hz,2H),7.04(s,1H),6.99(s,1H),6.67(d,J=15.7Hz,0.51H),3.85(d,J=6.1Hz,12H),3.71(d,J=1.9Hz,6H).MS(ESI)m/z:431.17(C22H26N2O7,[M+H]+).Anal.CalcdforC22H26N2O7:C,61.39;H,6.09;N,6.51.Found:C,61.48;H,6.09;N,6.49.
实施例二:
(E)-N′-((E)-3,4-二甲氧基亚苄基)-3-(3,4,5-三甲氧基苯基)乙酰肼(5e)的制备
制备方法参考实施例一。得黄色粉末,产率:87.7%.m.p.208-210℃.1HNMR(400MHz,DMSO-d6)δ:11.56(s,0.58H),11.40(s,0.42H),8.15(s,0.59H),7.98(s,0.41H),7.68-7.46(m,2H),7.33(s,0.56H),7.20(dd,J=8.3Hz,0.57H),7.17(d,J=8.1Hz,0.43H),7.11-6.95(m,3H),6.65(d,J=15.7Hz,0.56H),3.84(t,J=4.1Hz,9H),3.81(d,J=4.2Hz,3H),3.70(s,3H).MS(ESI)m/z:401.16(C21H24N2O6,[M+H]+).Anal.CalcdforC21H24N2O6:C,62.99;H,6.04;N,7.00.Found:C,62.86;H,6.02;N,7.01.
实施例三:
(E)-3-(2-溴-3,4,5-三甲氧基苯基)-N′-((E)-3,4,5-三甲氧基苄基)丙烯酸酰肼(6a)的制备
制备方法参考实施例一。得黄绿色晶体,产率78.4%.m.p.241-243℃.1HNMR(300MHz,DMSO-d6)δ:11.73(s,0.47H),11.67(s,0.53H),8.19(s,0.51H),8.03-7.79(m,1.49H),7.69(d,J=15.8Hz,0.51H),7.42(s,0.49H),7.20(s,0.49H),7.08(d,J=18.7Hz,2H),6.71(d,J=15.6Hz,0.51H),3.91(s,3H),3.89-3.77(m,12H),3.71(d,J=4.0Hz,3H).13CNMR(101MHz,DMSO-d6)δ:166.17,161.45,153.64,153.59,153.25,150.97,150.89,147.47,144.62,144.49,143.43,139.97,139.71,139.32,138.79,130.19,130.16,130.04,123.42,120.34,112.28,111.96,107.26,106.88,104.85,104.56,61.31,61.28,60.60,60.56,56.56,56.42,56.27,56.15.MS(ESI)m/z:509.08(C22H25BrN2O7,[M+H]+).Anal.CalcdforC22H25BrN2O7:C,51.88;H,4.95;N,5.50.Found:C,51.92;H,4.94;N,5.51.
实施例四:
(E)-3-(2-溴-3,4,5-三甲氧基苯基)-N′-((E)-2-甲氧基亚苄基)丙烯酸酰肼(6b)的制备
制备方法参考实施例一。得黄色晶体,产率70.8%.m.p.205-207℃.1HNMR(300MHz,DMSO-d6)δ:11.76(s,0.60H),11.58(s,0.40H),8.61(s,0.59H),8.43(s,0.41H),8.01-7.93(m,0.61H),7.86(dd,J=14.0,5.1Hz,1.39H),7.56(d,J=15.8Hz,0.46H),7.42(q,J=8.1Hz,1H),7.33(s,0.41H),7.18(s,0.59H),7.15-7.07(m,1H),7.02(q,J=7.2Hz,1H),6.67(d,J=15.6Hz,0.54H),3.93(d,J=12.1Hz,3H),3.87(d,J=4.0Hz,3H),3.83(d,J=6.6Hz,6H).13CNMR(101MHz,DMSO-d6)δ:166.13,161.30,158.19,158.08,153.32,153.25,150.98,144.59,144.47,142.91,140.32,139.52,138.69,132.14,131.79,130.49,130.21,126.12,126.02,123.55,122.58,121.24,120.75,112.29,112.20,111.99,111.89,107.77,106.88,61.31,61.28,56.78,56.51,56.20,56.13.MS(ESI)m/z:449.06(C20H21BrN2O5,[M+H]+).Anal.CalcdforC20H21BrN2O5:C,53.46;H,4.71;N,6.23.Found:C,53.45;H,4.69;N,6.21
实施例五:
(E)-3-(2-溴-3,4,5-三甲氧基苯基)-N′-((E)-3-甲氧基亚苄基)丙烯酸酰肼(6c)的制备
制备方法参考实施例一。得银色粉末,产率67.4%.m.p.180-182℃.1HNMR(300MHz,DMSO-d6)δ:11.76(s,0.56H),11.64(s,0.44H),8.24(s,0.54H),8.05(s,0.46H),7.98-7.82(m,1H),7.62(d,J=15.8Hz,0.49H),7.41-7.18(m,4H),7.00(t,J=9.0Hz,1H),6.71(d,J=15.6Hz,0.51H),3.92(d,J=9.0Hz,3H),3.83(d,J=6.8Hz,9H).13CNMR(101MHz,DMSO-d6)δ:166.26,161.52,160.00,153.26,150.98,147.40,144.52,140.27,138.91,136.10,136.01,130.40,130.26,130.14,123.37,120.54,116.94,116.79,111.97,111.82,110.96,107.57,106.89,61.32,61.28,56.55,55.66,55.44.MS(ESI)m/z:449.06(C20H21BrN2O5,[M+H]+).Anal.CalcdforC20H21BrN2O5:C,53.46;H,4.71;N,6.23.Found:C,53.52;H,4.72;N,6.22.
实施例六:
(E)-3-(2-溴-3,4,5-三甲氧基苯基)-N′-((E)-4-甲氧基亚苄基)丙烯酸酰肼(6d)的制备
制备方法参考实施例一。得黄色晶体,产率66.3%.m.p.218-220℃.1HNMR(300MHz,DMSO-d6)δ:11.63(s,0.61H),11.50(s,0.41H),8.22(s,0.61H),8.04(s,0.39H),7.96(s,0.18H),7.90(d,J=5.5Hz,0.51H),7.84(s,0.31H),7.70(t,J=8.1Hz,2H),7.56(d,J=15.8Hz,0.39H),7.35(s,0.41H),7.19(s,0.60H),7.01(dd,J=8.5,6.1Hz,2H),6.71(d,J=15.5Hz,0.61H),3.94(d,J=16.4Hz,3H),3.83(dd,J=9.6,3.0Hz,9H).13CNMR(101MHz,DMSO-d6)δ:166.00,161.35,161.26,161.10,153.32,153.24,150.97,150.89,147.33,144.57,144.43,143.82,140.22,138.52,130.48,130.23,129.27,129.09,127.22,127.14,123.58,120.72,114.77,112.02,111.92,107.73,106.80,61.30,61.27,56.81,56.51,55.77,55.74.MS(ESI)m/z:449.06(C20H21BrN2O5,[M+H]+).Anal.CalcdforC20H21BrN2O5:C,53.46;H,4.71;N,6.23.Found:C,53.56;H,4.70;N,6.21.
实施例七:
(E)-3-(2-溴-3,4,5-三甲氧基苯基)-N′-((E)-3,4-二甲氧基亚苄)丙烯酸酰肼(6e)的制备
制备方法参考实施例一。得黄色粉末,产率89.7%.m.p.237-239℃.1HNMR(400MHz,DMSO-d6)δ:11.67(s,0.54H),11.58(s,0.46H),8.18(s,0.53H),8.00(s,0.46H),7.98-7.81(m,1H),7.69(d,J=15.8Hz,0.50H),7.51(s,0.46H),7.43(s,0.46H),7.34(s,0.54H),7.26-7.14(m,1.60H),7.01(dd,J=15.6,8.3Hz,1H),6.70(d,J=15.5Hz,0.54H),3.92(d,J=9.2Hz,3H),3.82(dd,J=11.3,3.0Hz,12H).13CNMR(101MHz,DMSO-d6)δ:165.99,161.29,153.25,151.26,150.97,150.89,149.50,147.68,144.58,144.44,143.73,139.86,138.54,130.22,130.18,127.36,123.57,122.39,122.23,120.53,112.20,111.92,111.74,108.85,108.36,107.34,106.83,61.30,61.27,56.53,56.38,56.03,55.97,55.92,55.52.MS(ESI)m/z:479.07(C21H23BrN2O6,[M+H]+).Anal.CalcdforC21H23BrN2O6:C,52.62;H,4.84;N,5.84.Found:C,52.73;H,4.85;N,5.84.
实施例八:
(E)-3-(2-溴-3,4,5-三甲氧基苯基)-N′-((E)-2,4,5-三甲氧基苄基)丙烯酸酰肼(6f)的制备
制备方法参考实施例一。得亮黄色粉末,产率81.3%.m.p.250-252℃.1HNMR(400MHz,DMSO-d6)δ:11.66(s,0.52H),11.50(s,0.48H),8.52(s,0.53H),8.34(s,0.47H),7.93(d,J=15.8Hz,0.46H),7.83(d,J=15.5Hz,0.50H),7.70(d,J=15.8Hz,0.48H),7.54(s,0.47H),7.42(s,0.48H),7.33(s,0.52H),7.17(s,0.52H),6.74(d,J=10.3Hz,1H),6.66(d,J=15.5Hz,0.53H),3.91(s,3H),3.86(dd,J=10.0,4.2Hz,9H),3.82-3.75(m,6H).13CNMR(101MHz,DMSO-d6)δ:165.84,161.05,153.85,153.43,153.23,152.61,152.06,150.96,150.87,144.53,144.39,143.70,143.63,143.13,139.59,139.24,138.29,130.26,130.15,123.72,120.65,113.85,113.81,112.20,111.83,108.05,107.20,106.80,98.27,98.12,61.30,61.26,57.01,56.89,56.48,56.35,56.26,56.24,56.19,55.75.MS(ESI)m/z:509.08(C22H25BrN2O7,[M+H]+).Anal.CalcdforC22H25BrN2O7:C,51.88;H,4.95;N,5.50.Found:C,51.97;H,4.94;N,5.49.
实施例九:
(E)-3-(2-溴-3,4,5-三甲氧基苯基)-N′-((E)-2-羟基亚)丙烯酸酰肼(6g)的制备
制备方法参考实施例一。得黄色粉末,产率72.6%.m.p.206-209℃.1HNMR(400MHz,DMSO-d6)δ:12.01(s,0.81H),11.57(s,0.24H),11.16(s,0.76H),10.09(s,0.19H),8.46(s,0.81H),8.39(s,0.21H),7.98-7.85(m,1H),7.81(d,J=7.3Hz,0.20H),7.61-7.48(m,1H),7.36-7.27(m,1H),7.27-7.18(m,1H),7.00-6.83(m,2H),6.69(d,J=15.6Hz,0.77H),3.92(d,J=13.8Hz,3H),3.83(d,J=9.1Hz,6H).MS(ESI)m/z:435.05(C19H19BrN2O5,[M+H]+).Anal.CalcdforC19H19BrN2O5:C,52.43;H,4.40;N,6.44.Found:C,52.47;H,4.41;N,6.46.
实施例十:
(E)-3-(2-溴-3,4,5-三甲氧基苯基)-N′-((E)-3-羟基亚)丙烯酸酰肼(6h)的制备
制备方法参考实施例一。得淡黄色粉末,产率75.3%.m.p.192-194℃.1HNMR(400MHz,DMSO-d6)δ:11.73(s,0.65H),11.59(s,0.35H),9.66(s,0.64H),9.60(s,0.36H),8.16(s,0.60H),7.99(s,0.4H),7.95-7.81(m,1H),7.52(d,J=15.8Hz,0.36H),7.32(s,0.4H),7.29-7.08(m,3.57H),6.84(dd,J=10.4,4.2Hz,1H),6.70(d,J=15.5Hz,0.59H),3.95(s,1H),3.90(s,2H),3.84(d,J=2.7Hz,3H),3.82(d,J=2.1Hz,3H).MS(ESI)m/z:435.05(C19H19BrN2O5,[M+H]+).Anal.CalcdforC19H19BrN2O5:C,52.43;H,4.40;N,6.44.Found:C,52.39;H,4.40;N,6.42.
实施例十一:
(E)-3-(2-溴-3,4,5-三甲氧基苯基)-N′-((E)-4-羟基亚苄基)丙烯酸酰肼(6i)的制备
制备方法参考实施例一。得淡黄色晶体,产率48.7%.m.p.218-220℃.1HNMR(400MHz,DMSO-d6)δ:11.60(s,0.63H),11.46(s,0.37H),9.99(s,0.63H),9.93(s,0.36H),8.16(s,0.63H),7.99(s,0.38H),7.96-7.80(m,1H),7.68-7.46(m,2.37H),7.34(s,0.38H),7.19(s,0.63H),6.84(t,J=8.1Hz,2H),6.69(d,J=15.5Hz,0.61H),3.96(s,1H),3.91(s,2H),3.83(dd,J=8.8,3.2Hz,6H).13CNMR(101MHz,DMSO-d6)δ:165.90,161.19,159.97,159.68,153.32,153.24,150.97,150.90,147.79,144.55,144.41,144.25,140.11,138.40,130.55,130.27,129.45,129.22,125.65,125.58,123.66,120.86,116.16,111.95,111.88,107.73,106.82,61.30,61.27,56.80,56.52.MS(ESI)m/z:435.05(C19H19BrN2O5,[M+H]+).Anal.CalcdforC19H19BrN2O5:C,52.43;H,4.40;N,6.44.Found:C,52.56;H,4.41;N,6.45.
实施例十二:
(E)-3-(2-溴-3,4,5-三甲氧基苯基)-N′-((E)-2-氟亚苄基)丙烯酸酰肼(6j)的制备
制备方法参考实施例一。得灰色到白色晶体,产率52.4%.m.p.183-184℃.1HNMR(400MHz,DMSO-d6)δ:11.94(s,0.55H),11.78(s,0.45H),8.49(s,0.54H),8.31(s,0.45H),8.08(t,J=7.3Hz,0.47H),7.99-7.84(m,1.51H),7.57(d,J=15.8Hz,0.47H),7.54-7.43(m,1H),7.39-7.18(m,3H),6.69(d,J=15.6Hz,0.51H),3.94(d,J=19.5Hz,3H),3.88-3.79(m,6H).MS(ESI)m/z:437.04(C19H18BrFN2O4,[M+H]+).Anal.CalcdforC19H18BrFN2O4:C,52.19;H,4.15;N,6.41.Found:C,52.08;H,4.14;N,6.43.
实施例十三:
(E)-3-(2-溴-3,4,5-三甲氧基苯基)-N′-((E)-3-氟亚苄基)丙烯酸酰肼(6k)的制备
制备方法参考实施例一。得灰色晶体,产率34.8%.m.p.200-202℃.1HNMR(400MHz,DMSO-d6)δ:11.90(s,0.56H),11.76(s,0.44H),8.27(s,0.56H),8.09(s,0.45H),8.00-7.84(m,1H),7.72-7.44(m,3H),7.39(s,0.48H),7.34-7.17(m,2H),6.72(d,J=15.5Hz,0.54H),4.03-3.78(m,9H).MS(ESI)m/z:437.04(C19H18BrFN2O4,[M+H]+).Anal.CalcdforC19H18BrFN2O4:C,52.19;H,4.15;N,6.41.Found:C,52.32;H,4.13;N,6.42.
实施例十四:
(E)-3-(2-溴-3,4,5-三甲氧基苯基)-N′-((E)-4-氟亚苄基)丙烯酸酰肼(6l)的制备
制备方法参考实施例一。得银色粉末,产率59.8%.m.p.195-198℃.1HNMR(400MHz,DMSO-d6)δ:11.80(s,0.59H),11.66(s,0.41H),8.26(s,0.59H),8.08(s,0.43H),7.99-7.76(m,3H),7.57(d,J=15.8Hz,0.42H),7.40-7.16(m,3H),6.71(d,J=15.5Hz,0.57H),3.94(d,J=21.5Hz,3H),3.88-3.77(m,6H).MS(ESI)m/z:437.04(C19H18BrFN2O4,[M+H]+).Anal.CalcdforC19H18BrFN2O4:C,52.19;H,4.15;N,6.41.Found:C,52.27;H,4.16;N,6.39..
实施例十五:
(E)-3-(2-溴-3,4,5-三甲氧基苯基)-N′-((E)-2-溴苄基)丙烯酸酰肼(6m)的制备
制备方法参考实施例一。得白色粉末,产率78.8%.m.p.212-214℃.1HNMR(400MHz,DMSO-d6)δ:12.03(s,0.58H),11.85(s,0.41H),8.62(s,0.59H),8.44(s,0.44H),8.12(d,J=7.0Hz,0.40H),8.03-7.83(m,1.52H),7.70(t,J=7.2Hz,1H),7.57(d,J=15.8Hz,0.42H),7.52-7.31(m,2.34H),7.20(s,0.53H),6.68(d,J=15.6Hz,0.55H),3.92(d,J=14.7Hz,3H),3.83(d,J=9.2Hz,6H).MS(ESI)m/z:496.96(C19H18Br2N2O4,[M+H]+).Anal.CalcdforC19H18Br2N2O4:C,45.81;H,3.64;N,5.62.Found:C,45.73;H,3.65;N,5.62.
实施例十六:
(E)-3-(2-溴-3,4,5-三甲氧基苯基)-N′-((E)-3-溴苄基)丙烯酸酰肼(6n)的制备
制备方法参考实施例一。得淡黄色粉末,产率78.6%.m.p.205-207℃.1HNMR(400MHz,DMSO-d6)δ:11.89(s,0.61H),11.75(s,0.39H),8.22(s,0.57H),8.03(d,J=9.8Hz,1H),7.98-7.82(m,1.56H),7.75(d,J=7.6Hz,1H),7.62(t,J=11.2Hz,1.38H),7.47-7.35(m,1.40H),7.19(s,0.56H),6.71(d,J=15.6Hz,0.52H),3.96(s,1H),3.90(s,2H),3.82(d,J=9.1Hz,6H).MS(ESI)m/z:496.96(C19H18Br2N2O4,[M+H]+).Anal.CalcdforC19H18Br2N2O4:C,45.81;H,3.64;N,5.62.Found:C,45.89;H,3.63;N,5.63.
实施例十七:
(E)-3-(2-溴-3,4,5-三甲氧基苯基)-N′-((E)-4-溴亚苄基)丙烯酸酰肼(6o)的制备
制备方法参考实施例一。得白色粉末,产率75.1%.m.p.211-212℃.1HNMR(400MHz,DMSO-d6)δ:11.83(s,0.59H),11.70(s,0.41H),8.23(s,0.60H),8.05(s,0.46H),7.97-7.82(m,1H),7.76-7.60(m,4H),7.55(d,J=15.8Hz,0.41H),7.35(s,0.42H),7.19(s,0.57H),6.70(d,J=15.5Hz,0.57H),3.95(s,1H),3.90(s,2H),3.87-3.77(m,6H).MS(ESI)m/z:496.96(C19H18Br2N2O4,[M+H]+).Anal.CalcdforC19H18Br2N2O4:C,45.81;H,3.64;N,5.62.Found:C,45.93;H,3.65;N,5.61.
实施例十八:
(E)-3-(2-溴-3,4,5-三甲氧基苯基)-N′-((E)-2-氯亚苄基)丙烯酸酰肼(6p)的制备
制备方法参考实施例一。得灰色粉末,产率69.8%.m.p.203-205℃.1HNMR(400MHz,DMSO-d6)δ:11.83(s,0.59H),11.70(s,0.41H),8.25(s,0.60H),8.07(s,0.46H),7.97-7.72(m,3H),7.61-7.43(m,2.37H),7.27(d,J=62.6Hz,1H),6.70(d,J=15.5Hz,0.56H),3.95(s,1H),3.90(s,2H),3.87-3.79(m,6H).MS(ESI)m/z:453.01(C19H18BrClN2O4,[M+H]+).Anal.CalcdforC19H18BrClN2O4:C,50.30;H,4.00;N,6.17;N,8.46.Found:C,50.34;H,3.99;N,6.18
实施例十九:
(E)-3-(2-溴-3,4,5-三甲氧基苯基)-N′-((E)-4-硝基苯)丙烯酸酰肼(6q)的制备
制备方法参考实施例一。得黄色粉末,产率84.5%.m.p.217-219℃.1HNMR(400MHz,DMSO-d6)δ:12.06(s,0.56H),11.94(s,0.44H),8.38-8.23(m,2.41H),8.18(s,0.44H),8.09-7.85(m,3H),7.59(d,J=15.7Hz,0.42H),7.37(s,0.50H),7.21(s,0.59H),6.73(d,J=15.5Hz,0.53H),3.97(s,1H),3.90(s,2H),3.88-3.76(m,6H).MS(ESI)m/z:464.04(C19H18BrN3O6,[M+H]+).Anal.CalcdforC19H18BrN3O6:C,49.15;H,3.91;N,9.05.Found:C,49.22;H,3.90;N,9.04.
实施例二十:
(E)-3-(3,4-二甲氧基苯基)-N′-((E)-3,4,5-三甲氧基苄基)丙烯酸酰肼(7a)的制备
制备方法参考实施例一。得白色粉末,产率97.1%.m.p.222-224℃.1HNMR(400MHz,DMSO-d6)δ:11.63(s,0.56H),11.51(s,0.44H),8.17(s,0.58H),7.98(s,0.45H),7.67-7.51(m,1.48H),7.41(s,0.46H),7.30-7.16(m,1.64H),7.13-6.97(m,3H),6.61(d,J=15.7Hz,0.56H),3.91-3.77(m,12H),3.71(s,3H).MS(ESI)m/z:401.16(C21H24N2O6,[M+H]+).Anal.CalcdforC21H24N2O6:C,62.99;H,6.04;N,7.00.Found:C,63.19;H,6.03;N,6.98.
实施例二十一:
(E)-3-(3,4-二甲氧基苯基)-N′-((E)-3,4-二甲氧基亚苄)丙烯酸酰肼(7e)的制备
制备方法参考实施例一。得淡黄色粉末,产率87.7%.m.p.208-210℃.1HNMR(400MHz,DMSO-d6)δ:11.50(s,0.58H),11.35(s,0.42H),8.15(s,0.60H),7.98(s,0.44H),7.66-7.50(m,1.46H),7.46(s,0.40H),7.38(s,0.43H),7.33(d,J=1.3Hz,0.58H),7.28-7.16(m,2.56H),7.06-6.98(m,2H),6.58(d,J=15.7Hz,0.57H),3.83(dd,J=14.2,7.6Hz,12H).MS(ESI)m/z:371.15(C20H22N2O5,[M+H]+).Anal.CalcdforC20H22N2O5:C,64.85;H,5.99;N,7.56.Found:C,64.73;H,6.00;N,7.58.
上述含肉桂酰腙骨架的多甲氧基的抗肿瘤化合物的体外抗癌活性研究进展
实施例一:含肉桂酰腙骨架的多甲氧基的衍生物的体外抗菌活性研究
采用MTT[3-(4,5)-双甲基-2-噻唑-(2,5)-苯基溴化四氮唑蓝]法来测定含甲硝唑骨架的吡唑硝基咪唑衍生物对人肝癌细胞(HEPG2),人乳腺癌细胞(MCF-7),人肺癌细胞(A549)的抑制率达到50%时的药物浓度(halfmaximalinhibitoryconcentration,IC50)。
(1)培养液的配制:DMEM(基础培养基)89%,胎牛血清10%,青霉素链霉素溶液(10000IU/mL,10000μg/mL)1%。
(2)四种贴壁癌细胞的培养:利用上述培养液(培养液体积约为培养瓶容量的1/10),在37℃,5%CO2培养箱中培养,根据癌细胞的生长状态判断传代时间。
(3)不同浓度药物的配制:利用三蒸水(少量DMSO助溶)配制储备液,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%;用三蒸水把储备液稀释至六个浓度梯度(100μmol,50μmol,10μmol,1μmol,0.1μmol,0.01μmol);保存于-20℃冰箱中备用。
(4)细胞孵育:取对数生长期肿瘤细胞,调细胞悬液浓度为1-1.5×105/mL,混匀后加入96孔培养板中(100μL/孔),在37℃,5%CO2培养箱中培养24h。
(5)加药:将稀释好的不同浓度梯度的药物分别加入到96孔培养板中,每个浓度梯度设3个平孔,继续培养48h。实验分为实验组(培养液、细胞、药物)、对照组(培养液和细胞)和空白组(只有培养液)。
(6)存活细胞检测:在培养了48h后的96孔板中,加MTT(5mg/mL)10μL/孔;在37℃放置4h后,移除上清液,加DMSO150μL/孔,振荡至formazan结晶全部溶解;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:
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实验表示实验组的平均光密度,OD对照表示对照组的平均光密度,OD空白表示空白组的平均光密度)。
根据药物浓度-细胞生长抑制率的标准曲线,求其IC50。
本发明所列含肉桂酰腙骨架的多甲氧基衍生物对肿瘤细胞的抑制IC50值(μmol/mL)见下表
从上述实验可知:本发明对人肝癌细胞(HEPG2),人乳腺癌细胞(MCF-7),人肺癌细胞(A549)有明显的抑制作用,与对照组相比,活性明显提高。
实施例二:含肉桂酰腙骨架的多甲氧基的衍生物体外抗肿瘤活性关于细胞毒性的研究
本发明测试了新合成化合物对人肾上皮细胞(293T)的细胞毒性,细胞毒性结果如下表,每个化合物的毒性用抑制T细胞存活率到50%时的浓度(CC50)来表示。
实验方法:
(1)培养人肾上皮细胞(293T)直至达到其对数生长期末细胞趋于融合,用细胞消化液消化分散细胞,用细胞培养液配制成1×104个/mL的细胞悬液。取96孔培养板,每孔中加入100μL的细胞悬液。轻轻水平转动培养板使细胞均匀地分散在皿孔的表面。
(2)置于含5%CO2细胞培养箱中,在37℃温度下培养24h。弃去原培养液,每孔加入100μL的空白对照液,阴性对照液,阳性对照液,100%和50%浓度的试验样品浸提液。每组至少设8孔。注:浸提原液或以培养基作稀释剂的系列浸提稀释液。采用0.9%氯化钠注射液浸提时,在稀释浸提时使用浓缩的2倍培养基。
(3)置于含5%CO2培养箱中,在37℃温度下进行培养。培养48h。
(4)每个培养间期后,每孔加入MTT溶液20μL,置于含5%CO2培养箱中,在37℃温度下培养5h。
(5)弃去孔内液体,每孔分别加入200μLDMSO,将培养板放置10min,水平摇晃使孔内溶液颜色均匀。
(6)用酶标仪测定吸光度,波长采用570nm。
测得的CC50见下表所示。
从上述实验可知:本发明对人肾上皮细胞(293T)表现出了相当或者优于阳性对照药物的细胞毒性,可以用于制取抗肿瘤药物。
以上详细描述了本发明的优选实施方式,但是,本发明并不限于上述实施方式中的具体细节,在本发明的技术构思范围内,可以对本发明的技术方案进行多种等同变换,这些等同变换均属于本发明的保护范围。另外需要说明的是,在上述具体实施方式中所描述的各个具体技术特征,在不矛盾的情况下,可以通过任何合适的方式进行组合。为了避免不必要的重复,本发明对各种可能的组合方式不再另行说明。此外,本发明的各种不同的实施方式之间也可以进行任意组合,只要其不违背本发明的思想,其同样应当视为本发明所公开的内容。
Claims (4)
1.一类含肉桂酰腙骨架的多甲氧基的衍生物,其结构如式所示:
其中,R1选自:-H、-OCH3、;R2选自:-H、-Br;R3选自:3,4,5-OCH3、3,4-OCH3、2-OH、2-OCH3、3-OCH3、4-OCH3、2,4,5-OCH3、3-OH、4-OH、2-F、3-F、4-F、2-Br、3-Br、4-Br、4-Cl、4-NO2。
2.制备方法包括如下步骤:
步骤1.室温条件下,向反应容器中依次加入结构A化合物、HOBt和EDC·HCl,在乙腈中反应2小时。然后把反应物移至0~10℃加入水合肼。TLC跟踪反应,充分反应后,得到结构如式B所示的化合物。
步骤2.向反应容器中依次加入结构如式B所示的化合物以及结构如式C所示的化合物,乙酸作催化,在无水乙醇体系中回流,TLC跟踪反应。充分反应后,得到结构如式D所示的化合物。
式A~D中,R1选自:-H、-OCH3;R2选自:-H、-Br;R3选自:3,4,5-OCH3、3,4-OCH3、2-OH、2-OCH3、3-OCH3、4-OCH3、2,4,5-OCH3、3-OH、4-OH、2-F、3-F、4-F、2-Br、3-Br、4-Br、4-Cl、4-NO2。
3.含肉桂酰腙骨架的多甲氧基的衍生物在制备抗癌药物中的应用,其特征在于,其结构如式所示
其中,R1选自:-H、-OCH3、;R2选自:-H、-Br;R3选自:3,4,5-OCH3、3,4-OCH3、2-OH、2-OCH3、3-OCH3、4-OCH3、2,4,5-OCH3、3-OH、4-OH、2-F、3-F、4-F、2-Br、3-Br、4-Br、4-Cl、4-NO2。
4.一种抗癌药物,其特征在于,包括结构如式所示的化合物及医学上可接受的载体,
其中,R1选自:-H、-OCH3、;R2选自:-H、-Br;R3选自:3,4,5-OCH3、3,4-OCH3、2-OH、2-OCH3、3-OCH3、4-OCH3、2,4,5-OCH3、3-OH、4-OH、2-F、3-F、4-F、2-Br、3-Br、4-Br、4-Cl、4-NO2。
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