CN116283823B - 一种去氢枞酸基b环并噻唑-苯胺及二苯胺化合物的合成方法和应用 - Google Patents
一种去氢枞酸基b环并噻唑-苯胺及二苯胺化合物的合成方法和应用 Download PDFInfo
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Abstract
一种去氢枞酸基B环并噻唑‑苯胺及二苯胺化合物的合成方法和应用,包括如下步骤:用去氢枞酸基B环并噻唑‑胺为原料与不同的溴苯或氟苯反应得到去氢枞酸基B环并噻唑苯胺和二苯胺化合物。本发明首次实现了去氢枞酸基B环并噻唑‑苯胺和二苯胺化合物的合成。抗癌活性测试表明,该化合物有一定的抗癌性能,扩大了去氢枞酸的应用范围。
Description
技术领域
本发明属于有机合成技术领域,特别是基于去氢枞酸、噻唑、苯胺和二苯胺的松香衍生物,一种去氢枞酸基B环并噻唑-苯胺及二苯胺化合物的合成方法和应用。
背景技术
癌症是一种严重危害公共健康的疾病,也是全球排名第二的致死原因。化疗是癌症治疗的重要手段之一,但是,目前许多化疗药物仍存在一定的局限性,主要表现为用药后产生耐药性和具有较强的毒副作用等,这使得开发安全高效的癌症治疗药物成为了改善人类健康的重要挑战。
去氢枞酸,其结构为三环二萜类树脂酸,与有丰富生物活性的甾类化合物结构相似,是我国传统中药——松香的成分之一,其本身具有广泛的生物活性,并在抗癌药物的开发中受到关注。去氢枞酸分子骨架中含有羧基、苯环等多个反应中心,利用这些位置进行结构改造,向去氢枞酸分子中引入不同的活性基团可以合成得到具有优良生物活性的新型去氢枞酸基衍生物,这特性使得去氢枞酸成为一种有前途的药物中间体。噻唑类骨架广泛存在于许多天然化合物和活性分子中,常表现出抑菌、除草、抗肿瘤和抗病毒等广泛的生物活性。苯胺基团也常出现于具有抗癌活性的化合物中。将不同的具有活性的官能团进行融合获得新分子是一种有效的化合物开发策略。本发明合成的去氢枞酸基B环并噻唑-苯胺及二苯胺化合物是一种新型的去氢枞酸衍生物,该物质及其合成方法到目前为止未见国内外报道。
发明内容
本发明的目的是提供一种去氢枞酸基B环并噻唑-苯胺及二苯胺化合物合成方法和应用,该化合物在制备抗癌药物中的应用。
为了获得新型的具有抗肿瘤活性的去氢枞酸基衍生物,本发明采用以下技术方案达到上述目的:一种去氢枞酸基B环并噻唑-苯胺及二苯胺化合物,所述化合物结构式如下:
所述的去氢枞酸基B环并噻唑-苯胺及二苯胺化合物的合成方法,按下式反应:
式中,溴苯为1,3-双(三氟甲基)-5-溴苯或2,4-二硝基溴苯;氟苯为对硝基氟苯;R1为3,5-双(三氟甲基)苯基、2,4-二硝基苯基、对硝基苯基中的任意一种;R2为-H或对硝基苯基;碱为叔丁醇钠、碳酸铯、磷酸三钾和碳酸钾中的任意一种;有机膦为三苯基膦、叔丁基膦、丙基膦和1,1'-联萘-2,2'-双二苯膦中的任意一种;有机溶剂为甲苯和二甲苯。
所述化合物去氢枞酸基B环并噻唑-苯胺及二苯胺化合物的制备方法,包括如下步骤:
(1)去氢枞酸基B环并噻唑-3,5-双(三氟甲基)苯胺的制备
向10mL的圆底烧瓶中加入去氢枞酸1.3mmol、1,3-双(三氟甲基)-5-溴苯2.0mmol、碱1.5mmol、醋酸钯0.038mmol、有机膦0.06mmol和有机溶剂2mL,在氮气保护下搅拌升温至140℃,反应48h。降温后用200~300目硅胶柱层析分离提纯,洗脱剂按体积比为乙酸乙酸乙酯:石油醚=1:10,取同比例展开剂展板所得薄层色谱比移值为0.4~0.5的成分得到该化合物;
(2)去氢枞酸基B环并噻唑-2,4-二硝基苯胺的制备
向10mL的圆底烧瓶中加入去氢枞酸1.3mmol、2,4-二硝基溴苯2.0mmol、碱1.5mmol、醋酸钯0.038mmol、有机膦0.06mmol和有机溶剂2mL,在氮气保护下搅拌升温至140℃,反应48h。降温后用200~300目硅胶柱层析分离提纯,洗脱剂按体积比为乙酸乙酸乙酯:石油醚=1:10,取同比例展开剂展板所得薄层色谱比移值为0.2~0.3的成分得到该化合物;
(3)去氢枞酸基B环并噻唑-4-硝基苯胺的制备
向10mL的圆底烧瓶中加入去氢枞酸1.3mmol、对硝基氟苯2.0mmol、碱1.5mmol、醋酸钯0.038mmol、有机膦0.06mmol和有机溶剂2mL,在氮气保护下搅拌升温至140℃,反应48h。降温后用200~300目硅胶柱层析分离提纯,洗脱剂按体积比为乙酸乙酸乙酯:石油醚=1:10,取同比例展开剂展板所得薄层色谱比移值为的成分,0.2~0.3得到该化合物;
(4)去氢枞酸基B环并噻唑-二(4-硝基苯基)胺的制备
向10mL的圆底烧瓶中加入去氢枞酸1.3mmol、对硝基氟苯2.0mmol、碱1.5mmol、醋酸钯0.038mmol、有机膦0.06mmol和有机溶剂2mL,在氮气保护下搅拌升温至140℃,反应48h。降温后用200~300目硅胶柱层析分离提纯,洗脱剂按体积比为乙酸乙酸乙酯:石油醚=1:10,取同比例展开剂展板所得薄层色谱比移值为0.4~0.5的成分得到该化合物;
本发明的有益效果在于:
采用本发明的制备方法得到的去氢枞酸基B环并噻唑-苯胺及二苯胺化合物扩展了松香的用途,提高了松香产品的附加值,为松香产品的深加工提供了实验依据。
具体实施方式
以下通过具体实施例对本发明的技术方案作进一步说明,但本发明不限于下列实施例。
实施例1
本实施例为本发明所述的去氢枞酸基B环并噻唑-苯胺及二苯胺化合物的合成方法的一个实例,以制备去氢枞酸基B环并噻唑-3,5-双(三氟甲基)苯胺为例,包括如下步骤:
向10mL的圆底烧瓶中加入去氢枞酸1.3mmol、1,3-双(三氟甲基)-5-溴苯2.0mmol、磷酸三钾1.5mmol、醋酸钯0.038mmol、1,1'-联萘-2,2'-双二苯膦0.06mmol和二甲苯2mL,在氮气保护下搅拌升温至140℃,反应48h。降温后用200~300目硅胶柱层析分离提纯,洗脱剂按体积比为乙酸乙酸乙酯:石油醚=1:10,取同比例展开剂展板所得薄层色谱比移值为0.4~0.5的成分得到该化合物。1H NMR(600MHz,CDCl3)δ8.38(s,1H,NH),8.20(s,2H,H-Ph),7.76(d,J=1.6Hz,1H,H-14),7.45(s,1H,H-Ph),7.18(t,J=10.9Hz,1H,H-11),7.15(dd,J=8.0,1.7Hz,1H,H-12),3.81(s,1H,H-5),3.70(s,3H,COOCH3),2.96–2.85(m,1H,H-15),2.37–2.28(m,1H,H1-e),1.95–1.75(m,5H,H-3,H-2,H1-a),1.60(s,3H,H-19),1.28–1.25(m,6H,H-16,H-17),1.15(s,3H,H-20).13C NMR(151MHz,CDCl3)δ179.24,160.72,147.31,146.86,144.04,142.01,132.45,132.23,132.01,129.36,126.63,124.26,122.45,122.29,121.83,121.68,116.83,114.70,52.78,46.80,46.65,39.28,37.42,35.24,33.70,23.93,23.61,21.87,18.23,17.63.Mass spectrum(ESI),m/z:597.2014[M+H]+C30H30F6N2O2S caledM 596.1932。
实施例2
本实施例为本发明所述的去氢枞酸基B环并噻唑-苯胺及二苯胺化合物的合成方法的另一个实例,以制备去氢枞酸基B环并噻唑-2,4-二硝基苯胺为例,包括如下步骤:
向10mL的圆底烧瓶中加入去氢枞酸1.3mmol、2,4-二硝基溴苯2.0mmol、磷酸三钾1.5mmol、醋酸钯0.038mmol、1,1'-联萘-2,2'-双二苯膦0.06mmol和二甲苯2mL,在氮气保护下搅拌升温至140℃,反应48h。降温后用200~300目硅胶柱层析分离提纯,洗脱剂按体积比为乙酸乙酸乙酯:石油醚=1:10,取同比例展开剂展板所得薄层色谱比移值为0.2~0.3的成分得到该化合物。1H NMR(600MHz,CDCl3)δ10.99(s,1H,NH),9.22(d,J=2.4Hz,1H,H-Ph),9.10(d,J=9.5Hz,1H,H-Ph),8.49(dd,J=9.5,2.4Hz,1H,H-Ph),7.73(s,1H,H-14),7.22(q,J=8.1Hz,2H,H-11,H-12),3.81(s,1H,H-5),3.71(s,3H,COOCH3),3.03–2.96(m,1H,H-15),2.34(t,J=8.2Hz,1H,H1-e),1.94–1.80(m,5H,H-3,H-2,H1-a),1.61(s,3H,H-19),1.31(d,J=6.9Hz,6H,H-16,H-17),1.14(s,3H,H-20).13C NMR(151MHz,CDCl3)δ178.12,157.49,147.97,147.44,144.21,142.34,139.41,132.19,130.51,129.06,126.65,126.63,123.02,122.59,122.18,119.60,52.77,46.80,46.52,39.20,37.35,35.33,33.83,24.16,23.92,21.98,18.12,17.51.Mass spectrum(ESI),m/z:551.1966[M+H]+C28H30N4O6S caled M550.1886。
实施例3
本实施例为本发明所述的去氢枞酸基B环并噻唑-苯胺及二苯胺化合物的合成方法的又一个实例,以制备去氢枞酸基B环并噻唑-4-硝基苯胺为例,包括如下步骤:
向10mL的圆底烧瓶中加入去氢枞酸1.3mmol、对硝基氟苯2.0mmol、磷酸三钾1.5mmol、醋酸钯0.038mmol、1,1'-联萘-2,2'-双二苯膦0.06mmol和二甲苯2mL,在氮气保护下搅拌升温至140℃,反应48h。降温后用200~300目硅胶柱层析分离提纯,洗脱剂按体积比为乙酸乙酸乙酯:石油醚=1:10,取同比例展开剂展板所得薄层色谱比移值为的成分,0.2~0.3得到该化合物。1H NMR(600MHz,CDCl3)δ8.36–8.16(m,3H,NH,H-Ph),7.72(d,J=1.6Hz,1H,H-14),7.58(d,J=9.1Hz,2H,H-Ph),7.17(dt,J=8.1,4.8Hz,2H,H-11,H-12),3.78(s,1H,H-5),3.69(s,3H,COOCH3),2.98–2.92(m,1H,H-15),2.34–2.31(m,1H,H1-e),1.89–1.80(m,5H,H-3,H-2,H1-a),1.60(s,3H,H-19),1.29(d,J=6.9Hz,6H,H-16,H-17),1.13(d,J=4.1Hz,3H,H-20).13C NMR(151MHz,CDCl3)δ178.66,159.86,147.29,146.87,146.10,144.17,141.41,129.33,126.25,125.73,124.08,123.53,122.96,122.41,122.08,115.90,52.71,46.59,39.22,37.47,35.30,33.81,29.63,24.09,23.92,21.87,18.16,17.59.Mass spectrum(ESI),m/z:506.2117[M+H]+C28H30N4O6S caled M 505.2035。
实施例4
本实施例为本发明所述的去氢枞酸基B环并噻唑-苯胺及二苯胺化合物的合成方法的再一个实例,以制备去氢枞酸基B环并噻唑-二(4-硝基苯基)胺为例,包括如下步骤:
向10mL的圆底烧瓶中加入去氢枞酸1.3mmol、对硝基氟苯2.0mmol、磷酸三钾1.5mmol、醋酸钯0.038mmol、1,1'-联萘-2,2'-双二苯膦0.06mmol和二甲苯2mL,在氮气保护下搅拌升温至140℃,反应48h。降温后用200~300目硅胶柱层析分离提纯,洗脱剂按体积比为乙酸乙酸乙酯:石油醚=1:10,取同比例展开剂展板所得薄层色谱比移值为的成分,0.4~0.5得到该化合物。1H NMR(600MHz,CDCl3)δ8.25(d,J=9.1Hz,4H,H-Ph),7.61(d,J=1.5Hz,1H,H-14),7.40(d,J=9.1Hz,4H,H-Ph),7.19(dt,J=8.1,4.8Hz,2H,H-11,H-12),3.79(s,1H,H-5),3.59(s,3H,COOCH3),2.97–2.86(m,1H,H-15),2.38–2.28(m,1H,H1-e),1.89–1.78(m,5H,H-3,H-2,H1-a),1.53(s,3H,H-19),1.25(d,J=7.0Hz,6H,H-16,H-17),1.15(s,3H,H-20).13CNMR(151MHz,CDCl3)δ178.66,159.86,147.29,146.87,146.10,144.17,141.41,129.33,126.25,125.73,124.08,123.53,122.96,122.41,122.08,115.90,52.71,46.59,39.22,37.47,35.30,33.81,29.63,24.09,23.92,21.87,18.16,17.59.Massspectrum(ESI),m/z:627.2280[M+H]+C34H34N4O6S caled M 626.2199。
实施例5
将实施例1~4所制备得到的去氢枞酸基B环并噻唑-苯胺及二苯胺化合物进行抗癌活性测试,测试方法及结果如下:
将已培养两天且细胞形态良好的人舌鳞癌细胞Cal27,人舌鳞癌细胞SCC9,人舌鳞癌细胞SAS作为模型细胞,将细胞用0.25%的胰酶消化计数后,以5000个细胞每孔的密度接种到96孔细胞培养板中,每孔的接种体积为100μL。培养24小时后,向培养孔内加入10μL不同浓度的药物使孔内药物浓度分别为100,50,25,12.5,6.25,3.125,1.56,0μM(DMSO均为1%),放入培养箱中孵育48h。孵育时间结束后,每孔细胞中加入10μL的CCK-8溶液,放置于37度细胞培养箱中孵育4小时用酶标仪测定在450nm处的吸光度。选取5-氟尿嘧啶做阳性对照,以0μM药物无加细胞的孔作为空白,0μM药物含细胞的孔做阴性对照,计算抑制率。
抑制率=[(Ac-As)/(Ac-Ab)]×100%
As:实验孔(含有细胞的培养基、CCK8/待测物质);
Ac:实验孔(含有细胞的培养基、CCK8/无待测物质);
Ab:空白孔(不含细胞和待测物质的培养基、CCK-8)。
表1目标化合物的抗癌活性
抗癌活性测试表明,目标化合物总体上对测试的人舌鳞癌细胞具有一定的抗癌活性,对Cal27和SCC9癌细胞系具有较好的抑制能力,其中去氢枞酸基B环并噻唑-3,5-双(三氟甲基)苯胺对这两种细胞均表现出了最优的抑制能力,其IC50分别为8.357±0.216μM和7.592±1.847μM。但是对SAS癌细胞系只具有一般的抑制能力,抑制率最高的去氢枞酸基B环并噻唑-4-硝基苯胺表现出的IC50为13.801±1.072μM。
Claims (4)
1.一种去氢枞酸基B环并噻唑-苯胺及二苯胺化合物,其特征在于,具体化合物结构式如下:
2.根据权利要求1所述的去氢枞酸基B环并噻唑-苯胺及二苯胺化合物的合成方法,其特征在于,按下式反应进行:
式中,溴苯为1,3-双(三氟甲基)-5-溴苯或2,4-二硝基溴苯;氟苯为对硝基氟苯;R1为3,5-双(三氟甲基)苯基、2,4-二硝基苯基、对硝基苯基中的任意一种;R2为-H或对硝基苯基;碱为叔丁醇钠、碳酸铯、磷酸三钾和碳酸钾中的任意一种;有机膦为三苯基膦、叔丁基膦、丙基膦和1,1'-联萘-2,2'-双二苯膦中的任意一种;有机溶剂为甲苯和二甲苯。
3.根据权利要求2所述的去氢枞酸基B环并噻唑-苯胺及二苯胺化合物的合成方法,其特征在于,包括如下步骤:
(1)去氢枞酸基B环并噻唑-3,5-双(三氟甲基)苯胺制备
向10mL的圆底烧瓶中加入去氢枞酸基B环并噻唑-胺1.3mmol、1,3-双(三氟甲基)-5-溴苯2.0mmol、碱1.5mmol、醋酸钯0.038mmol、有机膦0.06mmol和有机溶剂2mL,在氮气保护下搅拌升温至140℃,反应48h,降温后用200~300目硅胶柱层析分离提纯,洗脱剂按体积比为乙酸乙酸乙酯:石油醚=1:10,取同比例展开剂展板所得薄层色谱比移值为0.4~0.5的成分得到该化合物;
(2)去氢枞酸基B环并噻唑-2,4-二硝基苯胺的制备
向10mL的圆底烧瓶中加入去氢枞酸基B环并噻唑-胺1.3mmol、2,4-二硝基溴苯2.0mmol、碱1.5mmol、醋酸钯0.038mmol、有机膦0.06mmol和有机溶剂2mL,在氮气保护下搅拌升温至140℃,反应48h,降温后用200~300目硅胶柱层析分离提纯,洗脱剂按体积比为乙酸乙酸乙酯:石油醚=1:10,取同比例展开剂展板所得薄层色谱比移值为0.2~0.3的成分得到该化合物;
(3)去氢枞酸基B环并噻唑-4-硝基苯胺的制备
向10mL的圆底烧瓶中加入去氢枞酸基B环并噻唑-胺1.3mmol、对硝基氟苯2.0mmol、碱1.5mmol、醋酸钯0.038mmol、有机膦0.06mmol和有机溶剂2mL,在氮气保护下搅拌升温至140℃,反应48h,降温后用200~300目硅胶柱层析分离提纯,洗脱剂按体积比为乙酸乙酸乙酯:石油醚=1:10,取同比例展开剂展板所得薄层色谱比移值为的成分,0.2~0.3得到该化合物;
(4)去氢枞酸基B环并噻唑-二(4-硝基苯基)胺的制备
向10mL的圆底烧瓶中加入去氢枞酸基B环并噻唑-胺1.3mmol、对硝基氟苯2.0mmol、碱1.5mmol、醋酸钯0.038mmol、有机膦0.06mmol和有机溶剂2mL,在氮气保护下搅拌升温至140℃,反应48h,降温后用200~300目硅胶柱层析分离提纯,洗脱剂按体积比为乙酸乙酸乙酯:石油醚=1:10,取同比例展开剂展板所得薄层色谱比移值为0.4~0.5的成分得到该化合物。
4.根据权利要求1至3任意一项所述的去氢枞酸基B环并噻唑-苯胺及二苯胺化合物在制备抗人舌鳞癌试剂中的应用。
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