CN106366151B - 具有抗肿瘤作用的齐墩果酸-3-酮衍生物及其制备方法和用途 - Google Patents

具有抗肿瘤作用的齐墩果酸-3-酮衍生物及其制备方法和用途 Download PDF

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CN106366151B
CN106366151B CN201610716482.XA CN201610716482A CN106366151B CN 106366151 B CN106366151 B CN 106366151B CN 201610716482 A CN201610716482 A CN 201610716482A CN 106366151 B CN106366151 B CN 106366151B
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刘洋
程卯生
李凤然
王帅
卫高菲
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Shenyang Pharmaceutical University
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Abstract

本发明属于医药技术领域，提供具有通式（）所示结构的齐墩果酸‑3‑酮衍生物，其中涉及的通式（）中的R的定义见说明书。本发明还涉及该类化合物的制备方法，以及它们在作为抗肿瘤药物方面的潜在应用。

Description

具有抗肿瘤作用的齐墩果酸-3-酮衍生物及其制备方法和 用途
技术领域
本发明属于医药技术领域，涉及一种含有三氮唑基团的齐墩果酸-3-酮衍生物的制备方法和医药用途，具体涉及新颖的齐墩果酸-3-酮-(1’-取代苯基-1H-1’,2’,3’-三氮唑-4’-基)甲酯化合物的制备方法和对肿瘤细胞的增殖抑制作用，在制备抗肿瘤药物方面具有潜在应用。
背景技术
齐墩果酸是自然界中分布广泛的一种五环三萜类化合物，具有多种重要的生物活性，如抗肿瘤、抗HIV病毒、保肝、抗炎等，但活性较弱，且生物利用度低，使其在临床中应用受限。
研究表明，齐墩果酸对多种肿瘤细胞株具有不同程度的抑制活性，在多种动物模型中对癌症的预防和治疗疗效显著，活性评价后显示具有明确的抗癌特性。齐墩果酸对白血病细胞HL-60具有诱导凋亡活性，作用途径是通过激活细胞凋亡蛋白-3和细胞凋亡蛋白-9，同时伴随着DNA修复酶(PARP)的裂解(Acta Biochim Biophys Sinica 2007,39:803–809)。齐墩果酸还能够诱导鼠***上皮细胞分化(Archives of Pharmacal Research1998,21:398–405)，诱导小鼠粒细胞白血病(M1)细胞与人急性早幼粒细胞白血病(HL-60)细胞分化(Chem Pharm Bull 1992,40:401–405)。Fernandes等发现齐墩果酸能够抑制K562白血病细胞的生长并促进其凋亡，更重要的是，对于耐受长春新碱的K562细胞多药耐药株(MDR)仍有抑制增殖作用(Cancer Lett 2003,190:165–169)。
齐墩果酸3β-OH经氧化后成为3-酮-齐墩果酸，抗肿瘤活性得到了明显提高，在体外对多种组织肿瘤细胞都有显著的抑制活性；同时体内实验表明它能选择性抑制黑色素瘤的生长，而且不同于以往的细胞毒药物，它还具有独特的抗血管生成活性，对正常细胞的毒性很小，这可能与它能够诱导恶性黑色素瘤细胞分化有关(Cancer Lett 2006,233:289–296)。
本发明合成了一类新型的齐墩果酸-3-酮衍生物，并通过体外活性筛选研究验证了其抗肿瘤活性和独特的肿瘤细胞作用选择性。
发明内容
本发明的目的在于设计与合成一类新型的齐墩果酸-3-酮-(1’-取代苯基-1H-1’,2’,3’-三氮唑-4’-基)甲酯化合物，进行具有治疗癌症的药物创制研究。
为了完成本发明之目的，可采用如下技术方案：
本发明是涉及具有通式(I)结构的新型齐墩果酸衍生物，及其光学活性体，非对映异构体。
其中，
R为下列基团中的任意一个基团：(1)氢原子，(2)卤原子，(3)氰基，(4)硝基，(5)C1-C4酰基。
R优选为下列基团中的任意一个基团：(1)氢原子，(2)氟原子，(3)氯原子，(4)溴原子，(5)氰基，(6)硝基，(7)乙酰基。
本发明优选如下结构的齐墩果酸衍生物，及其光学活性体，非对映异构体，
选自：
为了制备本发明通式(I)所述的化合物，及其光学活性体，采用如下路线合成该类化合物：在碳酸钾的水和二氯甲烷混合溶液中，以四丁基溴化铵为相转移催化剂，齐墩果酸1与炔丙基溴反应得到中间体2，中间体2的C3羟基经琼斯试剂氧化制得3-酮产物3，其再与各种取代的芳基叠氮化合物在叔丁醇-水混合溶液中，由无水硫酸铜与抗坏血酸钠原位生成的Cu(I)催化，发生1,3偶极环加成反应，得到通式(I)的化合物。
反应式如下：
具体地，其反应条件如下：
Reagents and conditions:(a)K2CO3,TBAB,H2O,CH2Cl2；(b)CrO3·H2SO4,acetone,0℃；(c)sodium ascorbate,CuSO4·5H2O,t-BuOH,H2O,60℃.
其中，
R如权利要求和说明书所述。
具体实施方案
联系如下实施例，将更好地理解本发明的化合物和他们的制备，这些实施例旨在阐述而不是限制本发明的范围。
实施例1：齐墩果酸-3-酮-(1’-苯基-1H-1’,2’,3’-三氮唑-4’-基)甲酯(T1)
将齐墩果酸1(2.0g,4.4mmol)、K2CO3粉末(1.8g,13.1mmol)和TBAB(290.0mg,0.9mmol)溶解于1mL水和200mL二氯甲烷的混合溶液中，加入炔丙基溴(1.0g,8.8mmol)，室温下搅拌反应5h，水洗，饱和NaCl洗，无水NaSO4干燥，过滤，浓缩，柱层析(石油醚：乙酸乙酯＝9:1)，得1.93g白色固体2，收率89.1％。
将化合物2(3.0g，6.0mmol)溶于50mL丙酮中，0℃下缓慢滴加Jones试剂(2.3mL，12.0mmol)。搅拌反应30分钟，抽滤，蒸除丙酮，加入80mL乙酸乙酯溶解，水洗(2×10mL)。有机层浓缩后经柱层析(石油醚：乙酸乙酯＝5:1)纯化得到2.64g化合物3，收率88.5％。
将化合物3(120.0mg,0.2mmol)溶解于15mL t-BuOH-H2O(2:1)中，依次加入抗坏血酸钠(38.7mg，0.2mmol)和CuSO4·5H2O(24.1mg,0.1mmol)，搅拌5min，然后向这一混合溶液中加入叠氮苯(1.0mmol)，于60℃反应1h。浓缩，二氯甲烷稀释，水洗，饱和NaCl洗，无水NaSO4干燥过滤，浓缩，柱层析(石油醚：乙酸乙酯＝8:1)，得黄色固体T1，收率87.4％。
Mp 92.1-93.9℃；1H NMR(600MHz,CDCl3)δ8.07(s,1H),7.95(s,1H),7.75-7.69(m,1H),7.61(d,J＝8.0Hz,1H),7.56(dd,J＝5.7,3.3Hz,1H),7.43(t,J＝8.1Hz,1H),5.35-5.24(m,3H),4.29-4.21(m,1H),2.90(dd,J＝13.8,3.9Hz,1H),2.57-2.50(m,1H),1.13(s,3H),1.09(s,3H),1.03(s,3H),0.95(s,3H),0.93(s,3H),0.92(s,3H),0.48(s,3H)；13C NMR(150MHz,CDCl3)δ217.68,177.81,167.75,144.03,143.61,137.84,132.46,131.85,131.08,130.88,128.80,123.62,123.34,122.71,122.30,118.94,68.16,57.20,55.22,47.39,46.78,46.74,45.79,41.79,41.47,39.25,39.09,38.74,36.69,34.11,33.82,33.04,32.40,32.14,30.67,30.37,29.70,28.93,27.59,26.48,25.62,23.75,23.57,23.43,22.99,22.95,21.44,19.50,16.65,14.93,14.05,10.97；ESI-MS(m/z):634.6[M+Na]+。
实施例2：齐墩果酸-3-酮-[1’-(2”-氟苯基)-1H-1’,2’,3’-三氮唑-4’-基]甲酯(T2)
实施例2的化合物制备方法同实施例1，只是使用邻氟苯基叠氮代替苯基叠氮，得到黄色固体T2，收率88.2％。
Mp 177.5-179.6℃；1H NMR(600MHz,CDCl3)δ8.45(d,J＝8.9Hz,2H),8.19(s,1H),8.00(d,J＝8.9Hz,2H),5.32(d,J＝20.0Hz,3H),2.90(dd,J＝13.7,3.3Hz,1H),2.58-2.51(m,1H),1.14(s,3H),1.09(s,3H),1.02(s,3H),0.94(s,3H),0.94(s,3H),0.92(s,3H),0.55(s,3H)；13C NMR(150MHz,CDCl3)δ217.49,177.86,147.32,144.69,143.58,141.04,126.35,125.54,122.47,122.34,120.47,57.11,55.27,47.41,46.83,46.76,45.74,41.81,41.47,39.27,39.10,36.70,34.10,33.77,33.02,32.37,32.16,30.66,29.70,27.62,26.38,25.66,23.57,23.44,22.97,22.69,21.44,19.49,16.65,14.88,14.12；ESI-MS(m/z):652.8[M+Na]+。
实施例3：齐墩果酸-3-酮-[1’-(3”-氟苯基)-1H-1’,2’,3’-三氮唑-4’-基]甲酯(T3)
实施例3的化合物制备方法同实施例1，只是使用间氟苯基叠氮代替苯基叠氮，得到白色固体T3，收率84.2％。
Mp 167.2-170.1℃；1H NMR(600MHz,CDCl3)δ8.05(s,1H),7.71(d,J＝8.8Hz,2H),7.54(d,J＝8.8Hz,2H),5.34-5.28(m,3H),2.90(dd,J＝13.6,3.8Hz,1H),2.57-2.51(m,1H),1.14(s,3H),1.09(s,3H),1.04(s,3H),0.94(s,3H),0.94(s,3H),0.92(s,3H),0.52(s,3H)；13C NMR(150MHz,CDCl3)δ217.59,177.80,144.03,143.63,135.43,134.69,129.94,122.47,122.30,121.60,57.26,55.24,47.39,46.78,45.78,41.80,41.47,39.26,39.10,36.70,34.11,33.80,33.04,32.37,32.15,30.67,29.70,27.62,26.46,25.65,23.58,23.44,22.96,22.69,21.43,19.51,16.66,14.88,14.12；ESI-MS(m/z):652.6[M+Na]+。
实施例4：齐墩果酸-3-酮-[1’-(4”-氟苯基)-1H-1’,2’,3’-三氮唑-4’-基]甲酯(T4)
实施例4的化合物制备方法同实施例1，只是使用对氟苯基叠氮代替苯基叠氮，得到白色固体T4，收率83.3％。
Mp 161.9-163.6℃；1H NMR(600MHz,CDCl3)δ8.02(s,1H),7.73(dd,J＝7.8,5.7Hz,2H),7.25(t,J＝8.4Hz,2H),5.35-5.25(m,3H),2.90(dd,J＝13.8,3.9Hz,1H),2.59-2.50(m,1H),1.14(s,3H),1.09(s,3H),1.04(s,3H),0.94(s,3H),0.93(m,3H),0.92(s,3H),0.53(s,3H)；13C NMR(150MHz,CDCl3)δ217.59,177.80,163.73,161.25,143.93,143.64,133.22,122.69,122.48,122.40,122.30,116.85,116.62,57.30,55.25,47.39,46.78,45.79,41.81,41.48,39.27,39.11,36.71,34.11,33.81,33.05,32.38,32.16,31.93,30.67,29.71,29.37,27.63,26.47,25.66,23.59,23.44,22.96,22.70,21.42,19.52,16.66,14.89,14.12；ESI-MS(m/z):653.3[M+Na]+。
实施例5：齐墩果酸-3-酮-[1’-(4”-氯苯基)-1H-1’,2’,3’-三氮唑-4’-基]甲酯(T5)
实施例5的化合物制备方法同实施例1，只是使用对氯苯基叠氮代替苯基叠氮，得到白色固体T5，收率84.5％。
Mp 170.8-173.0℃；1H NMR(600MHz,CDCl3)δ8.05(s,1H),7.69(d,J＝8.8Hz,2H),7.65(d,J＝8.9Hz,2H),5.30(dt,J＝19.0,7.9Hz,3H),2.90(dd,J＝13.7,4.1Hz,1H),2.58-2.51(m,1H),1.13(s,3H),1.09(s,3H),1.04(s,3H),0.94(s,3H),0.93(s,3H),0.92(s,3H),0.51(s,3H)；13C NMR(150MHz,CDCl3)δ217.70,177.80,144.05,143.62,135.90,132.92,122.52,122.43,122.29,121.82,57.25,55.23,47.39,46.77,46.75,45.77,41.79,41.46,39.24,39.09,36.69,34.11,33.80,33.04,32.37,32.14,30.67,29.70,27.61,26.45,25.64,23.58,23.43,22.95,21.44,19.50,16.66,14.88,14.12；ESI-MS(m/z):668.6[M+Na]+。
实施例6：齐墩果酸-3-酮-[1’-(4”-溴苯基)-1H-1’,2’,3’-三氮唑-4’-基]甲酯(T6)
实施例6的化合物制备方法同实施例1，只是使用对溴苯基叠氮代替苯基叠氮，得到黄色固体T6，收率90.9％。
Mp 75.5-78.0℃；1H NMR(600MHz,CDCl3)δ7.94(s,1H),7.75(dd,J＝7.4,1.7Hz,1H),7.67-7.61(m,2H),7.48(dd,J＝7.6,1.2Hz,1H),5.35-5.29(m,3H),2.90(dd,J＝13.8,3.9Hz,1H),2.58-2.52(m,1H),2.22(s,3H),1.15(s,3H),1.10(s,3H),1.05(s,3H),1.00(s,3H),0.93(s,3H),0.92(s,3H),0.68(s,3H)；13C NMR(150MHz,CDCl3)δ217.71,199.24,177.67,143.70,136.27,134.32,131.85,129.93,129.07,125.59,122.28,57.36,55.26,47.41,46.80,45.79,41.82,41.41,39.31,39.11,36.73,34.12,33.81,33.04,32.32,32.16,30.67,29.70,29.19,27.67,26.49,25.70,23.58,23.47,22.97,21.45,19.56,16.85,14.99；ESI-MS(m/z):714.6[M+Na]+。
实施例7：齐墩果酸-3-酮-[1’-(3”-溴苯基)-1H-1’,2’,3’-三氮唑-4’-基]甲酯(T7)
实施例7的化合物制备方法同实施例1，只是使用间溴苯基叠氮代替苯基叠氮，得到黄色固体T7，收率89.4％。
Mp 73.5-76.0℃；1H NMR(600MHz,CDCl3)δ7.98(s,1H),7.63(d,J＝9.0Hz,2H),7.03(d,J＝9.0Hz,2H),5.34-5.26(m,3H),4.11(q,J＝7.0Hz,2H),2.90(dd,J＝13.8,3.9Hz,1H),2.57-2.50(m,1H),1.13(s,3H),1.09(s,3H),1.03(s,3H),0.94(s,3H),0.94(s,3H),0.92(s,3H),0.53(s,3H)；13C NMR(150MHz,CDCl3)δ217.74,177.79,159.36,143.65,143.42,130.15,122.73,122.27,122.09,115.26,63.96,57.28,55.19,47.37,46.76,45.79,41.79,41.46,39.25,39.08,36.70,34.10,33.81,33.05,32.37,32.13,30.67,29.70,27.61,26.52,25.65,23.59,23.44,22.94,21.40,19.53,16.66,14.93,14.71；ESI-MS(m/z):714.6[M+Na]+。
实施例8：齐墩果酸-3-酮-[1’-(4”-氰基苯基)-1H-1’,2’,3’-三氮唑-4’-基]甲酯(T8)
实施例8的化合物制备方法同实施例1，只是使用对氰基苯基叠氮代替苯基叠氮，得到黄色固体T8，收率85.1％。
Mp 70.5-72.3℃；1H NMR(600MHz,CDCl3)δ8.16(d,J＝2.7Hz,1H),8.00(t,J＝7.7Hz,1H),7.48(dd,J＝13.0,7.4Hz,1H),7.38-7.31(m,2H),5.34-5.30(m,3H),2.91(dd,J＝13.8,3.9Hz,1H),2.58-2.50(m,1H),1.14(s,3H),1.10(s,3H),1.04(s,3H),0.95(s,3H),0.94(s,3H),0.92(s,3H),0.57(s,3H)；13C NMR(150MHz,CDCl3)δ217.75,177.63,154.52,152.03,143.65,130.31,130.23,125.26,125.22,124.80,122.32,117.18,116.99,57.32,55.23,47.39,46.79,45.80,41.80,41.45,39.26,39.10,36.71,34.12,33.82,33.06,32.37,32.15,31.93,30.68,29.71,29.66,29.37,27.63,26.53,25.68,23.59,23.43,22.97,22.72,22.70,21.42,19.55,16.58,14.91,14.12；ESI-MS(m/z):659.6[M+Na]+。
实施例9：齐墩果酸-3-酮-[1’-(4”-硝基苯基)-1H-1’,2’,3’-三氮唑-4’-基]甲酯(T9)
实施例9的化合物制备方法同实施例1，只是使用对硝基苯基叠氮代替苯基叠氮，得到白色固体T9，收率89.9％。
Mp 85.7-88.2℃；1H NMR(600MHz,CDCl3)δ8.16(s,1H),8.15(d,J＝2.2Hz,2H),7.90(d,J＝8.6Hz,2H),5.34-5.30(m,3H),2.90(dd,J＝13.8,4.0Hz,1H),2.68(s,3H),2.57-2.50(m,1H),2.40-2.34(m,1H),2.06-1.16(m,25H),1.14(s,3H),1.09(s,3H),1.02(s,3H),0.94(s,3H),0.92(s,3H),0.91(s,3H),0.53(s,3H)；13C NMR(150MHz,CDCl3)δ217.56,196.42,177.81,144.24,143.61,139.95,136.97,130.08,122.42,122.31,120.03,57.22,55.22,47.38,46.80,46.76,45.77,41.80,41.47,39.25,39.09,36.69,34.09,33.80,33.04,32.37,32.14,30.67,27.62,26.67,26.45,25.65,23.58,23.44,22.97,21.42,19.50,16.64,14.88,14.12；ESI-MS(m/z):679.6[M+Na]+。实施例10：齐墩果酸-3-酮-[1’-(2”-硝基苯基)-1H-1’,2’,3’-三氮唑-4’-基]甲酯(T10)
实施例10的化合物制备方法同实施例1，只是使用邻硝基苯基叠氮代替苯基叠氮，得到白色固体T10，收率87.5％。
Mp 91.3-93.2℃；1H NMR(600MHz,CDCl3)δ8.07(s,1H),7.76(d,2H),7.56(t,J＝7.9Hz,2H),7.47(t,J＝17.0,9.5Hz,1H),5.44-5.24(m,3H),4.15(q,J＝7.1Hz,1H),2.91(dd,J＝13.8,4.2Hz,1H),2.11-1.16(m,25H),1.13(s,3H),1.09(s,3H),1.02(s,3H),0.94(s,3H),0.92(s,3H),0.91(s,3H),0.51(s,3H)；13C NMR(150MHz,CDCl3)δ217.73,177.78,143.76,143.64,136.93,129.75,128.86,122.58,122.28,120.46,77.35,77.24,77.03,76.72,60.39,57.32,55.19,47.37,46.77,46.75,45.78,41.78,41.47,39.23,39.08,36.68,34.09,33.81,33.05,32.38,32.12,30.67,27.61,26.52,25.64,23.59,23.43,22.94,21.39,19.51,16.63,14.88；ESI-MS(m/z):679.6[M+Na]+。
实施例11：齐墩果酸-3-酮-[1’-(3”-硝基苯基)-1H-1’,2’,3’-三氮唑-4’-基]甲酯(T11)
实施例11的化合物制备方法同实施例1，只是使用间硝基苯基叠氮代替苯基叠氮，得到197.33mg白色固体T11，收率79.26％。
Mp 153.9-156.7℃；1H NMR(600MHz,CDCl3)δ8.61(s,1H),8.35(d,J＝8.3Hz,1H),8.20(d,J＝13.6Hz,2H),7.79(t,J＝8.2Hz,1H),5.35-5.29(m,3H),2.91(d,J＝9.6Hz,1H),2.57-2.51(m,1H),2.40-2.33(m,1H),2.20-1.17(m,38H),1.14(s,3H),1.09(s,3H),1.02(s,3H),0.95(s,3H),0.92(s,3H),0.92(s,3H),0.54(s,3H)；13C NMR(150MHz,CDCl3)δ217.56,177.85,148.98,144.57,143.59,137.65,131.02,125.93,123.30,122.62,122.35,115.28,57.17,55.25,47.39,46.83,46.75,45.77,41.83,41.49,39.29,39.09,36.69,34.10,33.81,33.03,32.40,32.17,31.93,30.67,29.70,29.66,29.36,27.63,26.42,25.65,23.58,23.44,22.98,22.72,21.41,19.49,16.68,14.83,14.12；ESI-MS(m/z):679.6[M+Na]+。
实施例12：齐墩果酸-3-酮-[1’-(4”-乙酰苯基)-1H-1’,2’,3’-三氮唑-4’-基]甲酯(T12)
实施例12的化合物制备方法同实施例1，只是使用对乙酰苯基叠氮代替苯基叠氮，得到黄色固体T12，收率89.0％。
Mp 132.5-134.7℃；1H NMR(600MHz,CDCl3)δ8.07(s,1H),7.54(ddd,J＝8.8,8.2,4.1Hz,3H),7.20-7.17(m,1H),5.34-5.26(m,3H),4.24(dd,J＝11.5,5.9Hz,1H),2.92-2.88(m,1H),2.57-2.50(m,1H),2.40-2.34(m,1H),1.13(s,3H),1.09(s,3H),1.03(s,3H),0.94(s,3H),0.92(s,6H),0.50(s,3H)；13C NMR(150MHz,CDCl3)δ217.69,177.80,144.02,143.62,131.26,131.17,130.88,128.81,122.59,122.30,115.86,115.76,115.73,115.65,108.43,108.17,68.16,57.22,55.21,47.38,46.78,46.74,45.77,41.78,41.47,39.24,39.08,38.74,36.69,34.10,33.80,33.04,32.38,32.12,30.67,30.37,28.93,27.60,26.48,25.63,23.75,23.58,23.42,22.99,22.94,21.38,19.49,16.65,14.85,14.05；ESI-MS(m/z):676.7[M+Na]+。
实施例13：齐墩果酸-3-酮-[1’-(2”-乙酰苯基)-1H-1’,2’,3’-三氮唑-4’-基]甲酯(T13)
实施例13的化合物制备方法同实施例1，只是使用邻乙酰苯基叠氮代替苯基叠氮，得到白色固体T13，收率79.6％。
Mp 96.5-98.2℃；1H NMR(600MHz,CDCl3)δ8.14(s,1H),7.94(d,J＝8.7Hz,2H),7.88(d,J＝8.7Hz,2H),5.33-5.29(m,3H),2.90(dd,J＝13.6,3.8Hz,1H),2.58-2.52(m,1H),1.14(s,3H),1.09(s,3H),1.03(s,3H),0.94(s,3H),0.94(s,3H),0.92(s,3H),0.53(s,3H)；13C NMR(150MHz,CDCl3)δ217.47,177.84,144.55,143.57,139.69,133.92,122.32,120.53,117.58,112.59,57.12,55.26,47.40,46.81,46.75,45.73,41.80,41.46,39.26,39.10,36.69,34.10,33.77,33.02,32.36,32.15,30.66,29.69,27.61,26.38,25.66,23.57,23.43,22.96,21.46,19.48,16.64,14.87；ESI-MS(m/z):676.7[M+Na]+。
实施例14：齐墩果酸-3-酮-[1’-(3”-乙酰苯基)-1H-1’,2’,3’-三氮唑-4’-基]甲酯(T14)
实施例14的化合物制备方法同实施例1，只是使用3-乙酰苯基叠氮代替苯基叠氮，得到白色固体T14，收率86.7％。
Mp 70.2-73.1℃；1H NMR(600MHz,CDCl3)δ8.30(s,1H),8.16(s,1H),8.04(d,J＝8.2Hz,2H),7.68(t,J＝7.9Hz,1H),5.355.27(m,3H),2.91(dd,J＝13.7,4.0Hz,1H),2.70(s,3H),2.55-2.49(m,1H),1.13(s,3H),1.08(s,3H),1.01(s,3H),0.94(s,3H),0.91(s,3H),0.89(s,3H),0.52(s,3H；13C NMR(150MHz,CDCl3)δ217.72,196.44,177.78,144.12,143.58,138.55,137.34,130.24,128.52,124.68,122.58,122.32,119.60,77.36,77.05,76.73,57.26,55.18,47.36,46.78,46.74,45.76,41.79,41.47,39.24,39.07,36.67,34.09,33.80,33.04,32.37,32.13,30.67,29.69,27.61,26.73,26.49,25.64,23.58,23.42,22.95,21.39,19.50,16.64,14.86；ESI-MS(m/z):676.7[M+Na]+。
本发明的合成产物的药理研究
人***细胞HeLa，人肝癌细胞HepG2，人结肠癌细胞HCT116，人黑色素瘤细胞A375-S2，人纤维肉瘤细胞HT-1080购于American Type CultureCollection(ATCC，Rockville，MD，USA)。细胞接种在含10％胎牛血清、2％谷氨酰胺的RPMI-1640培养液中，在37℃、5％CO2培养箱中培养。
选用对数生长期的肿瘤细胞，用胰酶消化后，用含10％小牛血清的RPMIl640培养基配成5×104/mL的细胞悬液，接种在96孔培养板中，每孔100μL，37℃、5％CO2培养24h。实验组更换新的含不同浓度被测样品的培养液，对照组则更换含等体积溶剂的培养液，每组设3个平行孔，37℃、5％CO2培养48h。弃去上清液，用PBS小心洗2次，每孔加入100μL新鲜配制的含0.5mg/mL MTT的培养基，37℃继续培养4h。小心弃去上清，并加入150μL DMSO，用微型振荡器混匀10min后，用酶标仪在492nm处测定光密度值。
按下式计算药物对肿瘤细胞生长的抑制率：
肿瘤细胞生长抑制率(％)
＝[A492(阴性对照)－A492(加药组)]/A492(阴性对照)×100％
从中求出样品的半数抑制浓度(IC50)。
化合物对五种人癌细胞体外增殖的抑制作用IC50(μM)
以上数据揭示，由本发明所获得的全新结构的化合物，对人黑色素瘤细胞A375-S2和人纤维肉瘤细胞HT-1080会产生特异性的增殖抑制作用，而对人***细胞HeLa，人肝癌细胞HepG2，人结肠癌细胞HCT116等不敏感。由此体现出齐墩果酸-3-酮衍生物显著的肿瘤细胞选择性作用，具有开发为特定肿瘤治疗药物的潜力。

Claims (9)

1.通式(I)所示的一类的具有抗肿瘤作用的齐墩果酸衍生物：
其中：
R为下列基团中的任意一个基团：(1)氢原子，(2)卤原子，(3)氰基，(4)硝基，(5)C1-C4酰基。
2.根据权利要求1所述的衍生物，其中，
R为(1)氢原子，(2)卤原子，(3)氰基，(4)硝基，(5)乙酰基。
3.根据权利要求1或2所述的衍生物，其中，
R为氢原子，氟原子，氯原子，溴原子，氰基，硝基，乙酰基。
4.权利要求1或2所述的衍生物，选自：
T1：齐墩果酸-3-酮-(1’-苯基-1H-1’，2’，3’-三氮唑-4’-基)甲酯，
T2：齐墩果酸-3-酮-[1’-(2”-氟苯基)-1H-1’，2’，3’-三氮唑-4’-基]甲酯，
T3：齐墩果酸-3-酮-[1’-(3”-氟苯基)-1H-1’，2’，3’-三氮唑-4’-基]甲酯，
T4：齐墩果酸-3-酮-[1’-(4”-氟苯基)-1H-1’，2’，3’-三氮唑-4’-基]甲酯，
T5：齐墩果酸-3-酮-[1’-(4”-氯苯基)-1H-1’，2’，3’-三氮唑-4’-基]甲酯，
T6：齐墩果酸-3-酮-[1’-(4”-溴苯基)-1H-1’，2’，3’-三氮唑-4’-基]甲酯，
T7：齐墩果酸-3-酮-[1’-(3”-溴苯基)-1H-1’，2’，3’-三氮唑-4’-基]甲酯，
T8：齐墩果酸-3-酮-[1’-(4”-氰基苯基)-1H-1’，2’，3’-三氮唑-4’-基]甲酯，
T9：齐墩果酸-3-酮-[1’-(4”-硝基苯基)-1H-1’，2’，3’-三氮唑-4’-基]甲酯，
T10：齐墩果酸-3-酮-[1’-(2”-硝基苯基)-1H-1’，2’，3’-三氮唑-4’-基]甲酯，
T11：齐墩果酸-3-酮-[1’-(3”-硝基苯基)-1H-1’，2’，3’-三氮唑-4’-基]甲酯，
T12：齐墩果酸-3-酮-[1’-(4”-乙酰苯基)-1H-1’，2’，3’-三氮唑-4’-基]甲酯，
T13：齐墩果酸-3-酮-[1’-(2”-乙酰苯基)-1H-1’，2’，3’-三氮唑-4’-基]甲酯，
T14：齐墩果酸-3-酮-[1’-(3”-乙酰苯基)-1H-1’，2’，3’-三氮唑-4’-基]甲酯，其结构如下：
。
5.权利要求1所述衍生物的制备方法，其特征在于：
通式(I)衍生物的合成方法如下：
在碳酸钾的水和二氯甲烷混合溶液中，以四丁基溴化铵为相转移催化剂，齐墩果酸1与炔丙基溴反应得到中间体2，中间体2的C3羟基经琼斯试剂氧化制得3-酮产物3，其再与各种取代的芳基叠氮化合物在叔丁醇-水混合溶液中，由无水硫酸铜与抗坏血酸钠原位生成的Cu(I)催化，发生1，3偶极环加成反应，得到通式(I)的衍生物；
反应式如下：
其中，R如权利要求1所述。
6.一种药物组合物，包含权利要求1-4任何一项所述的衍生物和药学上可接受的载体。
7.一种药物制剂，包含权利要求1-4任何一项所述的衍生物或权利要求6所述的药物组合物。
8.权利要求1-4任何一项所述的衍生物或权利要求6所述药物组合物或权利要求7所述的药物制剂在制备抗肿瘤药物中的应用。
9.权利要求1-4任何一项所述的衍生物或权利要求6所述药物组合物或权利要求7所述的药物制剂在制备治疗黑色素瘤和纤维肉瘤药物中的应用。
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