CN110604732B - 一种莪术醇衍生物在制备治疗结直肠癌药物中的应用 - Google Patents
一种莪术醇衍生物在制备治疗结直肠癌药物中的应用 Download PDFInfo
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Abstract
本发明属于天然药物及药物化学领域,具体公开了一种如下式所示的莪术醇衍生物在制备治疗结直肠癌药物中的应用,其对人结直肠癌细胞株Sw620、HCT116、CaCo2具有显著抑制活性,在制备抗结肠癌药物领域具有巨大的应用前景。上述莪术醇衍生物是以天然产物莪术醇为原料,经结构改造制得得到。另外,该类化合物制备方法简便、易于操作、原料易得且生产成本较低,适于工业化生产应用。
Description
技术领域
本发明属于天然药物及药物化学领域,具体涉及一种莪术醇衍生物的应用,特别涉及一种莪术醇衍生物在制备治疗结直肠癌药物中的应用。
背景技术
结肠直肠癌(carcinoma of colon and rectum)是胃肠道中常见的恶性肿瘤,发病率和病死率在消化系统恶性肿瘤中仅次于胃癌、食管癌和原发性肝癌。随着城市现代化程度提高,人民生活水平的提高,生活方式及饮食结构的改变,鸡鸭鱼肉等高热量、高脂肪、高蛋白食物摄入增多及人口老龄化进程,结直肠肿瘤高发的问题将越来越突出,值得引起我们的关注。
从目前临床治疗上的情况看,城市的大肠癌的发病率为第2-3位,40岁以下的年龄段得结直肠癌的比例约占结直肠癌总人数的20%,而且又进一步上升的趋势,结直肠癌有望取代肺癌而成为新的癌症之王。因此,寻找高效、低毒的治疗结肠癌的药物,变得越来越迫切。
我国有着丰富的中药资源,近年来,研究者对具有肿瘤活性的中药进行了大量的筛选,表明抗肿瘤中药有调节机体免疫功能、抑制肿瘤微血管生成、直接杀伤肿瘤细胞、诱导肿瘤细胞凋亡、诱导肿瘤细胞分化、逆转癌细胞的多重耐药、调节细胞信号传导、抑制端粒酶活性等多种作用机制,且中药具有多靶点、多环节等西药难以具备的特性,药理作用广泛,同一种中药常常从整体调节,提高机体自身抗病能力,通过多种机制达到抗肿瘤的作用。随着对中药抗肿瘤作用实验和临床研究的不断深入,中药抗肿瘤作用越来越受到国际社会的认可。
莪术醇(Curcumol)是传统中药莪术挥发油的重要组成部分,目前已从多种植物中分离获得,这些植物大多分布在东南亚、中国、印度尼西亚、印度和秘鲁等地。莪术醇(Curcumol),别称姜黄醇、姜黄环奥醇,结构上属于愈创木烷倍半萜类天然产物,由五元环和七元环稠合而成,其中七元环通过半缩酮的氧桥形成了一个新的五元环和六元环,从而使得三个环的张力变小,形成了具有一定刚性结构的稳定化合物。据文献报道,莪术醇具有抗病毒、抗炎、抗肿瘤、抗早孕等广泛的生物活性,尤其在抗肿瘤方面,莪术醇表现出潜在的抗癌活性,如肺癌、乳腺癌、鼻咽癌、肝癌、结直肠癌、卵巢癌等。(参阅文献Wei W,AzharRasul A S,Sarfraz I,et al.Curcumol:From Plant Roots to Cancer Roots[J].International journal of biological sciences,2019,15(8):1600.)
但是,由于莪术醇独特的化学结构,其水溶性较低,抗肿瘤活性表现尚不突出,还存在很大的优化改善空间。
发明内容
本发明的目的在于提供一种莪术醇衍生物在制备治疗结直肠癌药物中的应用,该莪术醇衍生物在有效剂量下对人结直肠癌细胞株Sw620、HCT116、CaCo2细胞株具有很好的抑制效果。
本发明采用的技术方案如下:
一种莪术醇衍生物在制备治疗结直肠癌药物中的应用,所述莪术醇衍生物的结构如下式(I)所示:
优选地,所述的R2、R3、R4独立地选自氢、C1-C6烷基、苯基或C1-C6烷酯基。
进一步优选,所述的R1选自C1-C4烷基,所述的R2、R3、R4独立地选自氢、C1-C4烷基、苯基或C1-C4烷酯基。
上述“C1-C6烷基”指具有1-6个碳原子的直链或支链饱和烃基,“C1-C4烷基”指具有1-4个碳原子的直链或支链饱和烃基;“C1-C6烷酯基”为-COO-烷基(烷基定义同上)。
更进一步优选,所述莪术醇衍生物的结构为下式(A-01)~(A-15)中的任意一种:
另一方面,本发明还公开了一种治疗结直肠癌的药物,所述药物包含有效剂量的上述莪术醇衍生物。
所述药物具有抑制人结直肠癌细胞株Sw620、HCT116、CaCo2活性的作用。
此外,本发明还提供如上式Ⅰ所示的莪术醇衍生物的合成方法,具体的合成路线如下:
所述的合成方法包括以下步骤:
(1)将式(II)化合物溶于有机溶剂A中,加入碱A,在-5~0℃滴加氯乙酰氯,滴加完毕,在0~50℃反应1~6h,反应结束后加水,乙酸乙酯萃取,合并有机相,有机相用饱和氯化钠溶液洗涤,浓缩,柱层析分离纯化,制得式(III)化合物;
(2)将莪术醇溶于有机溶剂B中,在碱B的作用下加入式(III)化合物,在30~100℃反应1~10h,反应结束,加水淬灭,乙酸乙酯萃取,浓缩,柱层析分离制得式(I)化合物。
(一)步骤(1)中:
所述有机溶剂A选自下列之一:四氢呋喃、2-四氢呋喃、二氯甲烷、氯仿、1,2-二氯乙烷、甲苯、乙腈或1,4-二氧六环,优选为四氢呋喃或二氯甲烷。所述有机溶剂A的用量以式(II)化合物的质量计为10~50mL/g。
所述的碱A选自有机碱或无机碱,其中,有机碱选自三乙胺、三丁胺、二异丙基乙基胺、吡啶、4-二甲氨基吡啶或2,6-二甲基吡啶;无机碱选自碳酸钠、碳酸氢钠、碳酸钾、碳酸铯、磷酸钠、氢氧化钠或氢氧化钾。
优选地,所述的反应温度为15~25℃,反应时间为0.5~2h。
所述的式(II)化合物、氯乙酰氯和碱的投料物质的量之比为1:1~2:1~3,优选1:1~1.2:1~1.5。
(二)步骤(2)中:
所述的有机溶剂B为甲苯、四氢呋喃、2-四氢呋喃或1,4-二氧六环。所述有机溶剂B的用量以莪术醇的质量计为10~50mL/g。
所述的碱B为氢化钠、甲醇钠、乙醇钠、吡啶、叔丁醇钾、氢氧化钠或氢氧化锂。
优选地,所述的反应温度为70~80℃,反应时间为5~8h。
所述的莪术醇、碱、式(III)化合物的投料物质的量之比为1:2~5:1~3,优选为1:2.5~3:1.5~2。
与现有技术相比,本发明具有以下有益效果:
(1)本发明通过对莪术醇8-位羟基结构改造,得到多个莪术醇衍生物,通过体外细胞实验显示,该类莪术醇衍生物对结肠癌细胞SW620、HCT116、Caco2均表现出良好的生物活性,可用于预防或/和治疗结直肠癌,在医药领域具有巨大的应用前景。
(2)本发明公开的莪术醇衍生物的合成方法简便、反应条件温和、易于操作,且合成过程中原料易得、生产成本较低,适于工业化生产应用。
附图说明
图1为实施例8得到的化合物A-09的核磁谱图;
图2为实施例12得到的化合物A-14的核磁谱图;
图3为实施例13得到的化合物A-15的核磁谱图。
具体实施方法
下文中提供的实施例和制备例进一步阐明和举例说明本化合物,应当理解,下述实施例和制备例的范围并不以任何方式限制本发明的范围。
实施例1:莪术醇衍生物A-01的合成
取二甲胺盐酸盐1.20g(26.62mmol),溶于15mL四氢呋喃中,加入三乙胺2.69g(26.62mmol),冰水浴条件下向其中逐滴缓慢加入氯乙酰氯3.01g(26.62mmol),30min滴加完毕,转移至室温下搅拌2h,通过TLC检测反应,直到反应完全,浓缩反应液,加入水,用乙酸乙酯萃取,合并乙酸乙酯相,饱和氯化钠水溶液洗涤乙酸乙酯层三次,无水硫酸钠干燥,减压浓缩,柱层析分离,流动相使用石油醚比乙酸乙酯5:1,制备得化合物2-1(2.43g),为淡黄色油状产物,收率为75.1%。
取莪术醇0.97g(4.11mmol),溶于10mL无水四氢呋喃中,加入氢化钠0.79g(32.90mmol),加热回流2h,自然冷却至室温,加入步骤1)所得化合物0.5g(4.11mmol),继续加热升温回流6h,通过TLC检测直到反应完全,加水淬灭反应,乙酸乙酯萃取,合并乙酸乙酯相,饱和氯化钠水溶液洗涤乙酸乙酯层三次,无水硫酸钠干燥,减压浓缩,柱层析分离,流动相使用石油醚比乙酸乙酯10:1得化合物A-01(1.11g),为淡黄色液体,收率41.60%。1H NMR(500MHz,chloroform-d)δ4.77(s,2H),4.29(d,J=12.5Hz,1H),4.11(d,J=12.5Hz,1H),3.01(s,3H),2.85(s,3H),2.50(d,J=14.7Hz,1H),2.40(d,J=14.7Hz,1H),2.12–2.05(m,1H),2.02–1.94(m,1H),1.90–1.75(m,2H),1.75–1.66(m,1H),1.66–1.50(m,3H),1.35(tdd,J=11.5,8.5,3.6Hz,1H),1.08(dd,J=12.5,6.4Hz,1H),0.87(t,J=6.2Hz,6H),0.76(d,J=6.4Hz,3H).
实施例2:莪术醇衍生物A-02的合成
取二乙胺1.00g(13.67mmol),溶于15mL四氢呋喃中,加入三乙胺1.38g(13.67mmol),冰水浴条件下向其中逐滴缓慢加入氯乙酰氯1.54g(13.67mmol),30min滴加完毕,转移至室温下搅拌2h,通过TLC检测反应,直到反应完全,浓缩反应液,加入水,用乙酸乙酯萃取,合并乙酸乙酯相,饱和氯化钠水溶液洗涤乙酸乙酯层三次,无水硫酸钠干燥,减压浓缩,柱层析分离,流动相使用石油醚比乙酸乙酯5:1,制备得化合物3-2(1.5g),为淡黄色油状产物,收率为73.33%。
取莪术醇1.04g(4.41mmol),溶于10mL无水四氢呋喃中,加入氢化钠粉末0.79g(32.90mmol),加热回流2h,自然冷却至室温,加入步骤1)所得化合物0.66g(4.41mmol),继续加热升温回流5h,通过TLC检测反应,直到反应完全,加入水淬灭残余氢化钠,加入乙酸乙酯萃取,合并乙酸乙酯相,饱和氯化钠水溶液洗涤乙酸乙酯层三次,无水硫酸钠干燥,减压浓缩,柱层析分离,流动相使用石油醚比乙酸乙酯10:1得化合物A-02(0.72g),为淡黄色液体,收率46.70%。1H NMR(500MHz,Chloroform-d)δ4.83(s,2H),4.34(d,J=12.1Hz,1H),4.14(s,1H),3.42(q,J=8.0,7.1Hz,2H),3.33(q,J=7.1Hz,2H),2.55(d,J=15.7Hz,1H),2.46(d,J=14.8Hz,1H),2.18–2.10(m,1H),2.04(t,J=12.3Hz,1H),1.97–1.80(m,2H),1.81–1.72(m,1H),1.71–1.57(m,3H),1.41(tdd,J=11.7,8.5,3.6Hz,1H),1.12(m,7H),0.94(d,J=6.5Hz,6H),0.82(d,J=6.4Hz,3H).
实施例3:莪术醇衍生物A-03的合成
取二丁胺1.00g(7.74mmol),溶于15mL四氢呋喃中,加入三乙胺0.78g(7.74mmol),冰水浴条件下向其中逐滴缓慢加入氯乙酰氯0.87g(7.74mmol),30min滴加完毕,转移至室温下搅拌2h,通过TLC检测反应,直到反应完全,浓缩,加入水,用乙酸乙酯萃取,合并乙酸乙酯相,饱和氯化钠水溶液洗涤乙酸乙酯层三次,无水硫酸钠干燥,减压浓缩,柱层析分离,流动相使用石油醚比乙酸乙酯5:1,制备得化合物3-3(1.2g),为淡黄色油状产物,收率为75.39%。
取莪术醇1.38g(5.83mmol),溶于10mL无水四氢呋喃中,加入氢化钠粉末0.99g(40.83mmol),加热回流2h,自然冷却至室温,加入步骤1)所得化合物1.20g(5.83mmol),继续加热升温回流5h,通过TLC检测反应,直到反应完全,加入水淬灭残余氢化钠,加入乙酸乙酯萃取,合并乙酸乙酯相,饱和氯化钠水溶液洗涤乙酸乙酯层三次,无水硫酸钠干燥,减压浓缩,柱层析分离,流动相使用石油醚比乙酸乙酯10:1得化合物A-03(0.78g),为淡黄色液体,收率38.26%。1H NMR(500MHz,Chloroform-d)δ4.78(s,2H),4.31(d,J=12.1Hz,1H),4.08(d,J=12.1Hz,1H),3.36–3.11(m,4H),2.53–2.37(m,2H),2.11(d,J=10.3Hz,1H),1.99(t,J=12.3Hz,1H),1.91–1.76(m,2H),1.72(td,J=11.7,6.5Hz,1H),1.67–1.55(m,3H),1.47(dp,J=23.2,7.8,6.4Hz,4H),1.41–1.32(m,1H),1.24(m,5H),1.10(dd,J=12.5,6.4Hz,1H),0.90(d,J=6.6Hz,6H),0.86(dt,J=12.5,7.4Hz,6H),0.78(d,J=6.3Hz,3H).
实施例4:莪术醇衍生物A-04的合成
取四氢吡咯1.00g(14.06mmol),溶于10mL四氢呋喃中,加入三乙胺1.42g(14.06mmol),冰水浴条件下向其中逐滴缓慢加入氯乙酰氯1.59g(14.06mmol),30min滴加完毕,转移至室温下搅拌2h,通过TLC检测反应,直到反应完全,浓缩,加入水,用乙酸乙酯萃取,合并乙酸乙酯相,饱和氯化钠水溶液洗涤乙酸乙酯层三次,无水硫酸钠干燥,减压浓缩,柱层析分离,流动相使用石油醚比乙酸乙酯5:1,得化合物3-4(1.20g),为淡黄色液体,收率为57.82%。
取莪术醇1.44g(6.10mmol),溶于10mL无水四氢呋喃中,加入氢化钠粉末1.02g(42.68mmol),加热回流2h,自然冷却至室温,加入步骤1)所得化合物0.90g(6.10mmol),继续加热升温回流5h,通过TLC检测反应,直到反应完全,加入水淬灭残余氢化钠,加入乙酸乙酯萃取,合并乙酸乙酯相,饱和氯化钠水溶液洗涤乙酸乙酯层三次,无水硫酸钠干燥,减压浓缩,柱层析分离,流动相使用石油醚比乙酸乙酯10:1得化合物A-04(0.8g),为淡黄色液体,收率为37.76%。1H NMR(500MHz,Chloroform-d)δ4.82(s,2H),4.30(d,J=12.9Hz,1H),4.13(d,J=12.9Hz,1H),3.52(s,2H),3.44(t,J=6.7Hz,2H),2.55(d,J=14.8Hz,1H),2.46(d,J=14.7Hz,1H),2.13(d,J=19.9Hz,1H),2.03(t,J=13.1Hz,1H),1.96–1.84(m,3H),1.84–1.75(m,4H),1.71–1.56(m,3H),1.45–1.33(m,1H),1.13(dd,J=11.4,5.3Hz,1H),0.93(d,J=6.5Hz,6H),0.81(d,J=6.3Hz,3H).
实施例5:莪术醇衍生物A-05的合成
将哌啶2.00g(23.49mmol),溶于10mL四氢呋喃中,加入三乙胺2.38g(23.49mmol),冰水浴条件下向其中逐滴缓慢加入氯乙酰氯2.65g(23.49mmol),30min滴加完毕,转移至室温下搅拌2h,通过TLC检测反应,直到反应完全,浓缩,加入水,用乙酸乙酯萃取,合并乙酸乙酯相,饱和氯化钠水溶液洗涤乙酸乙酯层三次,无水硫酸钠干燥,减压浓缩,柱层析分离,流动相使用石油醚比乙酸乙酯5:1,得化合物3-5(2.65g),为棕黄色液体,收率为69.80%。
取莪术醇2.92g(12.37mmol),溶于10mL无水四氢呋喃中,加入氢化钠粉末1.02g(42.68mmol),加热回流2h,自然冷却至室温,加入步骤1)所得化合物2.00g(12.37mmol),继续加热升温回流5h,通过TLC检测反应,直到反应完全,加入水淬灭残余氢化钠,加入乙酸乙酯萃取,合并乙酸乙酯相,饱和氯化钠水溶液洗涤乙酸乙酯层三次,无水硫酸钠干燥,减压浓缩,柱层析分离,流动相使用石油醚比乙酸乙酯10:1得化合物A-05(2.10g),为淡黄色液体,收率为46.94%。1H NMR(500MHz,Chloroform-d)δ4.77(s,2H),4.27(d,J=12.0Hz,1H),4.09(d,J=12.0Hz,1H),3.45(dddd,J=35.0,18.6,13.0,6.5Hz,4H),2.48(d,J=14.7Hz,1H),2.39(d,J=14.7Hz,1H),2.08(t,J=10.0Hz,1H),1.98(t,J=12.3Hz,1H),1.90–1.75(m,2H),1.70(td,J=11.7,6.6Hz,1H),1.59(ddd,J=25.3,11.8,7.6Hz,6H),1.52–1.42(m,5H),1.34(qd,J=11.8,3.5Hz,1H),1.08(dd,J=12.4,6.4Hz,1H),0.93–0.83(m,6H),0.76(d,J=6.4Hz,3H).
实施例6:莪术醇衍生物A-06的合成
取环己亚胺1.00g(10.08mmol),溶于10mL四氢呋喃中,加入三乙胺1.02g(10.08mmol),冰水浴条件下向其中逐滴缓慢加入氯乙酰氯1.14g(10.08mmol),30min滴加完毕,转移至室温下搅拌2h,通过TLC检测反应,直到反应完全,浓缩,加入水,用乙酸乙酯萃取,合并乙酸乙酯相,饱和氯化钠水溶液洗涤乙酸乙酯层三次,无水硫酸钠干燥,减压浓缩,柱层析分离,流动相使用石油醚比乙酸乙酯5:1,得化合物3-6(1.10g),为淡黄色液体,收率为62.11%。
取莪术醇1.35g(5.69mmol),溶于10mL无水四氢呋喃中,加入氢化钠粉末0.82g(34.16mmol),加热回流2h,自然冷却至室温,加入步骤1)所得化合物1.35g(5.69mmol),继续加热升温回流5h,通过TLC检测反应,直到反应完全,加入水淬灭残余氢化钠,加入乙酸乙酯萃取,合并乙酸乙酯相,饱和氯化钠水溶液洗涤乙酸乙酯层三次,无水硫酸钠干燥,减压浓缩,柱层析分离,流动相使用石油醚比乙酸乙酯10:1得化合物A-06(0.90g),为淡黄色液体,收率为42.10%。1H NMR(500MHz,Chloroform-d)δ4.76(s,2H),4.29(d,J=12.0Hz,1H),4.07(d,J=12.0Hz,1H),3.51–3.36(m,4H),2.47(d,J=14.2Hz,1H),2.39(d,J=14.7Hz,1H),2.12–2.03(m,1H),1.97(t,J=12.3Hz,1H),1.77(dt,J=17.1,7.7Hz,2H),1.62(ttd,J=22.2,10.0,8.9,4.6Hz,9H),1.47(s,5H),1.38–1.27(m,1H),1.07(dd,J=12.5,6.4Hz,1H),0.87(dd,J=6.5,2.4Hz,6H),0.75(d,J=6.4Hz,3H).
实施例7:莪术醇衍生物A-07的合成
取吗啉1.00g(11.48mmol),溶于10mL四氢呋喃中,加入三乙胺1.16g(11.48mmol),冰水浴条件下向其中逐滴缓慢加入氯乙酰氯1.30g(11.48mmol),30min滴加完毕,转移至室温下搅拌2h,通过TLC检测反应,直到反应完全,浓缩,加入水,用乙酸乙酯萃取,合并乙酸乙酯相,饱和氯化钠水溶液洗涤乙酸乙酯层三次,无水硫酸钠干燥,减压浓缩,柱层析分离,流动相使用石油醚比乙酸乙酯5:1,得化合物3-7(1.10g),为淡黄色液体,收率为58.58%。
取莪术醇1.29g(5.44mmol),溶于10mL无水四氢呋喃中,加入氢化钠粉末0.91g(38.08mmol),加热回流2h,自然冷却至室温,加入步骤1)所得化合物0.89g(5.44mmol),继续加热升温回流5h,通过TLC检测反应,直到反应完全,加入水淬灭残余氢化钠,加入乙酸乙酯萃取,合并乙酸乙酯相,饱和氯化钠水溶液洗涤乙酸乙酯层三次,无水硫酸钠干燥,减压浓缩,柱层析分离,流动相使用石油醚比乙酸乙酯10:1得化合物A-07(0.87g),为淡黄色液体,收率为44.00%。H NMR(500MHz,Chloroform-d)δ4.78(s,2H),4.27(d,J=12.2Hz,1H),4.11(d,J=12.2Hz,1H),3.66–3.55(m,7H),3.51(d,J=4.4Hz,2H),2.42(q,J=14.9Hz,2H),2.09(t,J=10.1Hz,1H),1.99(t,J=12.3Hz,1H),1.92–1.74(m,2H),1.69(td,J=11.7,6.4Hz,1H),1.65–1.53(m,3H),1.33(ddt,J=12.8,9.9,4.5Hz,1H),1.09(dd,J=12.5,6.4Hz,1H),0.86(dd,J=6.4,3.6Hz,6H),0.77(d,J=6.4Hz,3H).
实施例8:化合物A-08和A-09的合成
取N-Boc-N,N’-二甲基乙二胺1.00g(5.31mmol),溶于10mL四氢呋喃中,加入三乙胺0.54g(5.31mmol),冰水浴条件下向其中逐滴缓慢加入氯乙酰氯0.59g(5.31mmol),30min滴加完毕,转移至室温下搅拌2h,通过TLC检测反应,直到反应完全,浓缩,加入水,用乙酸乙酯萃取,合并乙酸乙酯相,饱和氯化钠水溶液洗涤乙酸乙酯层三次,无水硫酸钠干燥,减压浓缩,柱层析分离,流动相使用石油醚比乙酸乙酯5:1,制备得化合物3-8(1.01g),为淡黄色油状产物,收率71.82%。
取莪术醇0.79g(3.36mmol),溶于8mL无水四氢呋喃中,加入氢化钠粉末0.48g(20.17mmol),加热回流2h,自然冷却至室温,加入步骤1)所得化合物0.89g(3.36mmol),继续加热升温回流5h,通过TLC检测反应,直到反应完全,加入水淬灭残余氢化钠,加入乙酸乙酯20mL萃取3次,合并乙酸乙酯相,饱和氯化钠水溶液洗涤乙酸乙酯层三次,无水硫酸钠干燥,减压浓缩,柱层析分离,流动相使用石油醚比乙酸乙酯10:1得淡黄色油状化合物A-08(0.67g),收率为42.89%。1H NMR(500MHz,Chloroform-d)δ4.78(s,2H),4.34–4.21(m,1H),4.21–4.01(m,1H),3.60–3.20(m,4H),3.03(s,2H),2.84(d,J=30.9Hz,4H),2.55–2.33(m,2H),2.10(t,J=9.9Hz,1H),1.98(q,J=11.1,9.7Hz,1H),1.81(dt,J=24.3,9.0Hz,2H),1.60(td,J=12.6,12.2,6.9Hz,4H),1.38(s,11H),1.09(dd,J=12.6,6.2Hz,1H),0.88(d,J=6.3Hz,6H),0.77(d,J=5.7Hz,3H).
化合物A-09的合成:
取A-08 0.50g(1.08mmol),溶于8mL二氯甲烷中,加入三氟乙酸0.31g(3.23mmol),室温下搅拌2h,通过TLC检测反应,直到反应完全,加入饱和碳酸氢钠20mL中和剩余的三氟乙酸水,加入乙酸乙酯20mL萃取3次,合并乙酸乙酯相,饱和氯化钠水溶液洗涤乙酸乙酯层三次,无水硫酸钠干燥,减压浓缩,柱层析分离,流动相使用石油醚比乙酸乙酯1:1得淡黄色油状化合物A-09(0.17g),为淡黄色固体,收率为43.34%。1H NMR(500MHz,Chloroform-d)δ5.25(s,1H),4.80(s,2H),4.36(dd,J=26.5,12.3Hz,1H),4.14(dd,J=12.3,4.9Hz,1H),3.56–3.37(m,2H),3.04(d,J=10.3Hz,2H),2.88(d,J=3.6Hz,2H),2.74(t,J=6.6Hz,3H),2.40(s,3H),2.17–2.07(m,1H),2.01(t,J=12.3Hz,1H),1.92–1.68(m,4H),1.63(tq,J=9.8,5.5,4.8Hz,4H),1.38(ddt,J=12.0,7.4,4.0Hz,2H),1.11(ddd,J=12.5,6.3,3.3Hz,1H),0.93–0.87(m,6H),0.79(d,J=6.3Hz,3H).
实施例9:莪术醇衍生物A-10的合成
取4-甲基哌啶1.45g(14.62mmol),溶于10mL四氢呋喃中,加入三乙胺1.48g(14.62mmol),冰水浴条件下向其中逐滴缓慢加入氯乙酰氯1.65g(14.62mmol),30min滴加完毕,转移至室温下搅拌2h,通过TLC检测反应,直到反应完全,浓缩,加入水,用乙酸乙酯萃取,合并乙酸乙酯相,饱和氯化钠水溶液洗涤乙酸乙酯层三次,无水硫酸钠干燥,减压浓缩,柱层析分离,流动相使用石油醚比乙酸乙酯5:1,得化合物3-9(1.80g),为淡黄色液体,收率为70.09%。
取莪术醇1.35g(5.69mmol),溶于10mL无水四氢呋喃中,加入氢化钠粉末0.96g(39.85mmol),加热回流2h,自然冷却至室温,加入步骤1)所得化合物1.00g(5.69mmol),继续加热升温回流5h,通过TLC检测反应,直到反应完全,加入水淬灭残余氢化钠,加入乙酸乙酯萃取,合并乙酸乙酯相,饱和氯化钠水溶液洗涤乙酸乙酯层三次,无水硫酸钠干燥,减压浓缩,柱层析分离,流动相使用石油醚比乙酸乙酯10:1得化合物A-10(0.66g),为淡黄色液体,收率为30.87%。1H NMR(500MHz,Chloroform-d)δ4.76(s,2H),4.40(d,J=12.9Hz,1H),4.27(dd,J=18.6,12.1Hz,1H),4.15–4.02(m,2H),2.84(q,J=12.8Hz,1H),2.47(t,J=12.5Hz,2H),2.39(dd,J=14.7,9.6Hz,1H),2.12–2.03(m,1H),1.98(t,J=12.3Hz,1H),1.89–1.45(m,10H),1.39–1.30(m,1H),1.07(dd,J=12.5,6.2Hz,2H),0.87–0.83(m,6H),0.76(d,J=6.4Hz,3H).
实施例10:化合物A-11和A-12的合成
取N-Boc哌嗪3.00g(16.11mmol),溶于10mL四氢呋喃中,加入三乙胺1.63g(16.11mmol),冰水浴条件下向其中逐滴缓慢加入氯乙酰氯1.82g(16.11mmol),30min滴加完毕,转移至室温下搅拌2h,通过TLC检测反应,直到反应完全,浓缩,加入水,用乙酸乙酯萃取,合并乙酸乙酯相,饱和氯化钠水溶液洗涤乙酸乙酯层三次,无水硫酸钠干燥,减压浓缩,柱层析分离,流动相使用石油醚比乙酸乙酯5:1,制备得化合物3-10(2.77g),为淡黄色油状产物,收率65.46%。
取莪术醇1.30g(5.52mmol),溶于7mL无水四氢呋喃中,加入氢化钠粉末0.93g(38.63mmol),加热回流2h,自然冷却至室温,加入化合物3-10 1.45g(5.52mmol),继续加热升温回流5h,通过TLC检测反应,直到反应完全,加入水淬灭残余氢化钠,加入乙酸乙酯20mL萃取3次,合并乙酸乙酯相,饱和氯化钠水溶液洗涤乙酸乙酯层三次,无水硫酸钠干燥,减压浓缩,柱层析分离,流动相使用石油醚比乙酸乙酯10:1得淡黄色油状化合物A-11(1.06g),收率为41.52%。1H NMR(500MHz,Chloroform-d)δ4.83(s,2H),4.33(d,J=12.0Hz,1H),4.16(d,J=12.0Hz,1H),3.76–3.18(m,9H),2.55–2.33(m,2H),2.13(q,J=8.2,6.5Hz,1H),2.08–1.98(m,1H),1.95–1.78(m,2H),1.72(tt,J=10.0,5.0Hz,1H),1.64(dq,J=11.4,7.6,7.0Hz,3H),1.43(s,10H),1.13(dd,J=12.5,6.4Hz,1H),0.91(t,J=6.5Hz,6H),0.81(d,J=6.3Hz,3H).
化合物A-12的合成:
化合物A-11 0.20g(0.43mmol),溶于5mL二氯甲烷中,加入三氟乙酸0.13g(1.30mmol),室温下搅拌2h,通过TLC检测反应,直到反应完全,加入饱和碳酸氢钠20mL中和剩余的三氟乙酸水,加入乙酸乙酯20mL萃取3次,合并乙酸乙酯相,饱和氯化钠水溶液洗涤乙酸乙酯层三次,无水硫酸钠干燥,减压浓缩,柱层析分离,流动相使用石油醚比乙酸乙酯1:1得淡黄色油状化合物A-12(97mg),收率为61.89%。1H NMR(500MHz,Chloroform-d)δ4.80(s,2H),4.30(d,J=12.1Hz,1H),4.12(d,J=12.1Hz,1H),3.71–3.47(m,5H),2.92–2.70(m,5H),2.55–2.31(m,2H),2.19–2.07(m,1H),2.05–1.96(m,1H),1.86–1.66(m,3H),1.66–1.55(m,4H),1.35(ddt,J=18.6,10.0,4.2Hz,1H),1.10(dd,J=12.5,6.4Hz,1H),0.88(dd,J=6.4,4.3Hz,6H),0.79(d,J=6.3Hz,3H).
实施例11:化合物A-13的合成
取四氢喹啉1.00g(7.51mmol),溶于10mL四氢呋喃中,加入三乙胺0.76g(7.51mmol),冰水浴条件下向其中逐滴缓慢加入氯乙酰氯0.85g(7.51mmol),30min滴加完毕,转移至室温下搅拌2h,通过TLC检测反应,直到反应完全,浓缩,加入水,用乙酸乙酯萃取,合并乙酸乙酯相,饱和氯化钠水溶液洗涤乙酸乙酯层三次,无水硫酸钠干燥,减压浓缩,柱层析分离,流动相使用石油醚比乙酸乙酯5:1,制备得淡黄色油状产物3-11(1.02g),收率64.8%。
取莪术醇0.34g(1.43mmol),溶于7mL无水四氢呋喃中,加入氢化钠粉末0.24g(10.02mmol),加热回流2h,自然冷却至室温,加入步骤1)所得化合物0.30g(1.43mmol),继续加热升温回流5h,通过TLC检测反应,直到反应完全,加入水淬灭残余氢化钠,加入乙酸乙酯20mL萃取3次,合并乙酸乙酯相,饱和氯化钠水溶液洗涤乙酸乙酯层三次,无水硫酸钠干燥,减压浓缩,柱层析分离,流动相使用石油醚比乙酸乙酯10:1得淡黄色油状化合物A-13(210mg),收率为35.84%。1H NMR(500MHz,Chloroform-d)δ7.06(m,4H),4.89–4.78(m,2H),4.76(s,1H),4.65(s,1H),4.47–4.38(m,1H),4.20(dd,J=18.2,12.2Hz,1H),3.75(dd,J=64.7,5.9Hz,2H),2.85(t,J=5.3Hz,1H),2.79(s,1H),2.63–2.35(m,2H),2.13(t,J=9.9Hz,1H),2.09–1.99(m,1H),1.97–1.73(m,4H),1.64(m,4H),1.13(dd,J=12.4,6.3Hz,1H),0.94(dt,J=8.9,4.6Hz,6H),0.87(t,J=5.7Hz,3H).
实施例12:化合物A-14的合成
取四氢异喹啉1.00g(7.51mmol),溶于10mL四氢呋喃中,加入三乙胺0.76g(7.51mmol),冰水浴条件下向其中逐滴缓慢加入氯乙酰氯0.85g(7.51mmol),30min滴加完毕,转移至室温下搅拌2h,通过TLC检测反应,直到反应完全,浓缩,加入水,用乙酸乙酯萃取,合并乙酸乙酯相,饱和氯化钠水溶液洗涤乙酸乙酯层三次,无水硫酸钠干燥,减压浓缩,柱层析分离,流动相使用石油醚比乙酸乙酯5:1,制备得3-12(1.20g),淡黄色油状产物,收率76.23%。
取莪术醇0.56g(1.43mmol),溶于7mL无水四氢呋喃中,加入氢化钠粉末0.24g(10.02mmol),加热回流2h,自然冷却至室温,加入步骤1)所得化合物0.50g(1.43mmol),继续加热升温回流5h,通过TLC检测反应,直到反应完全,加入水淬灭残余氢化钠,加入乙酸乙酯20mL萃取3次,合并乙酸乙酯相,饱和氯化钠水溶液洗涤乙酸乙酯层三次,无水硫酸钠干燥,减压浓缩,柱层析分离,流动相使用石油醚比乙酸乙酯10:1得淡黄色油状化合物A-14(450mg),收率为46.07%。1H NMR(500MHz,Chloroform-d)δ7.06(m,4H),4.89–4.78(m,2H),4.76(s,1H),4.65(s,1H),4.47–4.38(m,1H),4.20(dd,J=18.2,12.2Hz,1H),3.75(dd,J=64.7,5.9Hz,2H),2.85(t,J=5.3Hz,1H),2.79(s,1H),2.63–2.35(m,2H),2.13(t,J=9.9Hz,1H),2.09–1.99(m,1H),1.97–1.73(m,4H),1.64(ddt,J=19.1,12.7,7.6Hz,4H),1.13(dd,J=12.4,6.3Hz,1H),0.91(dt,J=8.9,4.6Hz,6H),0.81(t,J=5.7Hz,3H).
实施例13:化合物A-15的合成
取4-苯基哌啶1.00g(6.20mmol),溶于10mL四氢呋喃中,加入三乙胺0.63g(6.20mmol),冰水浴条件下向其中逐滴缓慢加入氯乙酰氯0.70g(6.20mmol),30min滴加完毕,转移至室温下搅拌2h,通过TLC检测反应,直到反应完全,浓缩,加入水,用乙酸乙酯萃取,合并乙酸乙酯相,饱和氯化钠水溶液洗涤乙酸乙酯层三次,无水硫酸钠干燥,减压浓缩,柱层析分离,流动相使用石油醚比乙酸乙酯5:1,制备得3-13(0.89g),为淡黄色油状产物,收率60.37%。
取莪术醇0.44g(1.43mmol),溶于7mL无水四氢呋喃中,加入氢化钠粉末0.31g(10.02mmol),加热回流2h,自然冷却至室温,加入步骤1)所得化合物0.44g(1.43mmol),继续加热升温回流5h,通过TLC检测反应,直到反应完全,加入水淬灭残余氢化钠,加入乙酸乙酯20mL萃取3次,合并乙酸乙酯相,饱和氯化钠水溶液洗涤乙酸乙酯层三次,无水硫酸钠干燥,减压浓缩,柱层析分离,流动相使用石油醚比乙酸乙酯10:1得淡黄色油状化合物A-15(267mg),收率为32.96%。1H NMR(500MHz,Chloroform-d)δ7.34–7.21(m,2H),7.02–6.80(m,3H),4.89(s,2H),4.43(d,J=12.2Hz,1H),4.25(d,J=12.2Hz,1H),3.82(dtt,J=35.9,11.7,6.5Hz,4H),3.29–3.05(m,4H),2.58(d,J=14.8Hz,1H),2.51(d,J=14.7Hz,1H),2.23–2.16(m,1H),2.10(t,J=12.3Hz,1H),2.02–1.86(m,3H),1.81(td,J=11.7,6.7Hz,1H),1.75–1.64(m,3H),1.50–1.40(m,1H),1.19(dd,J=12.5,6.5Hz,1H),0.98(dd,J=11.8,6.5Hz,6H),0.87(d,J=6.4Hz,3H).
应用例:体外抗肿瘤实验
选取上述实施例合成的莪术醇衍生物进行体外抗肿瘤活性实验,分别对7种细胞系进行了筛选,A549(非小细胞肺癌),IR(非小细胞肺癌),PC-9(肺癌),KU812(人外周血嗜碱性白血病细胞),DU145(人前列腺癌细胞),SW620(人结肠癌细胞)细胞株,采用MTT还原测定莪术醇衍生物对多种人癌细胞株的抑制活性,并计算出抑制率达到50%时的药物浓度,即IC50。
选用对数生长期的SW620人结肠癌细胞,用胰酶进行消化后,L-15培养基配成6×104/mL的细胞悬液,然后将细胞悬液加入到96孔板中,每孔细胞数为15000个,37℃下,无CO2培养24小时,将事先配置好的不同浓度的药物分别加入到96孔板中,浓度梯度为50μM、25μM、10μM、5μM、1μM,每个浓度梯度设置4个副孔,37℃下,无CO2培养72小时,每孔加入10μLMTT,37℃下,无CO2培养3小时,弃去上清液,加入150μLDMSO,振荡均价后,酶标仪在490nm处测定光密度(OD值)
选用对数生长期的HCT116、CaCo2人结肠癌细胞,用胰酶进行消化后,DMEM培养基配成6×104/mL的细胞悬液,然后将细胞悬液加入到96孔板中,每孔细胞数为5000个,37℃下,5%CO2培养24小时,将事先配置好的不同浓度的药物分别加入到96孔板中,浓度梯度为50μM、25μM、10μM、5μM、1μM,每个浓度梯度设置4个副孔,37℃下,5%CO2培养72小时,每孔加入10μL MTT(5mg/mL)溶液,37℃下,5%CO2培养3小时,弃去上清液,加入150μL DMSO,振荡均价后,酶标仪在490nm处测定光密度(OD值)
抑制率计算:
生长抑制率=(OD对照组-OD实验组)/(OD对照组-OD空白组)
根据药物浓度-生长抑制率曲线,计算IC50,结果如下表1所示:
表1
由表1可知,本发明所提供化合物均具有较好的抗结肠癌作用,在药物化学领域拥有较好的发展前景。
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