CN115557889A - 2-芳基-3,4-二氢异喹啉衍生物及其作为制备抗肿瘤药物的应用 - Google Patents
2-芳基-3,4-二氢异喹啉衍生物及其作为制备抗肿瘤药物的应用 Download PDFInfo
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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Abstract
本发明涉及2‑芳基‑3,4‑二氢异喹啉衍生物及其作为制备抗肿瘤药物的应用。这类异喹啉衍生物的结构如式(I)，式中各基团的定义具体见说明书。本发明所述化合物对人肺癌细胞A‑549、人乳腺癌细胞MCF‑7、人宫颈癌细胞Hela、人结肠癌细胞HCT‑116、人结直肠癌细胞Caco‑2和HT‑29、早幼粒白血病细胞HL‑60等具有着显著的抑制活性，可用于制备抗癌肿瘤药物。
Description
技术领域
本发明涉及抗肿瘤药物领域，尤其是一类2-芳基-3,4-二氢异喹啉衍生物及其作为制备抗肿瘤药物的应用。
背景技术
肿瘤，尤其是恶性肿瘤(俗称癌症)一直以来是危险人类健康，造成死亡的重要因素之一。目前，治疗肿瘤的主要手段是放疗和化疗。放疗是利用射线照射肿瘤，但射线在杀死肿瘤细胞的同时，对正常细胞也有很大的危害作用。化疗是利用化学药物抑制或者杀死肿瘤细胞的生长、繁殖，但现有化疗药物选择性和靶向性差，经常出现不同程度的毒副作用。因此，筛选和研发选择性好、靶向性强、毒副作用小的抗肿瘤药物具有广阔的市场前景和深远的社会意义。
天然药物(俗称中药)来源于长期的中医药实践，在治疗慢性病及疑难杂症方面疗效独特。例如，从红豆杉树皮中分离得到的紫杉醇，已被广泛用于治疗乳腺癌、卵巢癌和肺癌等。季铵盐型异喹啉生物碱(Quternary Isoquinoline Alkaloids,QQAs)属于一类规模小，但生物活显著的异喹啉生物碱，结构中含有独特的C＝N+基团，具有抗肿瘤、抗炎、抗病毒等多种生物活性。血根碱(Sanguinarine)和小檗碱(Berberine)作为QQAs典型代表，可诱导肿瘤细胞凋亡或者抑制恶性细胞增殖，对前列腺癌细胞、乳腺癌细胞、肺癌细胞、黑色素瘤和胰腺癌细胞等具有显著的细胞毒性，其开发和应用的备受药物研究者的重视。但QQAs在自然界中含量低，难以分离提取；并且其母核为四元并环结构，化学合成产率低。周乐等以QQAs为先导化合物，通过结构优化，制备了系列结构简单的异喹啉-2-盐，表现出抗肿瘤、杀螨、抑菌等活性(CN 102627604,CN 101759637)。
基于QQAs抗肿瘤活性的构效关系，申请人采用活性药效团拼接的方法，优化异喹啉母核结构，合成了一系列新颖的2-芳基-3,4-二氢异喹啉衍生物，并研究了该类化合物的抗肿瘤活性。结果表明，本发明中涉及的化合物对人肺癌细胞A-549、人乳腺癌细胞MCF-7、人宫颈癌细胞Hela、人结肠癌细胞HCT-116、人结直肠癌细胞Caco-2和HT-29和早幼粒白血病细胞HL-60等显著的细胞毒性。此外，我们前期研究发现，该类化合物还对多种植物病原菌也具有抑制作用。
本发明所涉及的一类的异喹啉衍生物是文献鲜有报道的，并且之前的研究大多集中于农业领域的杀菌、杀虫和杀螨等。本专利是申请人首次对该类异喹啉衍生物的抗肿瘤活性报道。
发明内容
本发明目的在于提供一类2-芳基-3,4-二氢异喹啉衍生物及其作为制备抗肿瘤药物的应用。
本发明所述的一类2-芳基-3,4-二氢异喹啉衍生物，其化学结构式如下：
式(I)中，R1-R9为相同或者不同的氢基、羟基、卤素、氨基、硝基、羧基、酯基、甲氧基、胺酰基、C1-C6的烷基、C1-C6的烷硫基、C3-C7的环烷基、C3-C7的环烷基氨基、C2-C6的烯基、C2-C6的烯氧基、C2-C6的炔基、C1-C6的烷氨基、C2-C6的酰基、C1-C6的卤代烷基、C1-C6的羟基烷基；X为硫酸根、卤族负离子、碳酸根、碳酸氢根、磷酸根、磺酸根、磷酸氢根、四苯硼酸根、脂肪酸酸根。
该类2-芳基-3,4-二氢异喹啉衍生物作为制备抗肿瘤药物的应用。
与现有技术相比，本发明具有如下优点和效果。
本发明申请了一类结构如(I)所示的异喹啉衍生物，其结构源自于天然的季铵盐型异喹啉生物碱，具有生物相容性好的特点。并且该类化合物对多种肿瘤细胞具有显著的细胞毒性。
本申请所述的2-芳基-3,4-二氢异喹啉衍生物制备方法简单，可以实现其大量的合成。
具体实施方式
以下结合具体的实施实例，对本发明内容进行详细说明，但所列举之例不应视为对本发明保护内容的限制。
实施例1
化合物2-(4-氯-2-羟基苯基)-3,4-二氢异喹啉-2-溴化盐(I-1)的合成，具体合成路线如下：
中间体2的合成：将异色满1(0.05mol,6.71g)和溴化铜(0.06mol,13.4g)溶于80mL乙腈中，氮气保护下加热至回流，薄层色谱板(TLC)监测至反应完全.冷却后减压脱除溶剂，向残余物中加入100mL乙酸乙酯，饱和食盐水洗涤至中性，无水硫酸钠干燥，柱层析分离得无色液体2，产率92.6％。1H NMR(400MHz,CDCl3)δ10.16(s,1H),7.40～7.35(m,1H),7.34～7.25(m,3H),4.01(t,J＝5.7Hz,2H),2.90(t,J＝5.7Hz,2H)。
目标化合物I-1的合成。将1.0mmol的2-氨基-4-氯苯酚3a溶于10mL乙腈中，冰浴冷却，滴加溶有2(1.2mmol)的乙腈溶液，搅拌过夜。减压脱除溶剂，向残余物中加入10mL乙酸乙酯，充分搅拌，抽滤，固体用乙酸乙酯洗涤，烘干得目标化合物I-1。
其余目标化合物的合成方法与I-1相同，将反应底物2-氨基-4-氯苯酚替换为各种取代的苯胺3。
以下为目标化合物I的理化数据。
2-(4-氯-2-羟基苯基)-3,4-二氢异喹啉-2-溴化盐(I-1):浅褐色固体，熔点216～219℃，产率81.2％。
2-(4-溴-2-羟基苯基)-3,4-二氢异喹啉-2-溴化盐(I-2):褐色固体，熔点210～213℃，产率84.1％。
2-(4-溴-2-甲氧基苯基)-3,4-二氢异喹啉-2-溴化盐(I-3):浅褐色固体，熔点201～203℃，产率89.6％。
2-(4-羧基苯基)-3,4-二氢异喹啉-2-溴化盐(I-4):浅黄色固体，熔点211～214℃，产率69.8％。
2-(4-甲氧羰基苯基)-3,4-二氢异喹啉-2-溴化盐(I-5):黄色固体，熔点191～193℃，产率91.2％。
2-(2-甲氧羰基苯基)-3,4-二氢异喹啉-2-溴化盐(I-6):黄色固体，熔点144～146℃，产率60.3％。
2-(3-甲氧羰基苯基)-3,4-二氢异喹啉-2-溴化盐(I-7):黄色固体，熔点184～186℃，产率80.9％。
2-(4-丁氧羰基苯基)-3,4-二氢异喹啉-2-溴化盐(I-8):黄色固体，熔点155～157℃，产率87.4％。
2-(3-乙氧羰基苯基)-3,4-二氢异喹啉-2-溴化盐(I-9):黄色固体，熔点182～185℃，产率84.1％。
2-(3,5-二甲氧羰基苯基)-3,4-二氢异喹啉-2-溴化盐(I-10):黄色固体，熔点193～195℃，产率91.1％。
2-(2,5-二甲氧羰基苯基)-3,4-二氢异喹啉-2-溴化盐(I-11):白色固体，熔点196～198℃，产率79.5％。
2-(4-氯-2-乙氧羰基苯基)-3,4-二氢异喹啉-2-溴化盐(I-12):白色固体，熔点185～187℃，产率76.5％。
2-(3-羟基-4-甲氧羰基苯基)-3,4-二氢异喹啉-2-溴化盐(I-13):黄色固体，熔点150～152℃，产率74.7％。
2-(4-羧基-2-甲基苯基)-3,4-二氢异喹啉-2-溴化盐(I-14):白色固体，熔点280～282℃，产率81.3％。
2-(4-氯-2-羟基苯基)-3,4-二氢异喹啉-2-溴化盐(I-1):1H NMR(400MHz,DMSO-d6)δ11.36(s,1H),9.61(s,1H),8.01(d,J＝7.5Hz,1H),7.94～7.90(m,2H),7.67～7.59(m,2H),7.53(dd,J＝8.8,2.6Hz,1H),7.21(d,J＝8.9Hz,1H),4.41(t,J＝7.8Hz,2H),3.39(t,J＝7.8Hz,2H).HRMS(ESI)calcd for C15H13ClNO+([M－Br－]+)258.0686,found 258.0680.
2-(4-溴-2-羟基苯基)-3,4-二氢异喹啉-2-溴化盐(I-2):1H NMR(400MHz,DMSO-d6)δ11.40(s,1H),9.59(s,1H),8.01(dd,J＝8.4,5.0Hz,2H),7.91(t,J＝7.4Hz,1H),7.67～7.57(m,3H),7.18～7.13(m,1H),4.40(t,J＝7.8Hz,2H),3.38(t,J＝7.8Hz,2H).HRMS(ESI)calcd for C15H13BrNO+([M－Br－]+)302.0181,found 302.0190.
2-(2-羟基-4-硝基苯基)-3,4-二氢异喹啉-2-溴化盐(I-3):1H NMR(400MHz,DMSO-d6)δ9.57(s,1H),8.78(d,J＝2.4Hz,1H),8.35(dd,J＝9.1,2.7Hz,1H),8.00(d,J＝7.5Hz,1H),7.90(t,J＝7.4Hz,1H),7.64～7.59(m,2H),7.37(d,J＝9.2Hz,1H),4.41(t,J＝7.7Hz,2H),3.38(t,J＝7.7Hz,2H).HRMS(ESI)calcd for C15H13N2O3 +([M－Br－]+)269.0926,found 269.0926.
2-(4-溴-2-甲氧基苯基)-3,4-二氢异喹啉-2-溴化盐(I-4):1H NMR(400MHz,DMSO-d6)δ9.58(s,1H),8.01(d,J＝7.5Hz,1H),7.92(td,J＝7.6,1.1Hz,1H),7.78(d,J＝8.4Hz,1H),7.69～7.57(m,3H),7.46(dd,J＝8.4,1.9Hz,1H),4.38(t,J＝7.8Hz,2H),3.97(s,3H),3.39(t,J＝7.8Hz,2H).HRMS(ESI)calcd for C16H15BrNO+([M－Br－]+)316.0337,found 316.0350.
2-(4-羧基苯基)-3,4-二氢异喹啉-2-溴化盐(I-5):1H NMR(400MHz,DMSO-d6)δ13.40(br,1H),9.80(s,1H),8.20(d,J＝8.6Hz,2H),8.08(d,J＝7.4Hz,1H),8.02(d,J＝8.2Hz,2H),7.91(t,J＝7.4Hz,1H),7.65～7.61(m,2H),4.63(t,J＝7.8Hz,2H),3.44(t,J＝7.9Hz,2H).HRMS(ESI)calcd for C16H14NO2 +([M－Br－]+)252.1025,found 252.1042.
2-(4-甲氧羰基苯基)-3,4-二氢异喹啉-2-溴化盐(I-6):1H NMR(400MHz,DMSO-d6)δ9.80(s,1H),8.24(d,J＝8.7Hz,2H),8.09～8.04(m,3H),7.93(t,J＝7.3Hz,1H),7.67～7.62(m,2H),4.64(t,J＝7.8Hz,2H),3.93(s,3H),3.45(t,J＝7.8Hz,2H).HRMS(ESI)calcdfor C17H16NO2 +([M－Br－]+)266.1181,found 266.1204.
2-(2-甲氧羰基苯基)-3,4-二氢异喹啉-2-溴化盐(I-7):1H NMR(400MHz,DMSO-d6)δ9.85(s,1H),8.49(dd,J＝7.9,0.8Hz,1H),8.36(d,J＝7.1Hz,1H),8.18(dd,J＝7.9,1.4Hz,1H),7.82(td,J＝7.8,1.5Hz,1H),7.74(td,J＝7.6,1.1Hz,1H),7.65(td,J＝7.8,1.0Hz,1H),7.48(t,J＝7.6Hz,1H),7.39(d,J＝7.6Hz,1H),4.42(br,2H),3.89(s,3H),3.61(br,2H).HRMS(ESI)calcd for C17H16NO2 +([M－Br－]+)266.1181,found 266.1204.
2-(3-甲氧羰基苯基)-3,4-二氢异喹啉-2-溴化盐(I-8):1H NMR(400MHz,CDCl3)δ10.37(s,1H),8.57(dd,J＝8.1,1.7Hz,1H),8.44(d,J＝7.4Hz,1H),8.37(s,1H),8.14(d,J＝7.9Hz,1H),7.75(td,J＝7.6,1.0Hz,1H),7.66(t,J＝8.0Hz,1H),7.48～7.41(m,1H),4.65(t,J＝7.9Hz,2H),3.92(s,3H),3.57(t,J＝7.9Hz,2H).HRMS(ESI)calcd for C17H16NO2 +([M－Br－]+)266.1181,found 266.1204.
2-(4-丁氧羰基苯基)-3,4-二氢异喹啉-2-溴化盐(I-9):1H NMR(400MHz,CDCl3)δ10.48(s,1H),8.39(d,J＝7.4Hz,1H),8.18(d,J＝8.9Hz,2H),8.12(d,J＝8.8Hz,2H),7.74～7.67(m,1H),7.46～7.33(m,2H),4.63(t,J＝7.9Hz,2H),4.32(t,J＝6.6Hz,2H),3.51(t,J＝7.9Hz,2H),1.80～1.70(m,2H),1.55～1.40(m,2H),0.98(t,J＝7.4Hz,3H).HRMS(ESI)calcd for C20H22NO2 +([M－Br－]+)308.1651,found 308.1660.
2-(3-乙氧羰基苯基)-3,4-二氢异喹啉-2-溴化盐(I-10):1H NMR(400MHz,CDCl3)δ10.38(s,1H),8.62(dd,J＝8.1,1.7Hz,1H),8.46(d,J＝7.4Hz,1H),8.32(s,1H),8.16(d,J＝7.9Hz,1H),7.75(dt,J＝7.6,3.8Hz,1H),7.67(t,J＝8.0Hz,1H),7.48(t,J＝7.6Hz,1H),7.42(d,J＝7.6Hz,1H),4.63(t,J＝7.9Hz,2H),4.40(q,J＝7.1Hz,2H),3.57(t,J＝7.9Hz,2H),1.42(dd,J＝7.1Hz,3H).HRMS(ESI)calcd for C18H18NO2 +([M－Br－]+)280.1338,found280.1354.
2-(3,5-二甲氧羰基苯基)-3,4-二氢异喹啉-2-溴化盐(I-11):1H NMR(400MHz,CDCl3)δ10.37(s,1H),8.81(d,J＝1.1Hz,2H),8.76(s,1H),8.39(d,J＝7.6Hz,1H),7.76(t,J＝7.5Hz,1H),7.54～7.39(m,2H),4.64(t,J＝7.8Hz,2H),3.95(s,6H),3.60(t,J＝7.8Hz,2H).HRMS(ESI)calcd for C19H18NO4 +([M－Br－]+)324.1236,found 324.1247.
2-(2,5-二甲氧羰基苯基)-3,4-二氢异喹啉-2-溴化盐(I-12):1H NMR(400MHz,CDCl3)δ10.32(s,1H),8.78(s,1H),8.45(d,J＝7.6Hz,1H),8.30(s,2H),7.79(t,J＝7.5Hz,1H),7.51(t,J＝7.5Hz,1H),7.44(d,J＝7.6Hz,1H),4.44(br,2H),3.95(s,3H),3.94(s,3H),3.63(br,2H).HRMS(ESI)calcd for C19H18NO4 +([M－Br－]+)324.1236,found324.1247.
2-(4-氯-2-乙氧羰基苯基)-3,4-二氢异喹啉-2-溴化盐(I-13):1H NMR(400MHz,CDCl3)δ9.97(s,1H),8.61(s,1H),8.36(d,J＝7.3Hz,1H),8.15(d,J＝8.4Hz,1H),7.76(t,J＝7.4Hz,1H),7.62(d,J＝8.3Hz,1H),7.55～7.38(m,2H),4.37(br,2H),4.34(q,J＝7.1Hz,2H),3.64(br,2H),1.34(t,J＝7.1Hz,3H).HRMS(ESI)calcd for C18H17ClNO2 +([M－Br－]+)314.0948,found 314.0956.
2-(3-羟基-4-甲氧羰基苯基)-3,4-二氢异喹啉-2-溴化盐(I-14):1H NMR(600MHz,DMSO-d6)δ10.85(s,1H),9.74(s,1H),8.09～8.01(m,2H),7.91(s,1H),7.68～7.58(m,2H),7.57～7.37(m,2H),4.58(s,2H),3.93(s,3H),3.41(s,2H).HRMS(ESI)calcdfor C17H16NO3 +([M－Br－]+)282.1130,found 282.1149.
2-(4-羧基-2-甲基苯基)-3,4-二氢异喹啉-2-溴化盐(I-15):1H NMR(400MHz,DMSO-d6)δ9.62(s,1H),8.08(s,1H),8.05～8.01(m,2H),7.95(t,J＝7.6Hz,1H),7.88(d,J＝8.2Hz,1H),7.66(t,J＝7.0Hz,2H),4.46(t,J＝7.9Hz,2H),3.48(t,J＝7.9Hz,2H),2.52(s,3H).HRMS(ESI)calcd for C17H16NO2 +([M－Br－]+)266.1181,found 266.1204.
实施例2
利用本发明所提供的2-芳基3,4-二氢异喹啉-2-溴化盐(I-1～I-15)进行抗肿瘤活性测试。
供试肿瘤细胞：人肺癌细胞A-549、人乳腺癌细胞MCF-7、人宫颈癌细胞Hela、人结肠癌细胞HCT-116、人结直肠癌细胞Caco-2和HT-29、早幼粒白血病细胞HL-60。
试剂：胎牛血清(北京元亨圣马生物技术研究所)，RPMI1640培养液(Invitrogen)，SRB(Sigma)，DMSO(北京化学试剂公司)，生理盐水，5-氟尿嘧啶(Sigma)等。
实验仪器：CO2培养箱(Thermo)，微型超声振荡器(Mini shaker，Kylin-Bell Labinstruments)，酶标仪(MD公司，M5型)等。
试剂配制
0.4％SRB：称取0.8g SRB，溶于200ml 1％乙酸中，室温保存。
50％TCA(三氯乙酸)：称取50g TCA，加入水定容至100ml，4℃保存。
10mM Tris-base：0.6057g Tris-base，加水定容500ml，pH为10.5，4℃保存。
采用SRB法，具体试验操作如下：
选用对数生长期细胞，胰酶消化后用含10％胎牛血清RPMI1640培养液，接种在96孔培养板中，每孔细胞密度为4000个/100μL，37℃，5％CO2培养24h。施药前换液成190μL新鲜完全培养基，实验组加入初筛浓度的样品10μl(终浓度单体化合物5μg/mL；混合物50μg/mL)，对照组则换含等体积溶剂的培养液，37℃，5％CO2培养3天。弃去培养基。轻轻加入4℃预冷的10％TCA(1640无血清培养基配制)100μL将细胞固定在培养板上。先静置5min然后再移至4℃放置1h。倒掉固定液，蒸馏水洗5次去除TCA，空气干燥(至少1小时)。每孔加入0.4％SRB溶液80μL，室温染色30min。弃染液，1％TCA(去离子水配制)洗6遍充分去除未结合的SRB，空气干燥。加入150μL 10mM非缓冲Tris碱液(pH10.5)溶解，微量振荡器上5min。酶标仪M5检测仪测定OD510 nm值。
肿瘤细胞生长抑制率(％)＝(OD对照-OD实验)/(OD对照-OD空白)*100％
试验结果用Excel 2016进行处理，再用SPSS进行处理得到其毒力回归方程和相应的IC50值，部分抗肿瘤活性数据见表1。
表1 2-芳基-3,4-二氢异喹啉衍生物(I-1～I-15)对肿瘤细胞的活性
结果显示，衍生物I-1～I-15对A-549、MCF-7和Hela三种肿瘤细胞具有一定的抑制率，尤其是I-7、I-13和I-15的细胞增殖抑制率大于50％，并且其IC50值与阳性对照样5-氟尿嘧啶接近或者相当。
上述结果表明，本发明所述的2-芳基-3,4-二氢异喹啉衍生物具有制备抗肿瘤药物的潜力。
Claims (5)
1.一类2-芳基-3,4-二氢异喹啉衍生物，其结构如式(I)：
2.根据权利要求1，式(I)中R1-R9为相同或者不同的氢基、羟基、卤素、氨基、硝基、羧基、酯基、甲氧基、胺酰基、C1-C6的烷基、C1-C6的烷硫基、C3-C7的环烷基、C3-C7的环烷基氨基、C2-C6的烯基、C2-C6的烯氧基、C2-C6的炔基、C1-C6的烷氨基、C2-C6的酰基、C1-C6的卤代烷基、C1-C6的羟基烷基；X为硫酸根、卤族负离子、碳酸根、碳酸氢根、磷酸根、磺酸根、磷酸氢根、四苯硼酸根、脂肪酸酸根。
3.一类根据权利1、2要求所述的2-芳基-3,4-二氢异喹啉衍生物的应用，其特征在于制备抗肿瘤药物。
4.根据权利要求3，其抗肿瘤的对象为人肺癌细胞A-549，人乳腺癌细胞MCF-7、人宫颈癌细胞Hela、人结肠癌细胞HCT-116、人结直肠癌细胞Caco-2和HT-29、早幼粒白血病细胞HL-60等。
5.根据权利要求1、2、3、4，2-芳基-3,4-二氢异喹啉衍生物作为制备抗肿瘤药物的应用，选自以下化合物：
2-(4-氯-2-羟基苯基)-3,4-二氢异喹啉-2-溴化盐；
2-(4-溴-2-羟基苯基)-3,4-二氢异喹啉-2-溴化盐；
2-(4-溴-2-甲氧基苯基)-3,4-二氢异喹啉-2-溴化盐
2-(4-羧基苯基)-3,4-二氢异喹啉-2-溴化盐；
2-(4-甲氧羰基苯基)-3,4-二氢异喹啉-2-溴化盐
2-(2-甲氧羰基苯基)-3,4-二氢异喹啉-2-溴化盐；；
2-(3-甲氧羰基苯基)-3,4-二氢异喹啉-2-溴化盐；
2-(4-丁氧羰基苯基)-3,4-二氢异喹啉-2-溴化盐；
2-(3-乙氧羰基苯基)-3,4-二氢异喹啉-2-溴化盐；
2-(3,5-二甲氧羰基苯基)-3,4-二氢异喹啉-2-溴化盐；
2-(2,5-二甲氧羰基苯基)-3,4-二氢异喹啉-2-溴化盐；
2-(4-氯-2-乙氧羰基苯基)-3,4-二氢异喹啉-2-溴化盐；
2-(3-羟基-4-甲氧羰基苯基)-3,4-二氢异喹啉-2-溴化盐；
2-(4-羧基-2-甲基苯基)-3,4-二氢异喹啉-2-溴化盐。
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| CN101759637A (zh) * | 2010-01-08 | 2010-06-30 | 西北农林科技大学 | N-芳基-3,4-二氢异喹啉盐及其作为制备杀螨和抗菌药物的应用 |
| CN102603629A (zh) * | 2012-04-06 | 2012-07-25 | 西北农林科技大学 | 二氢异喹啉类化合物及其作为制备植物抗菌药物的应用 |
| CN102627604A (zh) * | 2012-04-06 | 2012-08-08 | 西北农林科技大学 | 两类异喹啉类化合物及其作为制备抗癌药物的应用 |
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| CN101759637A (zh) * | 2010-01-08 | 2010-06-30 | 西北农林科技大学 | N-芳基-3,4-二氢异喹啉盐及其作为制备杀螨和抗菌药物的应用 |
| CN102603629A (zh) * | 2012-04-06 | 2012-07-25 | 西北农林科技大学 | 二氢异喹啉类化合物及其作为制备植物抗菌药物的应用 |
| CN102627604A (zh) * | 2012-04-06 | 2012-08-08 | 西北农林科技大学 | 两类异喹啉类化合物及其作为制备抗癌药物的应用 |
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| 朱丽飞: "N-芳基-3, 4-二氢异喹啉类化合物：设计、合成、生物活性及构效关系", 《西北农林科技大学博士学位论文》, 15 January 2021 (2021-01-15), pages 4 * |
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