CN116621767B - 一种靛红衍生物及其制备方法和应用 - Google Patents
一种靛红衍生物及其制备方法和应用 Download PDFInfo
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- CN116621767B CN116621767B CN202310582245.9A CN202310582245A CN116621767B CN 116621767 B CN116621767 B CN 116621767B CN 202310582245 A CN202310582245 A CN 202310582245A CN 116621767 B CN116621767 B CN 116621767B
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Abstract
本发明属于医药化学技术领域，具体涉及一种靛红衍生物及其制备方法和应用。本发明的靛红衍生物具有如式(Ⅰ)所示的结构，该衍生物结构新颖，具有较好的抗肿瘤作用，对人骨肉瘤细胞、人结肠癌细胞和人乳腺癌细胞均具有较好的抑制作用，在抗肿瘤作用方面具有很大的应用价值，有望制备成抗肿瘤药物或抑制肿瘤细胞增殖的药物，尤其是抗人骨肉瘤、人结肠癌和人乳腺癌的药物；同时，本发明方法所涉及的原料廉价易得，反应步骤少，操作简单安全，成本低，产生废物少，具有高原子经济性，高选择性，高收率的优势。
Description
技术领域
本发明属于医药化学技术领域，具体涉及一种靛红衍生物及其制备方法和应用。
背景技术
癌症，亦称恶性肿瘤，是严重危害人类健康的常见病和多发病，具有发病率高、死亡率高、复发率高、治疗难等特点。进入21世纪，恶性肿瘤仍然是极大危害人类生命健康的严重疾病，是继心血管疾病后威胁人类健康的第二大杀手。因此，对癌症的治疗显得尤其紧迫。目前对于肿瘤的治疗主要有药物疗法、手术疗法和放射疗法。其中，药物治疗已经成为当今临床肿瘤治疗的重要手段。根据作用方式和化学机理的不同，抗癌药物可以分为直接作用于DNA的药物、干扰DNA合成的药物、以有丝分裂为靶点的药物、针对与肿瘤的各个生长阶段相关的酶的抑制剂、免疫治疗药物以及中药治疗药物等。尽管目前为止已有数十种化疗和辅助抗癌药物运用于临床，而且对其中的一些肿瘤已取得一定的治愈率，但大多数药物仅仅只能起到缓解病情的作用。因此，寻找新型高效的肿瘤治疗药物依然是抗肿瘤药物研究的主要方向。
近些年，一些天然存在或人工合成的以靛红为基本母核的化合物在抗肿瘤活性方面得到了全球认可，许多相关工作者们利用化学、生物和药理学方法，对其进行结构修饰及化学衍生，得到了大量新型结构的靛红衍生物，并在抗细胞增殖活性方面取得了不错的成果。例如，在2006年上市，由美国Pfizer公司研发的索坦(舒尼替尼Sunitinib)是一类具有靛红结构的抗肿瘤药物，可抑制许多受体的酪氨酸激酶，具有抗肿瘤血管增殖和抑制肿瘤细胞生长的作用，并对晚期肾癌细胞(RCC)，胃肠道间质瘤有(GIST)有较好的治疗作用，现已运用于临床上。然而，还有很多具有抗肿瘤活性的靛红骨架有待挖掘，靛红衍生物的药用价值还有很大的开发空间。为此，本发明提供了一种高效，一步构建靛红衍生物的合成方法，并合成系列具有抗肿瘤活性的靛红衍生物。
发明内容
为了克服上述现有技术的不足，本发明提出了一种靛红衍生物，所述衍生物结构新颖，同时还具有较好的抗肿瘤作用，对人骨肉瘤细胞、人结肠癌细胞和人乳腺癌细胞均具有较好的抑制作用，在抗肿瘤作用方面具有很大的应用价值。
为了实现上述目的，本发明所采用的技术方案是：
本发明第一方面提供了一种靛红衍生物，所述靛红衍生物具有式(Ⅰ)所示的结构：
式(Ⅰ)中，所述R1选自甲基、苄基、炔丙基、异丙基、2-甲基-2-丁烯、甲基环丙烷；R2选自氢，卤素；R3选自苄基，乙基，噻吩甲基，炔丙基，TMS乙基，环丙烷甲基，环丁烷甲基，1-溴丙基，1-甲氧基丙基，3,4-(亚甲二氧基)甲苯，双戊烯，肉桂醇，香叶醇；R4选自乙基，溴乙基，烯丙基，苄基。
优选地，所述R2选自4-Cl，5-Cl，6-Cl，5-Br，5-F,5-I,5-OMe，6-CF3。
优选地，所述衍生物选自下列结构式中的至少一种：
本发明第二方面提供了第一方面所述的靛红衍生物的制备方法，具体为：根据下列反应式，将式1、式2和式3所示的原料混溶于有机溶剂中，然后在金属催化剂存在的条件下经反应后得到式(Ⅰ)所示的衍生物：
所述反应式中R1、R2、R3、R4的取值同第一方面所述的R1、R2、R3、R4。
优选地，式1所示原料、式2所示原料、式3所示原料和金属催化剂的反应摩尔比为(2.0):(3):(1):(0.02)。
优选地，式2所示原料在有机溶剂中的反应浓度为(1.5)mol/L。
优选地，所述反应还加入了分子筛，所述分子筛的以靛红当量为基准投料量为0～500mg/mmol。
优选地，所述反应的时间为24-48h。
优选地，所述有机溶剂包括但不限于二氯甲烷、1,2二氯乙烷、甲苯、氯苯和三氟甲苯。
优选地，所述金属催化剂包括但不限于醋酸铑Rh2(OAc)4,辛酸铑二聚体Rh2(Oct)4,双核铑Rh2(esp)4。进一步地，所述金属催化剂为Rh2(Oct)4。
本发明第三方面提供了第一方面所述的靛红衍生物在制备抗骨肉瘤药物或抑制骨肉瘤细胞增值的药物中的应用。
优选地，所述骨肉瘤细胞为Sjsa-1细胞，所述衍生物选自下列结构式中的至少一种：
本发明第四方面提供了第一方面所述的靛红衍生物在制备抗结肠癌药物或抑制结肠癌细胞增值的药物中的应用。
优选地，所述结肠癌细胞为HCT116细胞，所述衍生物选自下列结构式中的至少一种：
本发明第五方面提供了第一方面所述的靛红衍生物在制备抗乳腺癌药物或抑制乳腺癌细胞增值的药物中的应用。
优选地，所述乳腺癌细胞为MCF-7细胞，所述衍生物选自下列结构式中的至少一种：
本发明第六方面提供了一种抗肿瘤药物，其特征在于，所述药物以第一方面所述的靛红衍生物作为主要活性成分。
优选地，上述抗肿瘤药物还包括药学上可接受的载体和/或赋形剂。即上述的抗肿瘤药物以靛红衍生物作为主要活性成分，与药学上可接受的载体和/或赋形剂混合制备成组合物，并制备成临床上可接受的剂型。所述剂型是指临床上常用的注射剂、片剂、胶囊剂等。药物制剂可以经口服或胃肠外方式(例如静脉、皮下、腹膜内或局部)给药，如果某些药物在胃部条件下是不稳定的，可将其制备成肠衣片剂。
进一步地，所述赋形剂是指可用于药学领域的稀释剂、黏合剂、润滑剂、崩解剂、助溶剂、稳定剂以及其他一些药用基质。
进一步地，所述载体是药物领域中可接受的功能性药用辅料，包括表面活性剂、助悬剂、乳化剂以及一些新型药用高分子材料，如环糊精、壳聚糖、聚乳酸(PLA)、聚乙醇酸聚乳酸共聚物(PLGA)、透明质酸等。
与现有技术相比，本发明的有益效果是：
本发明公开了一种靛红衍生物，该衍生物结构新颖，同时还具有较好的抗肿瘤作用，对人骨肉瘤细胞、人结肠癌细胞和人乳腺癌细胞均具有较好的抑制作用，在抗肿瘤作用方面具有很大的应用价值，有望制备成抗肿瘤药物或抑制肿瘤细胞增殖的药物，尤其是抗人骨肉瘤、人结肠癌和人乳腺癌细胞的药物。同时，本发明的衍生物通过以三价碘重氮化合物、醇和靛红为原料，以金属为催化剂，在有机溶剂中经过一步反应即可制备得到目标产物；所述制备方法的原料廉价易得，反应步骤少，操作简单安全，成本低，产生废物少，具有高原子经济性，高选择性，高收率的优势。
具体实施方式
下面对本发明的具体实施方式作进一步说明。在此需要说明的是，对于这些实施方式的说明用于帮助理解本发明，但并不构成对本发明的限定。此外，下面所描述的本发明各个实施方式中所涉及的技术特征只要彼此之间未构成冲突就可以相互组合。
下述实施例中的实验方法，如无特殊说明，均为常规方法，下述实施例中所用的试验材料，如无特殊说明，均为可通过常规的商业途径购买得到。
实施例1靛红衍生物的制备
具体制备反应如下：
当R1＝甲基、R2＝H、R3＝苄基、R4＝乙基时，根据上述反应式，制备方法具体为：将式3所示的N-甲基靛红(0.10mmol)，式2所示的苄醇(0.30mmol)，金属铑Rh2(Oct)4(0.002mmol，金属催化剂)，分子筛(100mg)溶于1.5mL有机溶剂氯苯中，配置成混合溶液；然后在-27℃下将式1所示的高价碘重氮(0.15mmol)一次性加入到前述的混合溶液中；高价碘重氮添加完毕后，继续在-27℃条件下搅拌24～48h，直到靛红消耗完全；对反应液进行过滤、柱层析分离纯化后，得到纯的产品，即目标产物。
制备得到的目标产物一共有27个，即化合物1至27，这些化合物的结构如表1所示，具体的核磁氢谱数据如下所示：
化合物1的谱图数据：1H NMR(400MHz,CDCl3))δ7.62–7.52(m,1H),7.45–7.20(m,9H),7.20–7.11(m,2H),7.04(td,J＝7.6,1.0Hz,1H),6.69(d,J＝7.8Hz,1H),4.90(d,J＝11.3Hz,1H),4.83(d,J＝1.3Hz,1H),4.81–4.72(m,2H),4.50(d,J＝12.5Hz,1H),4.31–4.13(m,2H),3.10(s,3H),1.22(t,J＝7.2Hz,3H)；
化合物2的谱图数据：1H NMR(400MHz,CDCl3)δ7.64–7.56(m,1H),7.42–7.05(m,16H),7.04–6.93(m,1H),6.56(d,J＝7.8Hz,1H),5.07(d,J＝1.1Hz,1H),4.95(d,J＝15.9Hz,1H),4.84(s,2H),4.74(d,J＝12.5Hz,1H),4.68(d,J＝15.9Hz,1H),4.36(d,J＝12.5Hz,1H),4.34–4.23(m,2H),1.26(t,J＝7.1Hz,3H)；
化合物3的谱图数据：1H NMR(400MHz,CDCl3)δ7.63–7.55(m,1H),7.47–7.17(m,9H),7.16–7.05(m,2H),7.01(t,J＝7.5Hz,1H),6.89(d,J＝7.9Hz,1H),4.86(d,J＝1.4Hz,1H),4.82(s,1H),4.79(d,J＝11.4Hz,1H),4.71(d,J＝12.2Hz,1H),4.50(p,J＝7.0Hz,1H),4.42(d,J＝12.1Hz,1H),4.35–4.19(m,2H),1.39(d,J＝7.0Hz,3H),1.33(d,J＝7.0Hz,3H),1.24(t,J＝7.1Hz,3H)；
化合物4的谱图数据：1H NMR(400MHz,CDCl3))δ7.61–7.55(m,1H),7.43–7.21(m,9H),7.21–7.15(m,2H),7.07(t,J＝7.6Hz,1H),6.96(d,J＝7.8Hz,1H),4.89(d,J＝11.4Hz,1H),4.82(s,1H),4.81–4.74(m,2H),4.53(d,J＝12.3Hz,1H),4.50–4.41(m,1H),4.40–4.31(m,1H),4.28–4.17(m,2H),2.14(t,J＝2.5Hz,1H),1.21(t,J＝7.1Hz,3H)；
化合物5的谱图数据:1H NMR(400MHz,CDCl3)δ7.42–7.03(m,16H),7.02–6.93(m,1H),6.47–6.36(m,1H),5.04(s,1H),4.96(d,J＝15.9Hz,1H),4.89(d,J＝11.4Hz,1H),4.80(d,J＝11.4Hz,1H),4.76(d,J＝12.4Hz,1H),4.62(d,J＝15.9Hz,1H),4.38–4.17(comp,3H),1.27(t,J＝7.2Hz,3H)；
化合物6的谱图数据:1H NMR(400MHz,CDCl3)δ7.57(d,J＝2.2Hz,1H),7.50–6.91(m,16H),6.46(d,J＝8.4Hz,1H),5.10(d,J＝0.9Hz,1H),4.93(d,J＝15.9Hz,1H),4.88(s,2H),4.78(d,J＝12.2Hz,1H),4.66(d,J＝15.9Hz,1H),4.47(d,J＝12.2Hz,1H),4.40–4.23(m,2H),1.29(t,J＝7.1Hz,3H)；
化合物7的谱图数据：1H NMR(400MHz,CDCl3)δ7.48(d,J＝7.9Hz,1H),7.41–7.06(m,16H),7.02–6.95(m,1H),6.54(d,J＝1.8Hz,1H),5.11(d,J＝1.2Hz,1H),4.90(d,J＝15.9Hz,1H),4.85(d,J＝11.3Hz,1H),4.81(d,J＝11.3Hz,1H),4.75(d,J＝12.3Hz,1H),4.65(d,J＝15.9Hz,1H),4.44(d,J＝12.3Hz,1H),4.37–4.26(m,2H),1.29(t,J＝7.1Hz,3H)；
化合物8的谱图数据:1H NMR(400MHz,CDCl3))δ7.56(dd,J＝7.5,1.3Hz,1H),7.41–7.21(m,9H),7.18–7.09(m,2H),7.02(td,J＝7.6,1.1Hz,1H),6.68(d,J＝7.8Hz,1H),5.09–5.00(m,1H),4.94–4.83(m,2H),4.79(d,J＝11.4Hz,1H),4.74(d,J＝12.3Hz,1H),4.45(d,J＝12.3Hz,1H),4.34–4.15(comp,4H),1.76(s,3H),1.62(s,3H),1.23(t,J＝7.1Hz,3H)；
化合物9谱图数据:1H NMR(400MHz,CDCl3)δ7.64–7.55(m,1H),7.43–7.17(m,9H),7.17–7.08(m,2H),7.08–6.99(m,1H),6.81(d,J＝7.8Hz,1H),4.90(d,J＝0.8Hz,1H),4.84(d,J＝11.4Hz,1H),4.78(d,J＝11.4Hz,1H),4.72(d,J＝12.3Hz,1H),4.44(d,J＝12.3Hz,1H),4.32–4.23(m,2H),3.58–3.43(m,2H),1.25(t,J＝7.1Hz,3H),1.09–1.00(m,1H),0.46–0.25(m,4H)；
化合物10谱图数据:1H NMR(400MHz,CDCl3))δ7.71(d,J＝2.1Hz,1H),7.45–7.03(m,16H),6.41(d,J＝8.3Hz,1H),5.09(s,1H),4.92(d,J＝15.9Hz,1H),4.88(s,2H),4.78(d,J＝12.2Hz,1H),4.65(d,J＝15.9Hz,1H),4.48(d,J＝12.2Hz,1H),4.37–4.16(m,2H),1.29(t,J＝7.1Hz,3H)；
化合物11谱图数据:1H NMR(500MHz,CDCl3))δ7.39–7.06(m,16H),6.89(td,J＝8.9,2.7Hz,1H),6.46(dd,J＝8.6,4.1Hz,1H),5.16(s,1H),4.95(d,J＝15.9Hz,1H),4.88–4.81(m,2H),4.77(d,J＝12.2Hz,1H),4.65(d,J＝15.9Hz,1H),4.41(d,J＝12.2Hz,1H),4.39–4.27(m,2H),1.30(t,J＝7.1Hz,3H)；
化合物12谱图数据:1H NMR(500MHz,CDCl3))δ7.56–7.03(m,16H),7.02–6.87(m,1H),6.46(d,J＝7.9Hz,1H),5.02(s,1H),4.91(d,J＝15.8Hz,1H),4.89–4.79(m,2H),4.74(d,J＝12.4Hz,1H),4.69(d,J＝15.8Hz,1H),4.41(d,J＝12.4Hz,1H),4.36–4.19(m,2H),2.26(s,3H),1.25(t,J＝7.1Hz,3H)；
化合物13谱图数据:1H NMR(500MHz,CDCl3))δ7.89–7.78(m,1H),7.63–7.55(m,1H),7.47–6.93(m,16H),5.11(d,J＝10.4Hz,3H),4.89(d,J＝11.2Hz,1H),4.83(d,J＝11.2Hz,1H),4.76(d,J＝12.0Hz,1H),4.48(d,J＝12.0Hz,1H),4.31(q,J＝7.1Hz,2H),1.27(t,J＝7.1Hz,3H)；
化合物14谱图数据:1H NMR(500MHz,CDCl3))δ7.89(s,1H),7.67–6.88(m,16H),6.31(d,J＝8.2Hz,1H),5.08(s,1H),4.90(comp,3H),4.77(d,J＝12.2Hz,1H),4.65(d,J＝15.9Hz,1H),4.48(d,J＝12.2Hz,1H),4.38–4.27(m,2H),1.29(t,J＝7.1Hz,3H)；
化合物15谱图数据:1H NMR(500MHz,CDCl3))δ7.57(d,J＝7.4Hz,1H),7.37–7.16(m,6H),7.00(t,J＝7.5Hz,1H),6.61(d,J＝7.8Hz,1H),5.08–4.91(m,2H),4.72(d,J＝15.7Hz,1H),4.37–4.18(m,2H),3.80(q,J＝7.7,7.2Hz,1H),3.76–3.68(m,1H),3.64–3.50(m,1H),3.31–3.17(m,1H),1.33(t,J＝7.0Hz,3H),1.25(t,J＝7.1Hz,3H),1.00(t,J＝7.0Hz,3H)；
化合物16谱图数据:1H NMR(500MHz,CDCl3))δ7.59(d,J＝7.4Hz,1H),7.35–7.31(m,1H),7.29–7.23(m,3H),7.23–7.12(m,4H),7.08(d,J＝3.4Hz,1H),7.05–6.96(m,2H),6.95–6.89(m,1H),6.84(d,J＝3.4Hz,1H),6.60(d,J＝7.8Hz,1H),5.23(d,J＝11.6Hz,1H),5.06(d,J＝11.6Hz,1H),5.00–4.90(m,2H),4.82–4.70(m,2H),4.62(d,J＝12.3Hz,1H),4.29–4.14(m,2H),1.17(t,J＝7.1Hz,3H)；
化合物17谱图数据:1H NMR(500MHz,CDCl3))δ7.92–7.84(m,1H),7.63–7.50(m,5H),7.49–7.41(m,1H),7.33–7.23(m,1H),6.94–6.84(m,1H),5.36(s,1H),5.22(d,J＝15.7Hz,1H),5.02(d,J＝15.7Hz,1H),4.66–4.52(m,2H),4.08–3.99(m,1H),3.98–3.89(m,1H),3.81–3.70(m,1H),3.42–3.29(m,1H),1.56(t,J＝7.1Hz,3H),1.47–1.40(m,1H),1.35–1.24(m,1H),1.06–0.95(m,1H),0.94–0.83(m,1H),0.33(s,9H),0.12(s,9H)；
化合物18谱图数据:1H NMR(500MHz,CDCl3))δ7.65(d,J＝7.4Hz,1H),7.44–7.12(m,17H),7.04(t,J＝7.6Hz,1H),6.68(d,J＝15.9Hz,1H),6.63(d,J＝7.8Hz,1H),6.45(d,J＝15.9Hz,1H),6.36(dt,J＝15.9,5.9Hz,1H),6.05(dt,J＝15.9,5.4Hz,1H),5.04(s,1H),4.99(d,J＝15.8Hz,1H),4.72(d,J＝15.8Hz,1H),4.50–4.39(m,2H),4.37–4.21(comp,3H),3.91–3.81(m,1H),1.29(t,J＝7.1Hz,3H)；
化合物19谱图数据:1H NMR(500MHz,CDCl3))δ7.81–7.66(m,1H),7.33–7.23(m,1H),7.23–7.04(m,1H),6.88–6.54(m,1H),5.11(dd,J＝16.1,4.2Hz,1H),4.85(dd,J＝16.1,4.2Hz,1H),4.56–4.22(m,2H),3.90–3.77(m,1H),3.76–3.52(m,2H),3.40–3.18(m,1H),1.47–1.25(m,5H),1.02–0.95(m,1H),0.72(t,J＝6.1Hz,2H),0.65–0.37(m,4H),0.25–0.15(m,1H),0.14–0.05(m,1H)；
化合物20谱图数据:1H NMR(500MHz,CDCl3))δ7.55(d,J＝7.8Hz,1H),7.43–7.21(m,5H),7.21–7.08(m,1H),7.05–6.86(m,1H),6.59(d,J＝7.8Hz,1H),5.06(s,1H),4.95(d,J＝15.8Hz,1H),4.72(d,J＝15.8Hz,1H),4.45–4.15(m,2H),3.85–3.63(m,2H),3.59–3.43(m,1H),3.31–3.11(m,1H),2.84–2.62(m,1H),2.39–2.26(m,1H),2.20–2.05(m,2H),2.02–1.63(m,8H),1.57–1.50(m,1H),1.46–1.39(m,1H),1.29(t,J＝7.1Hz,3H)；
化合物21谱图数据:1H NMR(500MHz,CDCl3))δ7.66–7.53(m,1H),7.34–7.21(m,5H),7.20–7.12(m,1H),7.09–6.94(m,1H),6.60(d,J＝7.8Hz,1H),5.48–5.36(m,1H),5.21–5.14(m,1H),5.13–5.08(m,1H),5.08–5.02(m,1H),4.984.86(m,2H),4.78(d,J＝15.7Hz,1H),4.40–4.33(m,1H),4.30–4.18(m,3H),4.14–4.03(m,1H),3.85–3.71(m,1H),2.14–1.91(m,8H),1.72–1.66(m,9H),1.62(s,3H),1.58(s,3H),1.42(s,3H),1.20(t,J＝7.1Hz,3H)；
化合物22谱图数据:1H NMR(500MHz,CDCl3))δ7.61–7.54(m,1H),7.34–7.22(m,5H),7.21–7.15(m,1H),7.07–6.96(m,1H),6.60(d,J＝7.8Hz,1H),5.79(d,J＝4.7Hz,1H),5.53(d,J＝5.3Hz,1H),5.09(s,1H),5.01–4.93(m,1H),4.78–4.63(m,5H),4.37–4.25(m,2H),4.15–4.02(m,2H),3.98–3.87(m,1H),3.52(d,J＝12.1Hz,1H),2.24–2.12(m,4H),2.10–1.79(m,7H),1.76(s,3H),1.71(s,3H),1.32–1.23(m,6H)；
化合物23谱图数据:1H NMR(500MHz,CDCl3))δ7.56–7.48(m,1H),7.36–7.17(m,6H),7.08–6.93(m,1H),6.70–6.57(m,1H),5.06–4.95(m,1H),4.95–4.82(m,1H),4.76–4.62(m,1H),4.42–4.24(m,2H),4.04–3.93(m,1H),3.93–3.84(m,1H),3.82–3.71(m,1H),3.69–3.55(m,2H),3.53–3.42(m,1H),3.23–3.12(m,1H),3.07–2.96(m,1H),2.36–2.18(m,2H),1.94–1.80(m,2H),1.36–1.27(m,3H)；
化合物24谱图数据:1H NMR(500MHz,CDCl3))δ7.61–7.51(m,1H),7.48–7.22(m,5H),7.21–7.10(m,1H),7.06–6.87(m,1H),6.74–6.53(m,1H),5.00(d,J＝15.7,2.3Hz,1H),4.69(d,J＝15.7,2.3Hz,1H),4.38–4.15(m,2H),4.00–3.86(m,1H),3.85–3.75(m,1H),3.75–3.65(m,1H),3.63–3.49(m,2H),3.46–3.37(m,1H),3.34(s,3H),3.23–3.00(comp,5H),2.03–1.93(m,2H),1.69–1.58(m,2H),1.25(t,J＝6.1Hz,3H)；
化合物25谱图数据:1H NMR(500MHz,CDCl3))δ7.54(d,J＝7.4Hz,1H),7.43–7.15(m,16H),7.07–6.93(m,1H),6.59(d,J＝7.8Hz,1H),5.20(d,J＝12.1Hz,1H),5.03(d,J＝12.1Hz,1H),4.90(d,J＝11.4Hz,1H),4.83(d,J＝12.4Hz,1H),4.70(d,J＝11.4Hz,1H),4.63(s,1H),4.56(d,J＝12.4Hz,1H),2.91(s,3H)；
化合物26谱图数据:1H NMR(500MHz,CDCl3))δ7.58–7.53(m,1H),7.44–7.15(m,11H),7.08–6.98(m,1H),6.69(d,J＝7.8Hz,1H),5.85–5.74(m,1H),5.38–5.28(m,1H),5.26–5.19(m,1H),4.94(d,J＝11.3Hz,1H),4.82(d,J＝12.4Hz,1H),4.77(d,J＝11.3Hz,1H),4.71(s,1H),4.67–4.61(m,1H),4.61–4.56(m,1H),4.54(d,J＝12.4Hz,1H),3.09(s,3H)；
化合物27谱图数据:1H NMR(500MHz,CDCl3))δ7.61–7.54(m,1H),7.54–6.83(m,14H),6.79–6.58(m,1H),4.87–4.70(m,3H),4.58–4.50(m,1H),4.49–4.35(m,2H),3.55–3.40(m,2H),3.09(s,3H)。
表1化合物1至27的结构及分子量
实施例2靛红衍生物对肿瘤细胞的抑制活性
(1)测试采用的肿瘤细胞为：人骨肉瘤细胞(Sjsa-1)、人结肠癌细胞(HCT116)、人乳腺癌细胞(MCF-7)，其中Sjsa-1细胞培养基为含有10％胎牛血清和1％链霉素/青霉素的RPMI 1640培养基；HCT116细胞培养基为含有10％胎牛血清和1％链霉素/青霉素的RPMI1640培养基；MCF-7细胞培养基为含有10％胎牛血清和1％链霉素/青霉素的DMEM培养基。
(2)测试方法：
对肿瘤细胞的抑制率测定实验方法包括以下步骤：
1)于96孔板中配制100uL细胞悬液(细胞接种量为5000个/孔)，其中向空白孔中加入不含细胞的100uL细胞培养液，将接种好的96孔培养板放在培养箱中预培养24小时(37℃，5％CO2)；
2)向培养板中加入1μL最终浓度为20μM的待测化合物溶液(靛红衍生物1-27的溶液)，其中于对照孔和空白孔中加入1μL DMSO溶液；
3)加入待测化合物48小时后，将96孔培养板从培养箱中取出并观察细胞生长状态。向每孔中加入10μL CCK-8溶液(Cell Counting Kits-8)，将培养板放置培养箱中孵育2小时；
4)用Gen5酶标仪测定96孔培养板每孔在450nm处的吸光度。根据下述公式测得化合物对肿瘤细胞的抑制活性：
抑制率＝【(Ac-As)/(Ac-Ab)】×100％，其中，As为样品孔；Ab为空白孔；Ac为对照孔。
从表2可知，本发明的靛红衍生物对多种肿瘤细胞(HCT116、MCF-7、Sjsa-1)均表现出一定的抑制作用，其中，化合物3、8、9、19-22对HCT116表现出明显抑制作用，化合物2-14、17、20、21、23、25、26、27对MCF-7表现出明显抑制作用，化合物1、2、6、7、15、17、20、21、23、25对Sjsa-1表现出明显抑制作用。可见，本发明的靛红衍生物有望制备成为抗3种肿瘤细胞(HCT116、MCF-7、Sjsa-1)的药物进行应用。
表2靛红衍生物对多种癌细胞系的抑制作用
综上所述可见，本发明的靛红衍生物结构新颖，具有较好的抗肿瘤作用，对人骨肉瘤细胞、人结肠癌细胞和人乳腺癌细胞均具有较好的抑制作用，在抗肿瘤作用方面具有很大的应用价值，有望制备成抗肿瘤药物或抑制肿瘤细胞增殖的药物，尤其是抗人骨肉瘤、人结肠癌和人乳腺癌的药物。
以上对本发明的实施方式作了详细说明，但本发明不限于所描述的实施方式。对于本领域的技术人员而言，在不脱离本发明原理和精神的情况下，对这些实施方式进行多种变化、修改、替换和变型，仍落入本发明的保护范围内。
Claims (7)
1.一种靛红衍生物，其特征在于，所述靛红衍生物具有式(Ⅰ)所示的结构：
式(Ⅰ)中，所述R1选自甲基、苄基、炔丙基、异丙基、2-甲基-2-丁烯；R2选自氢，卤素；R3选自苄基，乙基，噻吩甲基，炔丙基，TMS乙基，环丙烷甲基，环丁烷甲基，1-溴丙基，1-甲氧基丙基；R4选自乙基，溴乙基，烯丙基，苄基。
2.一种靛红衍生物，其特征在于，所述衍生物选自下列结构式中的至少一种：
3.权利要求1所述的靛红衍生物的制备方法，其特征在于，根据下列反应式，将式1、式2和式3所示的原料混溶于有机溶剂中，然后在金属催化剂存在的条件下经反应后得到式(Ⅰ)所示的衍生物：
所述反应式中R1、R2、R3、R4的取值同权利要求1。
4.权利要求1或2所述的靛红衍生物在制备抗骨肉瘤药物或抑制骨肉瘤细胞增值的药物中的应用。
5.权利要求1或2所述的靛红衍生物在制备抗结肠癌药物或抑制结肠癌细胞增值的药物中的应用。
6.权利要求1或2所述的靛红衍生物在制备抗乳腺癌药物或抑制乳腺癌细胞增值的药物中的应用。
7.一种抗肿瘤药物，其特征在于，所述药物以权利要求1或2所述的靛红衍生物作为主要活性成分。
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| CN106977508A (zh) * | 2017-05-05 | 2017-07-25 | 遵义医学院 | 具有靛红结构的吡唑衍生物用于防治肿瘤的药物及其制法 |
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| EP3400938A1 (en) * | 2017-05-08 | 2018-11-14 | Universidade de Évora | Novel n-(1,2,3-triazolmethyl)isatin and n-(1,2,3-triazolmethyl)-3-hydroxy-3-aryloxindoles with cytotoxic and anti-tumor activity |
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| CN106977508A (zh) * | 2017-05-05 | 2017-07-25 | 遵义医学院 | 具有靛红结构的吡唑衍生物用于防治肿瘤的药物及其制法 |
| EP3400938A1 (en) * | 2017-05-08 | 2018-11-14 | Universidade de Évora | Novel n-(1,2,3-triazolmethyl)isatin and n-(1,2,3-triazolmethyl)-3-hydroxy-3-aryloxindoles with cytotoxic and anti-tumor activity |
| CN107903248A (zh) * | 2017-11-14 | 2018-04-13 | 陕西师范大学 | N‑取代靛红杂合喹唑啉类化合物合成的靛红衍生物及在制备抗肿瘤药物中的应用 |
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