CN104530043B - 9‑取代β‑咔啉类化合物及其用于制备预防或治疗肿瘤药物的应用 - Google Patents
9‑取代β‑咔啉类化合物及其用于制备预防或治疗肿瘤药物的应用 Download PDFInfo
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Abstract
本发明涉及9‑取代β‑咔啉类化合物及其用于制备预防或治疗肿瘤药物的应用。所涉及的化合物的结构通式如式Ⅰ所示。本发明的化合物对肿瘤细胞的生长有很强的抑制作用,活性接近阳性对照紫杉醇;并且部分化合物的抗肿瘤活性明显优于紫杉醇,IC50值小于1μM,可成为肿瘤治疗的高效药物。
Description
技术领域
本发明属于药物化学技术领域,具体是9-取代β-咔啉类化合物的制备方法和在抗肿瘤方面的应用。
背景技术
目前,肿瘤(特别是恶性肿瘤)是威胁人类健康和生命的主要疾病之一。虽然已开发出多种较为有效的抗肿瘤药物,但是由于肿瘤的转移性、耐药性等原因都会导致治疗的失败,因此,不断研发新的抗肿瘤药物意义重大。从天然产物中寻找抗肿瘤活性成分,以得到的活性成分作为前体化合物,对其进行改造修饰是抗肿瘤药物开发的主要途径之一。
发明内容
针对现有技术的缺陷或不足,本发明提供了一种9-取代β-咔啉类化合物,该化合物的结构通式如式Ⅰ所示:
其中:
R1表示氢或甲基中的一种;
R2表示氢、羟基或甲氧基中的一种;
R3表示C1-C12酰基、苯磺酰基、对甲苯磺酰基、对甲苯磺酰基、邻甲基苄基、对甲基苄基、对氟苄基、邻氟苄基、3,5-二氟苄基、C2-C8溴代烷基中的一种。
本发明还提供了上述化合物药学可接受的盐或溶剂合物。
本发明又提供了一种药物组合,该药物组合物含有上述化合物或药学可接受的盐、制药学许可的载体或以该类化合物作为活性成分的混以药用赋形剂或者稀释剂的组合。
本发明同时还提供了上述化合物用于制备预防或治疗肿瘤药物的应用。
与现有技术相比,本发明的化合物对肿瘤细胞的生长有很强的抑制作用,活性接近阳性对照紫杉醇;并且部分化合物的抗肿瘤活性明显优于紫杉醇,IC50值小于1μM,可成为肿瘤治疗的高效药物。
本发明涉及化合物对人胃腺癌细胞系(SGC-7901)、人肝癌细胞系(SMMC-7721)、宫颈癌细胞系(Hela)、人早幼粒白血病细胞(HL-60)和人肺癌细胞系(A-549)表现出了很好的抑制活性,有望成为抗肿瘤候选药物。
具体实施方式
本发明的化合物可参考以下方法制得,方法包括:
步骤(1),以7-取代色胺或者色氨酸为起始原料,通过Piectet-Spengler反应,与甲醛或者乙醛发生环化,再经氧化后得第一步化合物:
或者,
步骤(2),利用卤代烃或酰氯在碱性条件下与步骤(1)中的产物反应,得式(Ⅰ)中的化合物:
以下实施实例仅用于对本发明进行说明,不以任何方式限制本发明内容。
本发明实施实例中所用原料均为市售商品,所得化合物波谱数据均按照常规测试方法所得。
以下实施例中相关中间体的制备方法可参考以下方法:
β-咔啉的合成:
5mmol色氨酸加入到100mL圆底烧瓶中,加入容有1mL浓盐酸的50mL水溶液,30℃下搅拌至完全溶解;加入10mmol甲醛继续反应6h,用碳酸氢钠水溶液调节pH值至6,过滤烘干后得3-羧基-四氢β-咔啉。将干燥的3-羧基-四氢β-咔啉加入到100mL圆底烧瓶中,加入50mL冰乙酸和7mmol二氧化硒,回流12h,调节pH值至8,经乙酸乙酯萃取后浓缩,再经丙酮重结晶得目标物β-咔啉(2.3mmol,产率46%)。
1-甲基-7-甲氧基-β-咔啉的合成:
5mmol 6-甲氧基色氨加入到100mL圆底烧瓶中,加入容有1mL浓盐酸的50mL水溶液,30℃下搅拌至完全溶解;加入10mmol乙醛继续反应10h,用碳酸氢钠水溶液调节pH值至8,过滤烘干后得1-甲基-7-甲氧基-四氢β-咔啉。将干燥的1-甲基-7-甲氧基-四氢β-咔啉加入到100mL圆底烧瓶中,加入50mL甲苯和5%的Pd/C 100mg,回流24h,热过滤,过滤液减压浓缩后,再经丙酮重结晶,可得1-甲基-7-甲氧基-β-咔啉(3.6mmol,产率72%)。
实施例1:
化合物10的合成:
1mmol 1-甲基-7-甲氧基-β-咔啉(8)加入到25mL圆底烧瓶中,加入10mL DMF,5mgNaH和2mmol 2-甲基-氯化苄,35℃下搅拌反应8h;加入10mL冰-水淬灭反应,与4℃静止12h,过滤,烘干后得1-甲基-7-甲氧基-9-(2-甲基)苄基-β-咔啉(化合物10)(0.69mmol,产率69%)。1H-NMR(400MHz,CDCl3):δ8.30(1H,d,J=5.1Hz),8.00(1H,d,J=8.6Hz),7.77(1H,d,J=5.1Hz),7.3-7.4(2H,m),6.92-6.97(3H,m),6.75(1H,d,J=1.7Hz),5.69(2H,s),3.33(3H,s),2.83(3H,s),2.20(3H,s);13C-NMR(400MHz,CDCl3):δ161.14,143.52,141.13,138.70,135.82,129.87,129.71,128.80,128.55,125.67,125.50,122.43,115.22,112.27,109.31,93.33,58.80,55.59,23.54,20.62;ESI-MS m/z:317.2[M+H]+。
实施例2:
化合物11的合成:
1mmol 1-甲基-7-甲氧基-β-咔啉(8)加入到25mL圆底烧瓶中,加入10mL四氢呋喃,室温搅拌,加入苯磺酰氯1.5mmol,室温反应2h;NaHCO3水溶液调pH值为8,乙酸乙酯萃取,减压浓缩乙酸乙酯相,可得1-甲基-7-甲氧基-9-苯磺酰基-β-咔啉(化合物11)(0.69mmol,产率69%)。1H-NMR(500MHz,CDCl3):δ8.49(1H,d,J=5.1Hz),7.89(1H,d,J=8.6Hz),7.64(1H,d,J=5.1Hz),7.50(1H,d,J=2.1Hz),6.98(1H,dd,J=8.5,2.1Hz),3.93(3H,s),2.90-2.94(2H,m),2.70(3H,s),1.78-1.85(2H,m),1.22-1.33(14H,m),0.86-0.89(3H,m);13C-NMR(500MHz,CDCl3):δ174.7,161.7,145.5,143.0,141.7,134.9,134.1,122.2,117.5,111.6,111.3,99.3,55.8,39.6,32.0,31.9,29.6,29.3,29.4,29.2,25.9,24.3,22.7,14.1;ESI-MSm/z:395.3[M+H]+。
化合物12的合成:
1mmol 1-甲基-7-甲氧基-β-咔啉(8)加入到25mL圆底烧瓶中,加入10mL四氢呋喃,室温搅拌,加入对甲基苯磺酰氯1.5mmol,室温反应2h;NaHCO3水溶液调pH值为8,乙酸乙酯萃取,减压浓缩乙酸乙酯相,可得1-甲基-7-甲氧基-9-(4-甲基)苯磺酰基-β-咔啉(化合物12)(0.73mmol,产率73%)。1H-NMR(500MHz,CDCl3):δ8.44(1H,d,J=5.0Hz),7.78(1H,d,J=2.2Hz),7.57(1H,d,J=8.5Hz),7.34-7.35(2H,m),7.23(2H,d,J=1.2Hz),7.21(1H,d,J=1.2Hz),7.11-7.15(2H,m),6.93(1H,dd,J=8.5,2.2Hz),3.96(3H,s),3.04(3H,s);13C-NMR(500MHz,CDCl3):δ161.4,150.5,145.1,143.6,137.6,136.2,135.1,133.6,128.4,126.8,121.7,120.6,114.4,111.0,103.7,56.0,25.3;ESI-MS m/z:353.1[M+H]+。
实施例3:
化合物14的合成:
1mmol 1-甲基-7-甲氧基-β-咔啉(8)加入到25mL圆底烧瓶中,加入10mL DMF,5mgNaH和2mmol 1,4-二溴丁烷,45℃下反应8h;10mL冰-水淬灭反应,与4℃下静止12h,过滤,烘干后得化合物14(0.69mmol,产率69%)。1H-NMR(400MHz,CDCl3):δ8.27(1H,d,J=5.2Hz),7.95(1H,d,J=8.5Hz),7.71(1H,d,J=5.1Hz),6.86(1H,dd,J=8.5,2.1Hz),6.84(1H,d,J=2.1Hz),4.42(2H,q,J=7.5Hz),4.23(2H,m),3.93(3H,s),3.00(3H,s),1.76-1.84(2H,m),1.41-1.47(2H,m);13C-NMR 400MHz,CDCl3):δ160.82,143.15,140.59,138.24,135.43,129.32,122.26,115.22,112.18,108.64,93.55,55.68,46.23,44.74,32.67,23.43,20.20;ESI-MS m/z:268.2[M-Br+H]+。
本发明部分化合物体外抗肿瘤活性试验:
利用MTT法测试了合成的化合物对人胃腺癌细胞系(SGC-7901)、人肝癌细胞系(SMMC-7721)、宫颈癌细胞系(Hela)、人早幼粒白血病细胞(HL-60)和人肺癌细胞系(A-549)5种肿瘤细胞的抑制活性。
具体试验方法:将细胞以约105个/mL的密度接种于96孔板,每孔接种150μL,置CO2培养箱中培养至对数生长期。然后按预设的浓度加入待测样品,每个浓度设6个重复。对照组加入等体积的溶解样品用的溶剂。继续培养72h后,取出96孔板,每孔加入20μL的MTT(5mg/mL),然后置于37℃,4h后,小心除去上清,每孔加入100μL的DMSO,振荡约10min溶解沉淀,在波长490nm处,用酶标仪检测各孔OD值。
用以下公式求出每个样品浓度的抑制率:
抑制率%=(1-样品组平均OD值/对照组平均OD值)×100%
用GraphPad Prism处理数据,以细胞抑制率对药物浓度对数作图,按作图法求出每个样品的IC50值。结果如表1所示。
表1 部分2,9-取代β-咔啉类化合物对肿瘤细胞生长抑制情况
上述部分化合物的体抗肿瘤活性表明:本发明所得化合物有较好的抗肿瘤活性,有可能成为肿瘤治疗的候选药物。并且,这类化合物的原料廉价,合成条件简单,便于进行放大生产,具有较好的应用前景。
Claims (2)
1.9-取代β-咔啉类化合物用于制备预防或治疗人早幼粒白血病药物的应用,所述9-取代β-咔啉类化合物为
2.9-取代β-咔啉类化合物药学可接受的盐用于制备预防或治疗人早幼粒白血病药物的应用,所述9-取代β-咔啉类化合物为:
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