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CN111269104B - 一种查尔酮类似物及其应用 - Google Patents

一种查尔酮类似物及其应用 Download PDF

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CN111269104B
CN111269104B CN202010084658.0A CN202010084658A CN111269104B CN 111269104 B CN111269104 B CN 111269104B CN 202010084658 A CN202010084658 A CN 202010084658A CN 111269104 B CN111269104 B CN 111269104B
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郑小辉
刘志国
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Wenzhou Medical University
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Abstract

本发明公开了一种查尔酮类似物及其应用，该查尔酮类似物的结构如式(I)所示，其中，R选自取代或者未取代的芳基或杂芳基；所述的芳基或者杂芳基上的取代基选自C1～C5烷基、C1～C5烷氧基、卤素或三氟甲基。体外抗肿瘤活性测试结果表明，本发明的查尔酮类似物大部分具有较高的抗肿瘤活性。

Description

一种查尔酮类似物及其应用
技术领域
本发明属于药物化学领域，具体涉及一种查尔酮类似物及其应用。
背景技术
端粒是真核细胞线性染色体末端的特殊结构，具有保护染色体末端、维持基因组稳定性的功能。处于线性染色体末端的端粒可以避免线性染色体末端被识别成DNA损伤，并抑制DNA损伤应答机制。在人类细胞中，端粒由端粒DNA重复序列5’-TTAGGG-3’与端粒结合蛋白“Shelterin”组成。蛋白复合物Shelterin由六种蛋白质组成：POT1(protection oftelomeres 1)、TRF1(telomeric repeat binding factor 1)、TRF2(telomeric repeatbinding factor 2)、TIN2(TRF1-interacting protein 2)、TPP1(the POT1-and TIN2-organizing protein)、RAP1(repressor/activator protein)]。在组织细胞中，Shelterin复合体中某种蛋白的异常表达或其功能障碍都可以破坏端粒的完整性及其基因组的稳定性。
TRF2是Broccoli等人于1997年发现的TRF1的同源物，能直接结合到端粒双链DNA上，是特异性的端粒序列结合蛋白。TRF2的分子量为66KD，由500个氨基酸组成，基因定位于16q22.1。TRF2亦含有3个重要的结构域：位于氨基末端的碱性区，位于中间的二聚体保守序列及位于羧基端的Myb型DNA结构域。TRF2的缺失会影响T-loop的形成，从而引起染色体末端融合。此外，端粒上TRF2的存在抑制了DNA损伤修复机制NHEJ的发生。大量的研究表明，TRF2在肿瘤组织中高表达。因此，TRF2能够作为治疗恶性肿瘤的潜在靶点。
卡瓦胡椒素B(Flavokawain B)是药用植物卡瓦胡椒根中的一种天然查耳酮类化合物，拥有广泛的生物活性，如抗肿瘤、抗氧化、糖尿病及其并发症的预防和治疗等。目前国内外对卡瓦胡椒素的研究,从文献报道来看,大多集中于抗焦虑和抑郁作用,而对其抗肿瘤活性的研究报道并不多。由于查耳酮结构的化合物具有多种抗癌活性,如抑制肿瘤增殖、恶化和迁移。在此基础上,本发明提供了卡瓦胡椒素B的新型查尔酮衍生物，该衍生物特别适用于TRF2高表达或突变而引起的疾病，尤其是肿瘤和癌症。
发明内容
本发明提供了一种查尔酮类似物及其应用，该查尔酮类似物具有较好的抗肿瘤活性。
一种查尔酮类似物，结构如式(I)所示：
式(I)中，R选自各种取代或者未取代的芳基或杂芳基；所述的芳基或者杂芳基上的取代基选自C1～C5烷基、C1～C5烷氧基、卤素或三氟甲基。
本发明以卡瓦胡椒素B结构骨架为基础，通过药物设计方法设计了新型查尔酮类化合物。体外抗肿瘤活性测试结果表明，本发明的查尔酮类似物大部分具有较高的抗肿瘤活性。
作为优选，所述的芳基为苯基；所述的杂芳基为噻吩基、嘧啶基或者2，3-二氢苯并[b][1，4]二噁英基。
作为优选，所述的芳基或者杂芳基上的取代基选自甲基、乙基、N,N-二甲基氨基、卤素、甲氧基。
作为优选，所述的R选自以下基团：
本发明还提供了一种所述的查尔酮类似物的应用，所述的查尔酮类似物用于制备抗肿瘤药物。
作为优选，所述的查尔酮类似物通过抑制TRF2的表达来治疗肿瘤以及与肿瘤相关的疾病。
作为优选，所述与肿瘤相关的疾病，包括但不限于：癌，例如肝癌(包括小细胞肝癌)、膀胱癌、乳腺癌、结肠癌、肾癌、肺癌、食道癌、胆囊癌、卵巢癌、胰腺癌、胃癌、宫颈癌、甲状腺癌和皮肤癌(包括鳞状细胞癌)；淋巴系的造血性肿瘤，包括白血病、急性淋巴细胞性白血病、急性成淋巴细胞性白血病、B细胞淋巴瘤、T细胞淋巴瘤、何杰金淋巴瘤、非何杰金淋巴瘤、外套细胞淋巴瘤、毛细胞淋巴瘤和Burkett淋巴瘤；骨髓系造血性肿瘤，包括急性和慢性髓性白血病、骨髓增生异常综合征和早幼粒细胞白血病；多发性骨髓瘤；间质细胞来源的肿瘤，包括纤维瘤和横纹肌肉瘤；其他肿瘤，包括黑色素瘤、精原细胞瘤、畸胎瘤、骨肉瘤、着色性干皮病、角质黄瘤、甲状腺囊癌和卡波西肉瘤。
作为最优选，所述的查尔酮类似物的结构式如下：
活性试验表明，该化合物具有最好的抗肿瘤活性。
本发明还提供了一种药物制剂，包括有效成分和药用辅料，所述的有效成分包括所述的查尔酮类似物。
作为优选，所述的药物制剂为注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、软膏剂、控释剂、缓释剂或纳米制剂的任一种。
同现有技术相比，本发明取得的有益效果在于：以卡瓦胡椒素B结构骨架为基础，通过药物设计方法设计合成了新型查尔酮类化合物。上述化合物具有优异的抑制TRF2过度表达或异常激活的细胞增殖效果以及优异的特异性或广谱性抑制TRF2激酶的效果，对于耐药突变株的抑制效果也很好，从而可以高效地治疗肿瘤。
为了便于理解，以下将通过具体的附图和实施例对本发明进行详细地描述。需要特别指出的是，具体实例和附图仅是为了说明，并不构成对本发明范围的限制。显然本领域的普通技术人员可以根据本文说明，在本发明的范围内对本发明做出各种各样的修正和改变，这些修正和改变也纳入本发明的范围内。
附图说明
图1为测试例2中合成化合物对HuH-7细胞的TRF2蛋白表达的影响；
图2为测试例2中不同浓度下5a04对HuH-7细胞多种DNA损伤相关蛋白表达的影响。
具体实施方式
通过以下实施例对本发明作进一步详细说明，但不应理解为限定本发明的范围。
实施例1制备2,4-二甲氧基-6-(甲氧基甲氧基)苯甲醛(化合物2a)
在100mL圆底烧瓶中，将2-羟基-4，6-二甲氧基苯甲醛1a(25g,0.14mol)溶解于50mL无水四氢呋喃，冰浴冷却后，向体系中缓慢加入60％氢化钠(8.2g,0.21mol)。冰浴搅拌20分钟后，向体系中再缓慢加入氯甲基甲醚(16.5g,0.21mol)薄层色谱监测反应进程，反应结束后，向反应体系中加入50mL蒸馏水终止反应。继续用乙酸乙酯萃取，合并有机层，用饱和食盐水洗涤后，无水硫酸镁干燥，减压旋干过柱后得目标产物2a 42.7g产率90％。
实施例2制备1-(2,4-二甲氧基-6-(甲氧基甲氧基)苯基)乙醇(化合物3a)
在-78℃氮气保护下，100mL圆底烧瓶中将2a(10g,0.044mol)溶解于50mL无水四氢呋喃，搅拌15分钟后，缓慢向体系中加入甲基溴化镁(15.36ml,0.22mol)。2小时后，向反应体系中加入50mL饱和氯化铵溶液终止反应。继续用乙酸乙酯萃取，合并有机层，用饱和食盐水洗涤后，无水硫酸镁干燥，减压旋干过柱后得目标产物3a9.68g，产率91.3％。
实施例3制备1-(2,4-二甲氧基-6-(甲氧基甲氧基)苯基)乙酮(化合物4a)
在100mL圆底烧瓶中，将1-(2,4-二甲氧基-6-(甲氧基甲氧基)苯基)乙醇3a(20g,0.083mol)溶解于50mL无水四氢呋喃，将活性二氧化锰(35.88g,0.415mol)缓慢加入反应体系后，室温反应过夜。薄层色谱监测反应进程，反应结束后，反应体系抽虑除去滤饼，滤液减压旋干过柱后得目标产物4a 14.0g产率70％。
实施4～27制备查尔酮类似物5a1～5a26的合成通法(以5a1为例)
将1-(2,4-二甲氧基-6-(甲氧基甲氧基)苯基)乙酮(0.1g，0.42mmol)(4a)和0.056g(0.42mmol)4-甲氧基苯甲醛溶于10mL乙醇中，搅拌条件下缓慢滴入20％氢氧化钠(NaOH)3mL,反应体系室温下搅拌过夜。反应结束后，向体系中加入过量冰水，直到析出黄色沉淀。抽滤，滤饼用少量冰水洗涤后抽干。将滤饼溶解于5mL甲醇(MeOH)/四氢呋喃(THF)＝1：1的混合溶剂中，室温下缓慢滴入1.0mol/L的盐酸0.5mL，反应持续1h，反应结束后，向反应液中加入冰水直到析出黄色沉淀。抽虑，滤饼用冰水洗涤，抽干。残渣继续用乙醇重结晶得黄色目标产物5a1 0.132g，收率56.4％。
合成的26个目标化合物的反应路线、收率、理化性质及波谱数据如下：
反应试剂和反应条件:(a)NaH,MOMCl,THF,rt,6h,90％；(b)MeMgBr,THF,-78℃,2h,91.3％；(c)MnO2,THF,rt,16h,70；(d)various benzaldehydes,NaOH,EtOH-H2O(v:v,3:1),rt,8-10h；4N-HCl,MeOH,rt,1-2h,35-73％.
表1目标化合物5a1～5a26的收率和表征数据
化合物2a
1H-NMR(500MHz,CDCl3)δ(ppm):10.37(s,1H),6.33(s,1H),6.14(s,1H),5.26(s,2H),3.88(s,3H,-OCH3),3.86(s,3H,-OCH3),3.51(s,3H,-OCH3)
化合物3a
1H-NMR(500MHz,CDCl3)δ(ppm):6.40(d,J＝2.2Hz,1H),6.23(d,J＝2.2Hz,1H),5.24(s,2H),3.87(s,3H),3.83(s,3H),3.53(s,3H),1.54(d,J＝6.7Hz,3H)
化合物4a
1H-NMR(500MHz,CDCl3)δ(ppm):6.33(s,1H),6.16(s,1H),5.15(s,2H),3.81(s,3H),3.79(s,3H),3.47(s,3H),2.48(s,3H).
化合物5a1
1H-NMR(500MHz,CDCl3)δ(ppm):14.45(s,1H),7.85(s,1H),7.62(d,J＝8.7Hz,2H),6.98(d,J＝8.7Hz,2H),6.16(d,J＝2.3Hz,1H),6.01(d,J＝2.3Hz,1H),3.97(s,3H),3.90(d,J＝4.3Hz,3H),3.89(s,3H).13C-NMR(125MHz,CDCl3)δ(ppm):192.22,167.85,165.76,162.61,161.26,142.44,129.95×2,127.84,124.73,116.39×2,105.92,94.09,91.69,54.48×3.
化合物5a2
(E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(4-nitrophenyl)prop-2-en-1-one(2)Yellow solid.1H-NMR(500MHz,acetone-d6)δ(ppm):14.61(s,1H),8.21(d,J＝15.0Hz,1H),8.09(d,J＝15.2Hz,1H),7.91(s,2H),7.67(d,J＝24.2Hz,4H),6.45(d,J＝2.2Hz,1H),6.31(d,J＝2.4Hz,1H),4.22(s,3H),4.14(s,3H).13C-NMR(125MHz,CDCl3)δ(ppm):193.27,168.41,166.27,162.62,142.32,135.62,130.26×2,128.87×2,128.36,127.58,106.32,93.85,91.30,55.87,55.59.
化合物5a3
(E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-phenylprop-2-en-1-one(3)Yellow solid.1H-NMR(500MHz,CDCl3)δ(ppm):14.34(s,1H),7.94(s,1H),7.85(s,1H),7.66(d,J＝7.7Hz,2H),7.45(d,J＝6.3Hz,3H),6.16(d,J＝2.1Hz,1H),6.02(d,J＝2.1Hz,1H),3.97(s,3H),3.89(s,3H),13C-NMR(125MHz,CDCl3)δ(ppm):192.38,168.25,166.83,162.53,140.76,135.97,132.06,129.47,129.18×2,128.52,128.15,106.44,93.97,91.39,55.92,55.63.
化合物5a4
(E)-3-(3-bromophenyl)-1-(2-hydroxy-4,6-dimethoxyphenyl)prop-2-en-1-one(4)Light yellow solid.1H-NMR(500MHz,acetone-d6)δ(ppm):14.11(s,1H),7.84(s,1H),7.72(s,1H),7.68(s,1H),7.50(d,J＝7.0Hz,2H),7.28(d,J＝7.8Hz,1H),6.09(d,J＝2.3Hz,1H),5.96(d,J＝2.2Hz,1H).13C-NMR(125MHz,CDCl3)δ(ppm):192.22,168.45,166.43,162.61,140.28,137.55,132.70,131.02,130.35,128.97,126.97,122.99,106.32,93.42,91.35,55.94,55.61.
化合物5a5
(E)-3-(3,5-dimethoxyphenyl)-1-(2-hydroxy-4,6-dimethoxyphenyl)prop-2-en-1-one(5)light yellow solid.1H-NMR(500MHz,CDCl3)δ(ppm):14.32(s,1H),7.87(s,1H),7.75(s,1H),6.80(d,J＝2.2Hz,3H),6.55(s,1H),6.15(d,J＝2.3Hz,1H),6.00(d,J＝2.3Hz,1H),3.95(s,3H),3.88(s,9H),13C-NMR(125MHz,CDCl3)δ(ppm):190.79,168.24,166.18,161.47,152.66,148.56,137.17,129.74,128.90,124.15,119.72,113.67,106.08,93.65,91.16,61.56,55.88,55.84,55.60.
化合物5a6
(E)-3-(3-bromo-4-methoxyphenyl)-1-(2-hydroxy-4,6-dimethoxyphenyl)prop-2-en-1-one(6)yellow solid.1H-NMR(500MHz,acetone-d6)δ(ppm):14.36(s,1H),7.86(d,J＝2.0Hz,1H),7.80(s,1H),7.74(s,1H),7.54(d,J＝8.5Hz,1H),6.97(s,1H),6.15(d,J＝2.3Hz,1H),6.00(d,J＝2.3Hz,1H),3.98(s,3H),3.97(s,3H),3.88(s,3H).13C-NMR(125MHz,acetone-d6)δ(ppm):192.26,167.84,162.32,157.77,140.62,133.38×2,129.57,126.47,112.20×2,111.88,106.32,94.83,90.64,56.47,55.91,55.57.
化合物5a7
(E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(5-methylthiophen-2-yl)prop-2-en-1-one(7)yellow solid.1H-NMR(500MHz,CDCl3)δ(ppm):14.35(s,1H),7.85(s,1H),7.61(s,1H),7.12(d,J＝3.3Hz,1H),6.74(d,J＝2.9Hz,1H),6.10(d,J＝2.1Hz,1H),5.97(d,J＝2.1Hz,1H),3.97(s,3H),3.79(s,3H),2.52(s,3H).13C-NMR(125MHz,CDCl3)δ(ppm):191.94,168.38,166.12,163.37,143.97,139.65,135.69,131.67,126.77,125.40,106.26,94.10,90.95,55.78,55.56,15.87.
化合物5a8
(E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(thiophen-2-yl)prop-2-en-1-one(8)yellow solid.1H-NMR(500MHz,CDCl3)δ(ppm):14.41(s,1H),7.91(s,1H),7.74(s,1H),7.35(d,J＝14.6Hz,2H),7.04(d,J＝12.7Hz,1H),6.14(d,J＝2.3Hz,1H),5.99(d,J＝2.2Hz,1H),3.91(s,3H),3.84(s,3H).13C-NMR(125MHz,CDCl3)δ(ppm):191.85,168.21,167.06,162.62,141.07,134.80,131.66,128.27,128.21,126.54,108.28,93.83,91.27,56.19,55.59.
化合物5a9
(E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(2,4,6-trimethoxyphenyl)prop-2-en-1-one(9)yellow solid.Yellow solid,56.3％yield,m.p:146.3-149℃.1H-NMR(500MHz,CDCl3)δ(ppm):8.35(s,1H),8.31(s,1H),6.18(s,2H),6.14(d,J＝2.3Hz,1H),5.99(d,J＝2.3Hz,1H),3.95(s,6H),3.94(s,3H),3.90(s,3H),3.87(s,3H3).13C-NMR(125MHz,CDCl3)δ(ppm):194.07,168.28,165.48,162.94,162.45×2,161.64,134.35,126.75,106.98,106.68,93.73,91.03,90.51×2,55.74,55.56,55.51×2,55.34.
化合物5a10
(E)-3-(2,3-dimethoxyphenyl)-1-(2-hydroxy-4,6-dimethoxyphenyl)prop-2-en-1-one(10)yellow solid.1H-NMR(500MHz,CDCl3)δ(ppm):14.40(s,1H),8.10(s,1H),8.03(s,1H),7.30(d,J＝8.5Hz,1H),7.13(d,J＝15.5Hz,1H),6.99(d,J＝8.1Hz,1H),6.14(d,J＝2.3Hz,1H),6.00(d,J＝2.3Hz,1H),3.95(s,3H),3.94(s,6H),3.88(s,3H).13C-NMR(125MHz,CDCl3)δ(ppm):192.93,168.40,165.74,162.56,153.24,137.57,130.25,128.94,124.11,120.56,114.66,106.46,93.83,92.00,61.42,55.90,55.83,55.56.
化合物5a11
(E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(3-nitrophenyl)prop-2-en-1-one(11)yellow solid.1H-NMR(500MHz,CDCl3)δ(ppm):14.43(s,1H),8.74(s,1H),8.51(s,1H),8.26(d,J＝11.8Hz,1H),8.15(s,1H),8.03(d,J＝12.5Hz,1H),7.90(d,J＝17.4Hz,1H),6.43(d,J＝2.3.Hz,1H),6.28(d,J＝2.1Hz,1H),4.23(s,3H),4.13(s,3H),13C-NMR(125MHz,CDCl3)δ(ppm):192.90,168.55,166.74,162.31,138.80,134.13,130.57,129.91,124.10,122.20,93.91,91.45,56.03,55.68.
化合物5a12
(E)-3-(4-chlorophenyl)-1-(2-hydroxy-4,6-dimethoxyphenyl)prop-2-en-1-one(12)yellow solid.1H-NMR(500MHz,CDCl3)δ(ppm):14.24(s,1H),7.85(s,1H),7.73(s,1H),7.53(d,J＝8.1Hz,2H),7.37(d,J＝8.1Hz,2H),6.13(d,J＝2.2Hz,1H),5.95(d,J＝2.2Hz,1H),3.92(s,3H),3.84(s,3H).13C-NMR(125MHz,CDCl3)δ(ppm):192.91,168.89,166.39,162.50,141.45,135.18,134.14×2,129.47×2,129.16×2,128.17,106.62,94.10,55.85×2.
化合物5a13
(E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(pyridin-4-yl)prop-2-en-1-one(13)yellow solid.1H-NMR(500MHz,acetone-d6)δ(ppm):14.42(s,1H),7.86(d,J＝15.2Hz,1H),7.62(d,J＝15.2Hz,1H),7.26(s,1H),7.12(d,J＝3.1Hz,1H),6.73(s,1H),6.10(d,J＝2.3Hz,1H),5.95(d,J＝2.3Hz,1H),3.91(s,3H),3.83(s,3H),13C-NMR(125MHz,CDCl3)δ(ppm):191.95,168.52,166.11,162.99,144.20,139.65,135.69,132.34,126.44×2,125.18,94.08,91.33×2,55.81×2,15.48.
化合物5a14
(E)-3-(4-(diethylamino)phenyl)-1-(2-hydroxy-4,6-dimethoxyphenyl)prop-2-en-1-one(14)yellow solid.1H-NMR(500MHz,CDCl3)δ(ppm):14.72(s,1H),7.81(s,1H),7.76(s,1H),7.51(d,J＝4.6Hz,2H),6.66(d,J＝2.6Hz,2H),6.12(d,J＝2.1Hz,1H),6.12(d,J＝2.1Hz,1H),3.91(s,3H),3.83(s,3H),3.54–3.30(m,4H),1.32–1.14(m,6H),13C-NMR(125MHz,CDCl3)δ(ppm):192.43,168.29,162.38,130.69,111.33,106.51,93.85,91.14,55.95,55.49,44.52,12.60.
化合物5a15
(E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(5-methylpyridin-2-yl)prop-2-en-1-one(15)yellow solid.1H-NMR(500MHz,CDCl3)δ(ppm):14.39(s,1H),7.88(s,1H),7.64(s,1H),7.12(d,J＝3.1Hz,1H),6.73(d,J＝2.2Hz,1H),6.10(d,J＝2.1Hz,1H),3.91(s,3H),3.83(s,3H,),2.52(s,3H),13C-NMR(125MHz,CDCl3)δ(ppm):191.95,168.37,166.05,162.45,143.96,139.32,135.85,132.19,127.09,125.18,106.31,93.82,89.91,55.81,55.49,16.22.
化合物5a16
(E)-3-(4-hydroxy-2-methoxyphenyl)-1-(2-hydroxy-4,6-dimethoxyphenyl)prop-2-en-1-one(16)yellow solid.1H-NMR(500MHz,CDCl3)δ(ppm):14.63(s,1H),8.12(s,1H),7.95(s,1H),7.52(d,J＝8.2Hz,1H),6.52(d,J＝8.2Hz,1H),6.48(s,1H),6.15(d,J＝2.3Hz,1H),6.00(d,J＝2.3Hz,1H),5.80(s,1H),3.95(s,3H)3.89(s,3H),3.87(s,3H),13C-NMR(125MHz,DMSO-d6)δ(ppm):192.05,165.85,165.45,150.30,146.85,143.07,127.70,124.62,121.90,113.90,112.15,106.20×2,93.99,91.14×2,56.14,55.61.
化合物5a17
(E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(2,3,4-trimethoxyphenyl)prop-2-en-1-one(17)yellow solid.1H-NMR(500MHz,CDCl3)δ(ppm):14.24(s,1H,Ar-OH),7.86(d,J＝15.5Hz,1H),7.71(d,J＝13.6Hz,1H),7.53(s,1H),7.38(s,1H),6.14(d,J＝2.2Hz,1H),5.99(d,J＝2.2Hz,1H),3.91(s,6H),3.84(s,6H),13C-NMR(125MHz,CDCl3)δ(ppm):191.85,168.03,166.81,162.50,156.40,153.62,140.38,136.94,134.13×2,129.95,129.14,128.09,106.99,93.87,91.34,61.40,60.90,56.07,55.82.
化合物5a18
(E)-3-(2-bromo-5-chlorophenyl)-1-(2-hydroxy-4,6-dimethoxyphenyl)prop-2-en-1-one(18)yellow solid.1H-NMR(500MHz,CDCl3)δ(ppm):14.14(s,1H),8.00(s,1H),7.84(s,1H),7.66(d,J＝2.4Hz,1H),7.59(s,1H),7.24(dd,J＝8.5,2.5Hz,1H),6.16(d,J＝2.3Hz,1H),6.01(d,J＝2.3Hz,1H),3.97(s,3H),3.89(s,3H),13C-NMR(125MHz,CDCl3)δ(ppm):190.86,167.88,165.79,161.98,137.84,136.33,133.79,132.36,130.30,129.26,126.87,122.40,105.30,92.91,90.39,55.15,54.62.
化合物5a19
(E)-3-(3-bromo-4-hydroxyphenyl)-1-(2-hydroxy-4,6-dimethoxyphenyl)prop-2-en-1-one(19),yellow solid.1H-NMR(500MHz,acetone-d6)δ(ppm):14.32(s,1H,Ar-OH),9.49(s,1H),7.90(d,J＝2.0Hz,1H),7.88(s,1H),7.73(s,1H),7.64(dd,J＝8.4,2.0Hz,2H),7.12(s,1H),6.13(d,J＝2.3Hz,1H),6.11(d,J＝2.3Hz,1H),4.02(s,3H,-OCH3),3.89(s,3H,-OCH3),1H-NMR(500MHz,acetone-d6)δ(ppm):193.19,169.10,167.46,163.74,156.82,141.73,134.29×2,129.90,126.76,117.73,111.06,106.92,94.76,91.84,56.55,56.08.ESI-MS m/z:381.02(M+H)+,calcd forC17H15BrO5:379.20
化合物5a20
(E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-one(20),yellow solid.1H-NMR(500MHz,CDCl3)δ(ppm):8.34(s,1H),8.31(s,1H),6.18(s,2H),6.15(d,J＝2.3Hz,1H),6.00(d,J＝2.3Hz,1H),3.95(s,6H,-OCH3),3.95(s,3H,-OCH3),3.91(s,3H),3.87(s,3H,-OCH3),13C-NMR(125MHz,CDCl3)δ(ppm):192.92,168.48,166.42,162.53,140.76,135.97,134.19,132.06,129.47,129.18,128.52,128.15,106.39,93.93,91.39,55.92,55.63.
化合物5a21
(E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(3-hydroxy-4-methoxyphenyl)prop-2-en-1-one(21)light Yellow solid.1H-NMR(500MHz,CDCl3)δ(ppm):14.36(s,1H,Ar-OH),7.86(s,1H),7.80(s,1H),7.74(s,1H),7.55(d,J＝2.0Hz,1H),6.97(s,1H),6.96(d,J＝8.5Hz,1H),6.15(d,J＝2.3Hz,1H),6.00(d,J＝2.3Hz,1H),3.98(s,3H,-OCH3),3.97(s,3H,-OCH3),3.88(s,3H,-OCH3),13C-NMR(125MHz,CDCl3)δ(ppm):193.98,162.50,158.83,156.43,142.18,137.26,132.93,131.08,130.35,130.28,126.79,123.02,,94.84,93.59,92.52,56.31,55.95,55.54.
化合物5a22
(E)-3-(2-bromo-5-fluorophenyl)-1-(2-hydroxy-4,6-dimethoxyphenyl)prop-2-en-1-one(22)yellow solid.1H-NMR(500MHz,CDCl3)δ(ppm):10.29(s,1H),7.80(s,1H),6.71(d,J＝8.6Hz,1H),6.63(s,1H),6.50(d,J＝2.1Hz,1H),6.47(d,J＝2.1Hz,1H),3.90(s,3H,-OCH3),3.88(s,3H,-OCH3),13C-NMR(125MHz,CDCl3)δ(ppm):190.20,167.52,165.79,161.51,137.84,136.33,133.44 132.69,130.41,129.56,126.71,122.40,105.30,92.91,90.39,54.97,54.49.
化合物5a23
(E)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-(2-hydroxy-4,6-dimethoxyphenyl)prop-2-en-1-one(23)yellow solid.1H-NMR(500MHz,CDCl3)δ(ppm):14.43(s,1H,7.79(s,1H),7.76(s,1H),7.18(d,J＝1.9Hz,1H),7.15(d,J＝1.9Hz,1H),6.93(s,1H),6.14(d,J＝2.3Hz,1H),6.00(d,J＝2.3Hz,1H),4.33(t,J＝4.0Hz,4H),3.95(s,3H,-OCH3),3.95(s,3H,-OCH3)13C-NMR(125MHz,CDCl3)δ(ppm):192.54,168.21,166.13,162.49,145.63,144.21,142.28,130.24,125.78,122.28,116.83,106.32,93.96,91.07,64.69,64.26,55.86,55.62.
化合物5a24
(E)-3-(3-chlorophenyl)-1-(2-hydroxy-4,6-dimethoxyphenyl)prop-2-en-1-one.Yellow solid,54.87％yield,m.p:92.6–94.2℃.1H NMR(500MHz,CDCl3)δ(ppm):14.12(s,1H),7.80(d,J＝15.6Hz,1H),7.61(d,J＝15.6Hz,1H),7.50(s,1H),7.28(s,1H),7.39(d,J＝6.63Hz,1H),7.19(s,1H),6.04(d,J＝2.30Hz,1H),5.90(d,J＝2.29Hz,1H),3.85(s,3H),3.77(s,3H).13CNMR(150MHz,CDCl3)δ(ppm):192.26,168.44,166.46,162.51,140.42,137.48,134.84,130.09,128.90,128.25,127.86,126.59,106.30,93.84,91.34,55.93,55.61.ESI-MS m/z:319.10(M+H)+,calcd for C17H15ClO4:318.01
化合物5a25
(E)-3-(3-fluorophenyl)-1-(2-hydroxy-4,6-dimethoxyphenyl)prop-2-en-1-one.Yellow solid,70.59％yield,m.p:104.1–105.8℃.1H NMR(500MHz,CDCl3)δ(ppm):14.26(s,1H),7.92(d,J＝15.59Hz,1H),7.76(d,J＝15.59Hz,1H),7.41(s,1H),7.40(s,1H),7.34(d,J＝11.40Hz,1H),7.13(ddd,J＝2.55,5.23,8.44Hz,1H),6.16(d,J＝2.35Hz,1H),6.02(d,J＝2.33Hz,1H),3.97(s,3H),3.89(s,3H).13C NMR(150MHz,CDCl3)δ(ppm):192.18,168.49,166.56,162.53,140.05,136.49,131.35,130.13,129.45,129.39,126.26,124.57,106.32,93.92,91.40,55.89,55.61.ESI-MS m/z:303.10(M+H)+,calcd forC17H15FO4:302.10
化合物5a26
(E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(3-(trifluoromethyl)phenyl)prop-2-en-1-one.Yellow solid,65.83％yield,m.p:118.2–120.0℃.1H NMR(500MHz,CDCl3)δ(ppm):14.12(s,1H),7.79(m,1H),7.63(m,1H),7.29(d,J＝7.87Hz,1H),7.28(s,J＝4.78Hz,1H),7.20(s,1H),7.00(m,1H),6.03(d,J＝2.21Hz,1H),5.89(d,J＝2.20Hz,1H),3.85(s,3H),3.76(s,3H).13C NMR(150MHz,CDCl3)δ(ppm):192.32,168.43,166.46,162.58,140.62,137.91,134.84,130.34,128.86,124.45,116.87,114.31,114.14,106.33,93.88,91.34,55.90,55.59.ESI-MS m/z:353.10(M+H)+,calcd for C18H15F3O4:352.10.
测试例1化合物抑制肝癌细胞的增殖
在本测试例中，以人肝癌细胞株Huh-7d、HepG2和SMMC7721为例说明我们所合成获得的化合物在抑制肝脏肿瘤细胞增殖方面的效用，但应理解的是，虽然仅以人肝癌细胞株Huh-7d、HepG2和SMMC7721为例说明其用于制备抗肝脏肿瘤药物的用途，但本发明所称的“人肝脏肿瘤”细胞包括但不限于例如人肝癌细胞株Huh-7d、HepG2和SMMC7721等。实验证明，5a04对于多种人肝脏肿瘤细胞，包括但不限于例如人肝癌细胞株Huh-7d、HepG2和SMMC7721等，均有显著抑制肿瘤细胞增殖的效用。将人肝癌细胞株Huh-7d、HepG2和SMMC7721细胞分别接种于96孔板中，接种密度为5000个细胞/160μL/孔，等细胞6小时贴壁后，加入40μL含有相应浓度化合物(查尔酮衍生物)的培养基或者等体积的含0.1％DMSO的培养基。继续孵育48h，之后再加入MTT(5mg/ml)孵育4h，终止培养，小心吸弃孔内培养上清液。每孔加100ul DMSO，振荡10分钟，使结晶物充分融解。选择490nm波长，在酶联免疫监测仪上测定各孔光吸收值，记录结果，计算半数抑制浓度IC50值，结果见下表：
Table 1.IC50(μM)values determined by MTT assaya.
aIC50值表示抑制一半肿瘤细胞活力所需要的药物浓度，本次实验的数据来源于3次独立重复实验的结果，且数据的处理方式为标准方差，本实验的药物处理时间为48小时。
测试例2化合物对体外培养Huh-7d细胞TRF2表达的影响
当细胞贴壁后，加入化合物处理48h。弃去培养基，用预冷的PBS清洗一遍，吸掉PBS，消化、离心收集细胞，每5×105个细胞加入100μL的1×细胞裂解液，沸水中煮10min使蛋白变性，样品保存在-20℃，避免反复冻融。将配制好的凝胶安装在电泳槽中，随后上样进行电泳分离和转膜。转膜结束后，用含5％脱脂奶粉的封闭液进行封闭，室温摇床封闭90min。封闭结束后，用TBST洗净奶粉，加入预先配好的一抗，4℃摇床孵育过夜。回收并清洗一抗，TBST洗7min×3次，加入二抗(按一抗的说明配置相关二抗，稀释比例为l:2000)，室温摇床孵育lh，清洗二抗，TBST7min×3次，随后在ECL显影液中进行显影。结果如图1所示。
图1的结果表明，采用上述Western-blot法检测合成化合物对HuH-7细胞中TRF2的表达。结果表明，大部分化合物都能降低HuH-7细胞中TRF2的表达水平，特别是化合物5a04可显著抑制HuH-7细胞中TRF2的表达水平，说明5a04是TRF2的高效抑制剂。
进一步我们发现化合物在1μM、2μM和4μM三个浓度下5a04可以剂量依赖性的降低TRF2、RPA和Rad51蛋白的表达，并计量依赖性的上调r-H2AX蛋白的表达量，具体结果见图2所示。

Claims (3)

1.一种查尔酮类似物在制备抗肝癌药物中的应用，其特征在于，所述的查尔酮类似物通过抑制TRF2的表达来治疗肝癌；
所述的查尔酮类似物的结构式如下：
。
2.根据权利要求1所述的查尔酮类似物在制备抗肝癌药物中的应用，其特征在于，所述抗肝癌药物包括有效成分和药用辅料，所述的有效成分包括权利要求1所述的查尔酮类似物。
3.根据权利要求1所述的查尔酮类似物在制备抗肝癌药物中的应用，其特征在于，所述的抗肝癌药物的药物制剂为注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、软膏剂、控释剂、缓释剂或纳米制剂的任一种。
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