CN115572244B - 2’-芳基查尔酮类化合物及其制备方法和在制药中的用途 - Google Patents
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Abstract
本发明属合成药物化学技术领域，涉及如下通式结构的具有显著抗肿瘤活性的新型2’‑芳基查尔酮类HDAC/Tubulin双功能抑制剂及其在抗肿瘤药物研发中的应用。本发明还包括所述化合物、其药学盐及其复方药物在制备预防或治疗与肿瘤相关疾病的药物中的应用。本发明的化合物或其在药学上可接受的盐通过抑制组蛋白去乙酰化酶和微管蛋白聚集，抑制肿瘤细胞增殖的调控机制，在体外、体内有效抑制肿瘤细胞的生长，可应用于制备预防或治疗与肿瘤相关疾病的药物。所述与肿瘤相关疾病包括良、恶性肿瘤以及肿瘤引起的其他疾病。
Description
技术领域
本发明属合成药物化学技术领域，涉及2’-芳基查尔酮类化合物及其制备方法和在制药中的用途，具体涉及2’-芳基查尔酮类HDAC/Tubulin双功能抑制剂及制备方法和在制药中的用途，尤其涉及具有显著抗肿瘤活性的新型2’-芳基查尔酮类HDAC/Tubulin双功能抑制剂、制备方法、体内外抗肿瘤活性以及该类化合物及其可接受的药学盐或以其为成分之一的复方药物在制备预防和***相关疾病的药物中的应用。
背景技术
据世界卫生组织国际癌症研究机构IARC于2020年12月发表的全球癌症数据报告中的统计数据显示，全球2020年新发癌症病例高达1929万，同期死亡病例高达996万。其中我国新发癌症病例为457万例，癌症死亡病例为300万例，均远超世界其他国家，位居全球第一。由于人口老龄化、环境恶化、吸烟、不健康饮食、肥胖等因素，预测到2040年，全球癌症负担将增加50％，届时每年新增病例将达到近3000万例。相关技术领域需要采取有效的医疗措施来解决癌症对人类健康的威胁。
微管(microtubule)是构成细胞骨架的主要成分，是细胞有丝***所必须，在保持细胞形态、细胞运动、细胞***与增殖等方面也发挥着不可或缺的作用。恶性肿瘤细胞有丝***与转移极其旺盛，因此以微管为靶标，打破微管蛋白聚合与解聚的动态平衡，即可有选择性地抑制肿瘤细胞的***增殖(Science 2013,339,587-590)。尽管有关作用于秋水仙碱的微管蛋白聚集抑制剂的研究，尤其是针对康普立停(Combretastatin A-4)的结构改造研究已经取得了一些重大进展，如康普立停的磷酸酯二钠盐(CA-4P)与BNC105的磷酸酯二钠盐(BNC105P)已分别进入I期和II期临床试验，但这些药物临床效果欠佳，具有一定毒副作用，如恶心、呕吐、视觉障碍和头痛，此外在延长患者生存期等方面也存在不足，截止目前还没有一个该类药物被批准上市(J.Med.Chem.2016,59,8685-8711)。因此，开发抗肿瘤活性更好、选择性更高、毒副作用更小的微管蛋白聚集抑制剂是未来这类药物研发的主要方向。
作为调控细胞表观遗传的关键酶，组蛋白去乙酰化酶(HDACs)在多个肿瘤细胞系内高表达，它与肿瘤细胞的生长、增殖与侵袭高度相关，被认为是肿瘤治疗最有前途的靶标之一(Nat.Rev.Drug Discovery 2012,11,384-400)。上市的pan-HDAC抑制剂主要用于血液系肿瘤的治疗，对实体瘤的治疗效果不佳，因此HDAC抑制往往与其他抗肿瘤药物联合使用，尽管联合用药的模式能够产生协同增效的抗肿瘤作用，但又会引起复杂不可预测的药代动力学、患者的依从性变差甚至于产生药物-药物相互作用。而“一药多靶”的药物模式能够有效地克服这些缺点，是传统“单靶单药”与联合用药治疗较为理想的替代治疗模式(J.Med.Chem.2005,48,6523-6543)。大量的研究报道已经证明，基于HDAC双靶点药物的设计是合理可行的，对于提高肿瘤治疗效果也是明显的。
临床前研究表明，微管蛋白聚集抑制剂(vincristine)与HDAC抑制剂SAHA在联合治疗白血病时能够产生协同增效的抗肿瘤效果。在MOLT-4裸鼠移植瘤模型中，vincristine与SAHA联合给药组的抑瘤率明显高于两个单药组，并且联合给药组也大大延长了小鼠生存期(J.Hematol.Oncol.2017,8,82)。此外也有机理研究表明，微管蛋白与HDAC在肿瘤的发生发展过程中相互关联、相互协同。在早期的研究中，HDAC主要催化位于细胞核内染色体上的组蛋白赖氨酸残基的去乙酰化，但事实上，HDAC的催化底物也广泛存在于细胞质，如α-tubulin与HSP90。肿瘤细胞中过量表达的HDAC能够使细胞质中α-tubulin过度去乙酰化，从而加速微管的聚集与解聚，并促进肿瘤细胞的迁移与侵袭。而微管自身也具聚集和解聚的动力学特性，这种微管与HDAC互相协同的作用过程在***旺盛的恶性肿瘤细胞中表现得非常明显(J.Med.Chem.2020,63,23-39)。这些机制研究以及临床前研究的数据结果为HDAC/Tubulin双靶点抑制剂的设计提供了合理的依据。
基于现有技术的现状与研究基础，本申请的发明人拟提供2’-芳基查尔酮类化合物及其制备方法和在制药中的用途，具体涉及2’-芳基查尔酮类HDAC/Tubulin双功能抑制剂及制备方法和在制药中的用途。
发明内容
本发明的目的是基于现有技术的现状与研究基础，提供2’-芳基查尔酮类化合物及其制备方法和在制药中的用途，具体涉及2’-芳基查尔酮类HDAC/Tubulin双功能抑制剂及制备方法和在制药中的用途。尤其是提供新型2’-芳基查尔酮类HDAC/Tubulin双功能抑制剂及其制备方法以及该类化合物及其药学盐或以其为成分的复方药物在制备预防和***相关疾病的药物中的应用。
本申请基于Tubulin聚集抑制剂和HDAC抑制剂的结构特点，运用融合药效团的药物设计原理，设计并构建了2’-芳基查尔酮类HDAC/Tubulin双靶标分子化合物库，经过分子水平与细胞水平的抗肿瘤活性测试后，从中筛选出活性较好的先导化合物，最终获得了结构新颖、具有潜在药物开发前景的候选化合物供进一步研究。
具体的，本发明提供了下述通式结构的新型2’-芳基查尔酮类HDAC/Tubulin双功能抑制剂或其药学盐，
其中，R1与R2取自氢原子、烷基、取代烷基、烷氧基、卤素原子、氨基、羟基、酰氧基、甲氧甲酰基、烯丙氧基、炔丙氧基、磺酰氧基、烷氨基、酰氨基、磺酰氨基或者2-3个上述相同或不同基团的组合；X取自碳、氮、氧、酯基、酰胺基；L取自其中n取自0、1、2、3、4、5、6、7；L也可取自 等脂环与芳杂环；R3取自/> 优选化合物为：
本发明中所述的“药学上可接受的盐”，具体地可列举为与苹果酸、乳酸、樟脑磺酸、枸橼酸、富马酸、草酸等有机酸，以及磷酸、氢卤酸、硫酸、硝酸等无机酸形成的盐。
本发明的另一个目的是提供上述化合物或这些化合物在药学上可接受的盐以及包含该化合物或其盐的组合物用于制备预防或治疗与肿瘤相关疾病的药物中的应用。
所述的与肿瘤相关疾病具体可列举为甲状腺癌、淋巴瘤、***癌、肾癌、膀胱癌、脑胶质瘤、鼻咽癌，神经内分泌癌、头颈部鳞状细胞癌、***、卵巢癌、乳腺癌、结直肠癌、胰腺癌、食管癌、骨肉瘤、间质肉瘤、绒癌、恶性***、恶性畸胎瘤、胃癌、肺癌、肝癌、黑色素瘤、未分化癌以及良性肿瘤等，但不受限于此。
本发明提供并证明了具有显著抗肿瘤活性的新型2’-芳基查尔酮类HDAC/Tubulin双功能抑制剂或其在药学上可接受的盐，通过抑制HDAC与微管蛋白聚集从而抑制肿瘤细胞生长的调控机制及其在体外、体内的抗肿瘤实验中对肿瘤细胞具有显著的增殖抑制作用和血管生成抑制作用。
附图说明
图1.化合物9a体外抑制微管自组装实验——吸光度-时间曲线。
图2.化合物9a对肿瘤细胞周期的影响。
图3.化合物9a对肿瘤细胞周期的影响。
图4.化合物9a对肿瘤细胞周期相关蛋白表达的影响。
图5.化合物9a诱导细胞凋亡测试。
图6.化合物9a对凋亡相关蛋白表达的影响。
图7.化合物9a对肿瘤细胞集落生成的抑制。
具体实施方式
下面结合实施例进一步说明本发明。这些实施例只是用于进一步说明本发明，并不改变本发明的保护范围。本发明目标化合物的制备方法可以进一步用代表性化合物制备过程体现如下：
实施例1目标化合物(5a-5c)的合成
1.1(E)-1-(2-溴苯基)-3-(3-羟基-4-甲氧基)苯基-2-丙烯-1-酮(2)的合成
合成方法参考文献报道，具体操作如下：在100mL茄形瓶中加入3-羟基-4-甲氧基苯甲醛(2.29g,15mmol)，用20mL乙醇溶解。后加入NaOH水溶液(6M,6mL,36mmol)与2-溴苯乙酮(3.00g,15mmol)，室温下搅拌24h。反应完成后，加水，并加入10％稀盐酸调节pH至中性，用乙酸乙酯萃取三次，合并有机相用饱和食盐水洗一次，无水硫酸钠干燥。旋蒸浓缩后硅胶柱层析分离(PE/EA3:1)，得黄色油状液体(2)4.92g，收率98％。1H NMR(400MHz,CDCl3):δ7.45(d,J＝7.5Hz,1H),7.25-7.05(m,4H),7.00(s,1H),6.87(d,J＝8.3Hz,1H),6.77(d,1H),6.66(d,J＝8.2Hz,1H),5.65(s,1H),3.74(s,3H).ESI-MS(m/z):334.26(M+H+).
1.2(E)-1-(2-(3-氟苯基)苯基)-3-(3-羟基-4-甲氧基苯基)-2-丙烯-1-酮(3)的合成
于50mL Schlenk管中依次加入3-氟苯硼酸(1.09g,7.8mmol)、[1,1-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(0.29g,0.36mmol)和原料2(2.00g,6mmol)，抽换氮气后，注入二氧六环(10mL)与碳酸钾水溶液(2M,10mL)，在氮气保护下加热回流反应12小时。反应完全后冷却，加水淬灭，用乙酸乙酯萃取三次，合并有机相后用饱和食盐水洗一次，无水硫酸钠干燥。旋蒸浓缩后硅胶柱层析分离(PE/EA 3:1)，旋干得到黄色油状液体1.98g，收率95％。1H NMR(400MHz,CDCl3):δ7.63-7.51(m,2H),7.45(d,J＝8.0Hz,2H),7.27(s,2H),7.11(q,J＝11.1,8.3Hz,2H),6.99(d,J＝10.9Hz,1H),6.91-6.81(m,2H),6.80-6.72(m,1H),6.48(dd,J＝15.9,4.8Hz,1H),5.62(s,1H),3.89(s,3H).ESI-MS(m/z):349.3(M+H+).
1.3化合物(4a-c)的合成
合成方法参考文献报道，具体操作如下：于25mL茄型瓶中加入化合物3(150mg,0.43mmol)、碳酸钾(179mg,1.29mmol)、溴代烷基酸乙酯(0.86mmol)与乙腈(3mL)，加热回流条件下过夜反应。反应结束后冷却，加水，用乙酸乙酯萃取三次，合并有机相后用饱和食盐水洗一次，无水硫酸钠干燥。旋蒸浓缩后硅胶柱层析分离(PE/EA 3:1)，旋干得到相应中间体产物。
1.3.1(E)-4-[5-(3-(2-(3-氟苯基)苯基)-3-氧代丙烯基)-2-甲氧基苯氧基]丁酸乙酯(4a)的合成
黄色油状液体(4a)150mg，收率75％。1H NMR(400MHz,CDCl3):δ7.70-7.39(m,4H),7.38-7.27(m,2H),7.17-7.05(m,2H),7.04-6.86(m,2H),6.76(m,2H),6.53-6.43(m,1H),4.19-4.05(m,2H),4.02-3.92(m,2H),3.86(s,3H),2.60-2.42(m,2H),2.26-2.00(m,2H),1.24(m,3H).13C NMR(150MHz,CDCl3):δ195.9,190.9,173.2,163.5,161.9,151.8,148.4,144.5,142.9,139.9,139.6,130.7,130.1,128.9,127.9,127.4,125.2,124.7,123.5,115.9,114.5,111.2,67.8,60.5,55.9,30.7,24.4,14.2.ESI-MS(m/z):463.2(M+H+).ESI-HRMS(m/z):calcd for C28H28FO5[M+H+],463.1915；found,463.1915.
1.3.2(E)-5-[5-(3-(2-(3-氟苯基)苯基)-3-氧代丙烯基)-2-甲氧基苯氧基]戊酸乙酯(4b)的合成
黄色油状液体(4b)156mg，收率77％。1H NMR(400MHz,CDCl3):δ7.70-7.38(m,4H),7.28(m,2H),7.13(d,J＝8.5Hz,2H),6.95(m,2H),6.76(m,2H),6.46(m,1H),4.12(m,2H),3.94(q,J＝6.1Hz,2H),3.85(s,3H),2.40(t,J＝7.2Hz,2H),1.96-1.71(m,4H),1.26(t,J＝7.1Hz,3H).13C NMR(150MHz,CDCl3):δ195.9,191.0,173.5,163.5,161.9,151.8,148.5,144.5,142.9,139.9,139.6,130.7,130.1,128.9,127.9,127.4,125.2,124.7,123.3,115.9,114.5,111.1,68.4,60.4,55.9,33.9,28.5,21.5,14.2.ESI-MS(m/z):477.2(M+H+).ESI-HRMS(m/z):calcd for C29H30FO5[M+H+],477.2072；found,477.2074.
1.3.2(E)-6-[5-(3-(2-(3-氟苯基)苯基)-3-氧代丙烯基)-2-甲氧基苯氧基]己酸乙酯(4c)的合成
黄色油状液体(4c)170mg，收率80％。1H NMR(400MHz,CDCl3):δ7.70-7.42(m,4H),7.40-7.24(m,2H),7.14(m,2H),6.95(m,2H),6.86-6.72(m,2H),6.60-6.39(m,1H),4.24-4.05(m,2H),4.04-3.83(m,5H),2.36(m,2H),1.96-1.46(m,6H),1.25(t,J＝6.9Hz,3H).13CNMR(150MHz,CDCl3):δ195.9,191.0,173.7,163.5,161.9,151.8,148.6,144.5,142.9,139.9,139.6,130.7,130.1,128.9,127.9,127.4,125.2,124.7,123.3,115.9,114.5,111.1,68.6,60.3,55.9,34.2,28.8,25.6,24.7,14.3.ESI-MS(m/z):491.2(M+H+).ESI-HRMS(m/z):calcd for C30H32FO5[M+H+],491.2228；found,491.2233.
1.4化合物(5a-c)的合成
于25mL茄型瓶中加入原料(0.14mmol)、一水合氢氧化锂(18mg,0.43mmol)、四氢呋喃(1mL)与水(0.5mL)。加热回流反应，待原料完全消失后，加水，用乙酸调节pH调节至6，用乙酸乙酯萃取三次，合并有机相后用饱和食盐水洗一次，无水硫酸钠干燥。过滤，旋蒸浓缩后，加入DMF(1mL)、HOBt(18mg,0.13mmol)和EDCI(25mg,0.13mmol)，室温下搅拌6小时，后加入盐酸羟胺(45mg,0.65mmol)和三乙胺(66mg,0.65mmol)，室温下继续搅拌反应2小时。待原料完全消失后，加水，用乙酸乙酯萃取三次，合并有机相后用饱和食盐水洗一次，无水硫酸钠干燥。过滤，旋蒸浓缩后硅胶柱层析分离(CH2Cl2/MeOH 30:1)。
1.4.1(E)-4-[5-(3-(2-(3-氟苯基)苯基)-3-氧代丙烯基)-2-甲氧基苯氧基]-N-羟基丁酰胺(5a)的合成
黄色油状液体(5a)26mg，收率53％。1H NMR(400MHz,DMSO-d6):δ10.48(s,1H),8.77(s,1H),7.65-7.53(m,4H),7.46-7.40(m,1H),7.26(d,J＝16.6Hz,1H),7.19-7.13(m,4H),7.00-6.94(m,1H),6.78(d,J＝16.6Hz,1H),3.98-3.94(m,2H),3.80(s,2H),2.18-2.12(m,2H),1.98-1.91(m,2H).13C NMR(150MHz,DMSO-d6):δ195.0,168.4,162.6,161.00,151.3,147.9,144.8,142.6,139.5,138.7,130.4,130.3,130.0,128.2,127.8,126.7,125.0,124.3,123.3,115.4,115.3,114.2,114.0,111.6,111.3,67.5,55.5,28.5,24.6.ESI-MS(m/z):450.2(M+H+).ESI-HRMS(m/z):calcd for C26H25FNO5[M+H+],450.1711；found,450.1710.
1.4.2(E)-5-[5-(3-(2-(3-氟苯基)苯基)-3-氧代丙烯基)-2-甲氧基苯氧基]-N-羟基戊酰胺(5b)的合成
黄色油状液体化合物(5b)12mg，收率23％。1H NMR(400MHz,DMSO-d6):δ10.40(s,1H),8.75(s,1H),7.65-7.52(m,4H),7.44-7.36(m,1H),7.25(d,J＝14.9Hz,1H),7.20(m,5H),7.15-7.11(m,4H),6.94(d,J＝7.5Hz,1H),6.76(d,J＝15.0Hz,1H),3.94-3.91(m,2H),3.79(s,3H),2.02(m,2H),1.71-1.62(m,4H).13C NMR(151MHz,DMSO-d6):δ195.1,168.8,162.6,161.0,151.3,148.1,144.8,142.6,139.5,138.7,130.5,130.2,130.1,128.2,127.8,126.7,125.0,124.3,123.2,115.4,114.1,111.3,67.6,55.4,31.8,28.0,21.7.ESI-MS(m/z):464.2(M+H+).ESI-HRMS(m/z):calcd for C27H27FNO5[M+H+],464.1868；found,464.1864.
1.4.3(E)-6-[5-(3-(2-(3-氟苯基)苯基)-3-氧代丙烯基)-2-甲氧基苯氧基]-N-羟基己酰胺(5c)的合成
黄色油状液体化合物(5c)20mg，收率27％。1H NMR(400MHz,DMSO-d6):δ10.38(s,1H),8.71(s,1H),7.64-7.52(m,4H),7.45-7.37(m,1H),7.26(d,J＝15.6Hz,1H),7.22-7.18(m,1H),7.15-7.11(m,4H),6.95(t,J＝7.9Hz,1H),6.77(d,J＝15.3Hz,1H),3.96-3.90(m,2H),3.79(s,3H),2.03-1.97(m,2H),1.74-1.69(m,2H),1.60-1.55(m,2H),1.41-1.37(m,2H).13C NMR(150MHz,DMSO-d6):δ195.0,168.9,162.6,161.0,151.7,148.1,144.8,142.6,139.5,138.7,130.4,130.2,130.0,128.2,127.8,126.7,125.0,124.3,123.2,115.4,114.1,111.5,111.0,67.9,55.4,32.1,28.3,25.0,24.7.ESI-MS(m/z):478.2(M+H+).ESI-HRMS(m/z):calcd for C28H29FNO5[M+H+],478.2024；found,478.2025.。
实施例2目标化合物(9a-9d)的合成
合成方法参考文献报道，具体操作如下：于50mL Schlenk管中依次加入芳基硼酸(0.91g,6.5mmol)、[1,1-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(0.21g,0.05mmol)和2-溴苯乙酮(1.0g,5.0mmol)，抽换氮气后，注入二氧六环(10mL)与碳酸钾水溶液(2M,10mL)，在氮气保护下加热回流反应12小时。反应完全后冷却，加水淬灭，用乙酸乙酯萃取三次，合并有机相后用饱和食盐水洗一次，无水硫酸钠干燥。旋蒸浓缩后硅胶柱层析分离(PE/EA 10:1)，旋干得到相应中间体。
2.1.1 2-(3-氟苯基)苯乙酮(6a)的合成
黄色油状液体(6a)，收率96％。1H NMR(400MHz,CDCl3):δ7.56-7.55(m,1H),7.52-7.51(m,1H),7.46-7.43(m,1H),7.38-7.37(m,2H),7.09(m,3H),2.08(s,3H).ESI-MS(m/z):215.34(M+H+).
2.1.2 2-(4-氟苯基)苯乙酮(6b)的合成
黄色油状液体(6b)，收率92％。1H NMR(400MHz,CDCl3):δ7.56(d,J＝7.3Hz,1H),7.51(d,J＝7.3Hz,1H),7.45-7.41(m,1H),7.36(d,J＝7.4Hz,1H),7.31-7.27(m,2H),7.15-7.05(m,2H),2.06(s,3H).ESI-MS(m/z):215.24(M+H+).2.2中间体(7a-d)的合成
于100mL茄形瓶中加入芳基甲醛(0.47g,2.2mmol)与氢氧化钾(0.63g,12mmol)，用8mL乙醇溶解。后加入芳基乙酮(2mmol)，室温下搅拌15分钟。反应完全后，加水，用乙酸乙酯萃取三次，合并有机相用饱和食盐水洗一次，无水硫酸钠干燥。旋蒸浓缩后硅胶柱层析分离(PE/EA 10:1)，旋干得到相应中间体。
2.2.1(E)-3-(3-溴-4-甲氧基苯基)-1-(2-(3-氟苯基)苯基)丙烯-1-酮(7a)的合成
白色固体(7a)，收率79％。mp 66-68℃.1H NMR(400MHz,CDCl3):δ7.64(d,J＝7.7Hz,1H),7.56(d,J＝6.7Hz,1H),7.47(d,J＝7.8Hz,3H),7.34-7.31(m,1H),7.24-7.21(m,2H),7.15-7.09(m,2H),7.00(d,J＝9.1Hz,1H),6.81(t,J＝8.8Hz,1H),6.48(d,J＝15.5Hz,1H),3.90(s,3H).13C NMR(150MHz,CDCl3):δ195.6,163.5,161.9,157.5,142.8,142.4,139.7,139.6,132.8,130.8,130.1,129.1,128.9,128.6,127.9,125.7,125.1,116.1,115.9,114.8,114.6,112.2,111.8,56.4.ESI-MS(m/z):411.0(M+H+).ESI-HRMS(m/z):calcd for C22H17BrFO2[M+H+],411.0390；found,411.0395.
2.2.2(E)-3-(3-溴-4-甲氧基苯基)-1-(2-(4-氟苯基)苯基)丙烯-1-酮(7b)的合成
淡黄色固体(7b)，收率76％。mp 68-70℃.1H NMR(400MHz,CDCl3):δ7.63(d,J＝7.0Hz,1H),7.56(d,J＝6.9Hz,1H),7.49-7.43(m,3H),7.35-7.33(m,2H),7.24(d,J＝16.5Hz,2H),7.09-7.04(m,2H),6.84-6.81(m,1H),6.46(d,J＝16.4Hz,1H),3.90(s,3H).13CNMR(150MHz,CDCl3):δ195.9,163.3,161.7,157.6,142.4,139.8,139.7,136.5,132.8,130.8,130.7,130.2,129.0,128.8,128.6,127.6,125.7,115.6,115.5,112.2,111.8,56.4.ESI-MS(m/z):411.2(M+H+).ESI-HRMS(m/z):calcd for C22H17BrFO2[M+H+],411.0390；found,411.0392.
2.2.3(E)-3-(3-溴苯基)-1-(2-(3-氟苯基)苯基)丙烯-1-酮(7c)的合成
黄色油状液体(7c)，收率66％。1H NMR(400MHz,CDCl3):δ7.66(d,J＝7.4Hz,1H),7.58(d,J＝7.3Hz,1H),7.51(d,J＝7.4Hz,1H),7.46(d,J＝8.0Hz,2H),7.35(d,J＝11.5Hz,2H),7.28(d,J＝15.2Hz,1H),7.18(s,2H),7.15-7.09(m,2H),7.03(m,1H),6.55(d,J＝15.2Hz,1H).13C NMR(150MHz,CDCl3):δ195.4,163.6,161.9,142.6,142.1,139.7,139.4,136.7,133.1,131.1,130.8,130.3,130.2,130.2,130.1,128.9,127.9,127.7,126.7,125.1,122.9,116.1,115.9,114.9,114.7.ESI-MS(m/z):381.7(M+H+).ESI-HRMS(m/z):calcd for C21H15BrFO[M+H+],381.0285；found,381.0290.
2.2.4(E)-3-(4-溴苯基)-1-(2-(3-氟苯基)苯基)丙烯-1-酮(7d)的合成
淡黄色固体(7d)，收率56％。mp 78-80℃.1H NMR(400MHz,CDCl3):δ7.49(d,J＝7.3Hz,1H),7.43(d,J＝7.4Hz,1H),7.36-7.25(m,4H),7.16-7.10(m,2H),6.97(m,4H),6.87-6.83(m,1H),6.41(d,J＝16.5Hz,1H).13C NMR(150MHz,CDCl3):δ195.6,163.5,161.9,142.6,142.5,139.6,139.5,133.4,132.1,130.9,130.2,130.1,129.5,128.9,127.9,127.0,125.1,124.7,116.1,115.9,114.8,114.7.ESI-MS(m/z):381.2(M+H+).ESI-HRMS(m/z):calcd for C21H15BrFO[M+H+],381.0285；found,381.0287.
2.3中间体(8a-d)的合成
合成方法参考文献报道，具体操作如下：于15mL具塞螺纹封管内加入原料(1.5mmol)、丙烯酸乙酯(1.3mL,11.7mmol)、三乙胺(2.0mL,14.6mmol)和N-甲基吡咯烷酮(8mL)，通入氮气充分除氧后加入醋酸钯(49mg,0.22mmol)和三(邻甲基苯基)膦(133mg,0.44mmol)，严格密封后于128℃条件下加热12小时。反应结束后，冷却，加乙酸乙酯，用水洗三次，有机相用饱和食盐水洗一次，无水硫酸钠干燥。旋蒸浓缩后硅胶柱层析分离(PE/EA5:1)，旋干得到相应中间体。
2.3.1(E)-3-[5-((E)-3-(2-(3-氟苯基)苯基)-3-氧代丙烯基)-2-甲氧基苯基]丙烯酸乙酯(8a)的合成
黄色固体(8a)，收率46％。mp 68-70℃.1H NMR(400MHz,CDCl3):δ7.91-7.82(m,1H),7.64(s,1H),7.56(s,1H),7.48-7.44(m,2H),7.38-7.27(m,3H),7.16-7.09(m,3H),7.03-6.96(m,1H),6.83(dd,J＝14.5,5.8Hz,1H),6.51(d,J＝16.1Hz,1H),6.43(d,J＝14.9Hz,1H),4.24(q,J＝7.1Hz,1H),3.88(s,3H),1.33(t,J＝7.1Hz,1H).13C NMR(150MHz,CDCl3):δ195.7,167.2,163.5,159.9,143.3,142.4,139.6,138.9,132.8,131.9,130.8,130.8,129.1,128.9,128.6,127.9,125.7,125.3,125.1,119.8,114.8,114.6,111.8,111.4,60.5,56.4,14.4.ESI-MS(m/z):431.2(M+H+).ESI-HRMS(m/z):calcd for C27H24FO4[M+H+],431.1653；found,431.1657.2.3.2(E)-3-[5-((E)-3-(2-(4-氟苯基)苯基)-3-氧代丙烯基)-2-甲氧基苯基]丙烯酸乙酯(8b)的合成
黄色油状液体(8b)，收率48％。1H NMR(400MHz,CDCl3):δ7.88(d,J＝16.3Hz,1H),7.63(d,J＝7.0Hz,1H),7.55(d,J＝8.4Hz,1H),7.48-7.43(m,2H),7.37-7.33(m,3H),7.28-7.24(m,3H),7.09-7.03(m,2H),6.85(d,J＝8.9Hz,1H),6.50-6.44(m,2H),4.27(q,J＝7.1Hz,2H),3.89(s,3H),1.35(t,J＝7.1Hz,3H).13C NMR(150MHz,CDCl3):δ195.9,167.2,163.3,161.7,159.9,143.1,139.8,138.9,136.6,131.4,130.8,130.8,130.2,128.8,128.6,127.6,127.2,125.4,123.9,119.8,115.6,115.5,111.4,60.5,55.8,14.4.ESI-MS(m/z):431.3(M+H+).ESI-HRMS(m/z):calcd for C27H24FO4[M+H+],431.1653；found,431.1663.
2.3.3(E)-3-[3-((E)-3-(2-(3-氟苯基)苯基)-3-氧代丙烯基)苯基]丙烯酸乙酯(8c)的合成
黄色油状液体(8c)，收率88％。1H NMR(400MHz,CDCl3):δ7.67(d,J＝7.0Hz,1H),7.63(d,J＝6.4Hz,1H),7.58(d,J＝7.0Hz,1H),7.52-7.48(m,3H),7.39-7.34(m,4H),7.28(d,J＝8.7Hz,1H),7.14(m,2H),7.04-7.00(m,1H),6.61(d,J＝15.7Hz,1H),6.41(d,J＝16.5Hz,1H),4.28(q,J＝7.1Hz,2H),1.35(t,J＝7.1Hz,3H).13C NMR(150MHz,CDCl3):δ195.6,166.7,163.6,161.9,143.5,142.9,139.7,139.5,135.3,135.1,131.0,130.2,130.2,130.1,129.7,129.6,129.4,128.9,127.9,127.5,127.4,125.1,119.3,116.2,116.0,114.8,114.7,60.7,14.3.ESI-MS(m/z):401.3(M+H+).ESI-HRMS(m/z):calcd forC26H22FO3[M+H+],401.1547；found,401.1556.
2.3.4(E)-3-[4-((E)-3-(2-(3-氟苯基)苯基)-3-氧代丙烯基))苯基]丙烯酸乙酯(8d)的合成
白色固体(8d)，收率86％。mp 58-60℃.1H NMR(400MHz,CDCl3):δ7.65(d,J＝7.3Hz,1H),7.60(d,J＝7.3Hz,1H),7.50(d,J＝8.2Hz,1H),7.47-7.45(m,3H),7.34(d,J＝15.9Hz,2H),7.29-7.26(m,2H),7.14-7.10(m,2H),7.01(d,J＝7.5Hz,1H),6.61(d,J＝16.0Hz,1H),6.44(d,J＝16.0Hz,1H),4.27(q,J＝6.9Hz,2H),1.33(t,J＝6.9Hz,3H).13CNMR(150MHz,CDCl3):δ195.7,166.7,163.6,161.9,143.3,142.8,139.6,139.6,136.4,136.2,130.9,130.2,130.1,128.9,128.6,128.4,127.9,127.4,125.1,119.4,116.1,115.9,114.8,114.7,60.7,14.3.ESI-MS(m/z):401.5(M+H+).ESI-HRMS(m/z):calcd forC26H22FO3[M+H+],401.1547；found,401.1550.
2.4目标化合物(9a-d)的合成
于25mL茄型瓶中加入原料(0.98mmol)，用乙醇(3mL)溶解后缓慢滴入氢氧化钠水溶液(1M,1.9mL)。加热回流反应，待原料完全消失后，加水，用乙酸调节pH调节至6，用乙酸乙酯萃取三次，合并有机相后用饱和食盐水洗一次，无水硫酸钠干燥。过滤，旋蒸浓缩后，加入DMF(3mL)、HOBt(131mg,0.97mmol)和EDCI(186mg,0.97mmol)，室温下搅拌6小时，后加入盐酸羟胺(179mg,2.58mmol)和三乙胺(0.54mL,3.88mmol)，室温下继续搅拌反应2小时。待原料完全消失后，加水，用乙酸乙酯萃取三次，合并有机相后用饱和食盐水洗一次，无水硫酸钠干燥。过滤，旋蒸浓缩后硅胶柱层析分离(CH2Cl2/MeOH 30:1)，旋干得到相应目标化合物。
2.4.1(E)-3-[5-((E)-3-(2-(3-氟苯基)苯基)-3-氧代丙烯基)-2-甲氧基苯基]-N-羟基丙烯酰胺(9a)的合成
红色固体(9a)，收率86％。mp 108-110℃.1H NMR(400MHz,DMSO-d6):δ10.68(s,0H),9.00(s,1H),7.71(s,1H),7.55-7.49(m,5H),7.32-7.38(m,1H),7.24(d,J＝15.4Hz,1H),7.14-7.05(m,5H),6.80(d,J＝15.3Hz,1H),6.52(d,J＝14.7Hz,1H),3.84(s,3H).13CNMR(150MHz,DMSO-d6):δ195.2,162.8,162.6,160.9,159.2,144.2,142.5,139.4,138.7,132.5,131.0,130.5,130.3,130.2,130.0,128.5,128.1,127.8,126.6,124.9,123.6,120.6,115.4,115.3,114.2,114.1,112.0,55.8.ESI-MS(m/z):418.3(M+H+).ESI-HRMS(m/z):calcd for C25H21FNO4[M+H+],418.1449；found,418.1455.
2.4.2(E)-3-[5-((E)-3-(2-(4-氟苯基)苯基)-3-氧代丙烯基)-2-甲氧基苯基]-N-羟基丙烯酰胺(9b)的合成
红色固体(9b)，收率76％。mp 88-90℃.1H NMR(400MHz,DMSO-d6):δ7.72-7.69(m,1H),7.63-7.57(m,2H),7.54-7.49(m,4H),7.38-7.34(m,2H),7.24-7.18(m,3H),7.08-7.04(m,2H),6.77(d,J＝15.7Hz,1H),6.56(d,J＝15.5Hz,1H),3.89(s,3H).13C NMR(150MHz,DMSO-d6):δ195.3,162.3,160.7,159.1,143.8,139.4,138.9,136.5,130.7,130.6,130.4,130.1,128.2,128.1,127.4,126.8,125.1,115.2,115.0,111.9,55.8.ESI-MS(m/z):418.4(M+H+).ESI-HRMS(m/z):calcd for C25H21FNO4[M+H+],418.1449；found,418.1454.
2.4.3(E)-3-[3-((E)-3-(2-(3-氟苯基)苯基)-3-氧代丙烯基)苯基]-N-羟基丙烯酰胺(9c)的合成
红色固体(9c)，收率54％。mp 78-80℃.1H NMR(400MHz,DMSO-d6):δ7.90-7.86(m,1H),7.70(d,J＝7.9Hz,1H),7.60-7.58(m,2H),7.52-7.46(m,3H),7.40-7.33(m,3H),7.08-6.15(m,4H),6.90(d,J＝15.0Hz,1H),6.47(d,J＝16.3Hz,1H).13C NMR(150MHz,DMSO-d6):δ195.2,162.6,162.2,161.0,143.8,142.4,139.1,138.9,135.4,134.6,130.7,130.3,130.3,130.1,129.3,129.1,128.9,128.3,127.8,127.6,127.0,124.9,115.5,115.3,114.2,114.1.ESI-MS(m/z):388.2(M+H+).ESI-HRMS(m/z):calcd for C24H19FNO3[M+H+],388.1343；found,388.1346.
2.4.4(E)-3-[4-((E)-3-(2-(3-氟苯基)苯基)-3-氧代丙烯基))苯基]-N-羟基丙烯酰胺(9d)的合成
红色固体(9d)，收率57％。mp 86-88℃.1H NMR(400MHz,DMSO-d6):δ7.68-7.64(m,2H),7.57(m,4H),7.46-7.41(m,3H),7.33(dd,J＝16.1,5.7Hz,1H),7.22-7.15(m,4H),6.90(dd,J＝16.1,4.8Hz,1H),6.53(d,J＝14.7Hz,1H).13C NMR(150MHz,DMSO-d6):δ195.1,162.6,162.1,161.0,143.4,142.5,142.4,139.1,138.8,136.8,134.9,130.7,130.3,130.3,130.1,128.8,128.3,127.9,127.8,126.8,125.0,120.2,115.5,115.3,114.3,114.1.ESI-MS(m/z):388.3(M+H+).ESI-HRMS(m/z):calcd for C24H19FNO3[M+H+],388.1343；found,388.1348.
2.4.1(E)-3-[5-((E)-3-(2-(3-氟苯基)苯基)-3-氧代丙烯基)-2-甲氧基苯基]丙烯酸(10)的合成
于25mL茄型瓶中加入原料(0.98mmol)，用乙醇(3mL)溶解后缓慢滴入氢氧化钠水溶液(1M,1.9mL)。加热回流反应，待原料完全消失后，加水，用乙酸调节pH调节至6，用乙酸乙酯萃取三次，合并有机相后用饱和食盐水洗一次，无水硫酸钠干燥。过滤，旋蒸浓缩后硅胶柱层析分离(PE/EA1:1)，旋干得到黄色固体(10)，收率57％。mp 72-74℃.1H NMR(400MHz,DMSO-d6):δ12.31(s,1H),7.91(s,1H),7.73(d,J＝16.3Hz,1H),7.56(d,J＝9.0Hz,2H),7.48(d,J＝6.2Hz,2H),7.49-7.44(m,2H),7.37-7.31(m,3H),7.22(d,J＝6.5Hz,2H),7.16(d,J＝8.5Hz,2H),7.06-7.02(m,1H),6.96-6.90(m,1H),6.85(d,J＝16.0Hz,1H),6.58(d,J＝16.3Hz,1H),3.86(s,3H).13C NMR(150MHz,DMSO-d6):δ195.4,167.6,162.3,160.7,159.2,143.8,142.2,139.4,138.9,137.5,136.5,132.0,130.7,128.4,128.1,127.4,126.8,125.6,125.2,122.8,120.2,115.2,112.0,55.9.ESI-MS(m/z):402.4(M+H+).ESI-HRMS(m/z):calcd for C25H19FO4[M+H+],403.1340；found,403.1346.。
实施例3体外肿瘤细胞增殖抑制活性检测实验
取对数生长期的肿瘤细胞，处理后接种于96孔板中，并于37℃、5％CO2的条件下培养24小时。加入6个梯度浓度的供试化合物，并以CA-4作为阳性对照。同样的条件下继续培养48小时，后加入MTT，培养4小时后弃去含MTT的上清液，每孔加入DMSO，震荡溶解掉紫色结晶，然后在酶标仪上490nm或540nm处测得OD值，并计算出抑制率。化合物的半数抑制浓度(IC50值)根据6个浓度的抑制率计算所得。每个浓度梯度设置三个复孔，重复检测三次。活性结果如表1与表2所示。
表1化合物对肿瘤细胞增殖抑制活性(IC50/μM)
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注释：a抗肿瘤活性由MTT法测定，数据均是三次测量的平均值；bBE-(2)-C是人神经母细胞瘤细胞株；cA549是人肺癌细胞株；dU87MG是人恶性胶质母细胞瘤细胞株；eHCT-116是人结肠癌细胞株。
表2化合物9a对肿瘤细胞增殖抑制活性(IC50/μM)
注释：a抗肿瘤活性由MTT法测定，数据均是三次测量的平均值；bHeLa是人***细胞株；cA2780是人卵巢癌细胞株；dMDA-MB-231是人乳腺癌细胞株；eHUH-7是人肝癌细胞株；fSKOV3是人卵巢癌细胞株；gMCF-7是人乳腺癌细胞株；hMDA-MB-468是人乳腺癌细胞株。
实施例4体外微管蛋白自组装实验
用浊度法测试优选化合物9a在体外对微管聚集的抑制作用，检测试剂盒购自于美国Cytoskeleton公司。操作步骤如下，pH＝6.6的微管聚集体系(0.1M PIPES、10mM MgCl2、1mM GTP、1mM EGTA和3.4M甘油)预先在冰上预孵育，加入不同浓度的受试化合物9a，并设置Colchicine处理组作为阳性对照和DMSO(4％，v/v)处理组组作为阴性对照。向以上体系加入微管蛋白(10mM)后，立刻转移，置于37℃条件下进行聚集反应，保持温度不变，每隔1分钟用分光光度计(Synergy H4 Hybrid)在340nm下测定吸光度，共持续测试30分钟，然后绘制吸光度曲线图(如图1所示)。结果显示化合物9a能够明显抑制微管聚集，其IC50为9.0μM(如表3所示)。
表3.化合物9a体外抑制微管自组装实验
实施例5体外HDAC抑制活性测试
采用酶联免疫荧光法测试化合物对HDACs的抑制活性，所有的酶促反应均在37℃下进行30分钟。将化合物用5％的DMSO稀释至不同浓度范围，取5微升化合物溶液加入到50微升pH＝8.0并含有25mM的Tris、1mM的MgCl2、0.1mg/ml的BSA、137mM的NaCl、2.7mM的KCl、HDAC及其底物反应混合物中。酶促反应结束之后，于SpectraMax M5微量滴定板读数器上以350-360nm的激发和450-460nm的发射波长检测荧光强度。最后使用Prism GraphPad软件通过归一化后进行拟合进行非线性回归计算得到受试化合物的IC50值。测试结果如表4所示，9a与9b都能够明显地抑制HDAC8的活性，其IC50值分别为0.548μM与0.417μM，同时两者对HDAC1具有与HDAC8相同的抑制活性，而对HDAC6选择性分别为24倍与18倍，说明这两个化合物为class I型HDAC抑制剂。
表4化合物对HDAC1/6/8抑制活性(IC50/μM)
注释：aIC50均是三次测量的平均值；bSAHA是非选择性HDACs抑制剂；cPCI-34051是选择性HDAC8抑制剂；NT＝not tested.。
实施例6 HDAC相关蛋白表达检测
取对数生长期的BE-(2)-C细胞，处理后按2×105个/孔的数量接种于6孔板中，于37℃、5％CO2及饱和湿度的培养箱中培养24小时，加入梯度浓度的化合物9a处理肿瘤细胞后(同时设置DMSO处理组为阴性对照)，24小时后收集并用裂解液裂解细胞。蛋白样品经加热变性后，上样于聚丙烯酰胺凝胶，SDS-PAGE电泳分离，湿法转膜，封闭，依次经一抗反应、二抗反应后，曝光显色。结果如图2所示，化合物9a能够明显地促进HDAC8底物蛋白SMC3与HDAC1的底物蛋白组蛋白H3的乙酰化，而对HDAC6的底物蛋白α-tubulin的乙酰化影响不明显，说明优选化合物9a能够抑制HDAC1与HDAC8。
实施例7体外细胞周期阻滞实验
取对数生长期的BE-(2)-C细胞，处理后按2×105个/孔的数量接种于6孔板中，于37℃、5％CO2及饱和湿度的培养箱中培养12小时，待细胞贴壁后更换新鲜培养液，用不同浓度的化合物9a处理细胞24小时，同时设置DMSO处理组为阴性对照。弃去上清液，收集贴壁细胞，用PBS冲洗两次，再用75％乙醇固定，-20℃条件下固定过夜，用PI染色后采用流式细胞仪进行测试，结果显示化合物9a能明显将肿瘤细胞周期阻滞于G2/M期(如图3所示)。
实施例8体外细胞周期相关蛋白检测
取对数生长期的BE-(2)-C细胞，处理后按2×105个/孔的数量接种于6孔板中，于37℃、5％CO2及饱和湿度的培养箱中培养24小时，加入梯度浓度的化合物9a处理肿瘤细胞后(同时设置DMSO处理组为阴性对照)，24小时后收集并用裂解液裂解细胞。蛋白样品经加热变性后，上样于聚丙烯酰胺凝胶，SDS-PAGE电泳分离，湿法转膜，封闭，依次经一抗反应、二抗反应后，曝光显色。结果如图4所示，化合物9a能明显促进有丝***检验点蛋白Bubr-1、磷酸化组蛋白P-Histone 3、细胞周期蛋白B1的表达。
实施例9体外诱导细胞凋亡实验
取对数生长期的BE-(2)-C细胞，处理后按2×105个/孔的数量接种于6孔板中，于37℃、5％CO2及饱和湿度的培养箱中培养24小时，加入梯度浓度的化合物9a，同时设置DMSO处理组为阴性对照。继续培养48小时后，收集上清液细胞和贴壁细胞，用PI和Annexin V双染色，采用流式细胞仪进行检测。结果如图5所示，化合物9a能浓度依赖性地诱导细胞凋亡。
实施例10体外凋亡相关蛋白的检测实验
取对数生长期的BE-(2)-C细胞，处理后按2×105个/孔的数量接种于6孔板中，于37℃、5％CO2及饱和湿度的培养箱中培养24小时，加入梯度浓度的化合物9a，同时设置DMSO处理组为阴性对照。48小时后收集并用裂解液裂解细胞。上样于聚丙烯酰胺凝胶，SDS-PAGE电泳分离，湿法转膜，封闭，依次经一抗反应、二抗反应后，曝光显色。结果如图6所示，化合物9a能明显促进抑癌基因p53、促凋亡蛋白Bax与剪切的DNA修复酶PAPR-1的表达。
实施例11集落形成抑制实验
取对数生长期的BE-(2)-C细胞，处理后接种于6孔板中，每孔接种1500个细胞，并于37℃、5％CO2及湿度饱和的条件下培养24小时，待细胞贴壁后，加入不同浓度的化合物9a处理细胞48小时，并设置DMSO处理组为阴性对照。更换新鲜培养基并继续培养两周，后弃去上清液，用PBS冲洗两次，细胞用无水甲醇固定30分钟，并用结晶紫染料染色1小时，洗去染色液，充分干燥后于显微镜下计数大于50个细胞形成的集落数，结果显示化合物9a能够明显地抑制HeLa细胞集落的形成(如图7所示)。
Claims (3)
1.2’-芳基查尔酮类化合物，其特征在于，所述的化合物为：
。
2.权利要求1中所述的化合物及其在药学上可接受的盐在制备预防和治疗与肿瘤相关疾病的药物中的应用，所述疾病选自神经母细胞瘤、***、卵巢癌、乳腺癌、结直肠癌、肺癌、肝癌、脑胶质瘤；
所述的“药学上可接受的盐”为与苹果酸、乳酸、樟脑磺酸、枸橼酸、富马酸、草酸有机酸，或磷酸、氢卤酸、硫酸、硝酸无机酸形成的盐。
3.一种用于预防和治疗与肿瘤相关疾病的复方药物，其特征在于，其含有权利要求1中所述的化合物，所述的与肿瘤相关疾病是神经母细胞瘤、肺癌、肝癌、***、卵巢癌、乳腺癌、结直肠癌、脑胶质瘤。
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