CN115624544A - 查耳酮类似物作为活性物质在制备抗肿瘤药物中的应用 - Google Patents
查耳酮类似物作为活性物质在制备抗肿瘤药物中的应用 Download PDFInfo
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Abstract
本发明公开了一种查耳酮类似物的医药新用途，即作为活性物质在制备抗肿瘤药物中的应用。本发明公开的内容包括查耳酮类似物的结构、查尔酮类似物的合成方法，以及查尔酮类似物的抑制肿瘤细胞活性。本发明查尔酮类似物经体外抗肿瘤活性筛选结果表明，对人宫颈癌细胞（HeLa）、人结肠癌细胞（HCT‑116）及人胃癌细胞（MGC‑803）表现出较强的抑制活性，且一些化合物的抑制活性高于目前临床药物顺铂，因此本发明的化合物可用于制备抗肿瘤的药物。
Description
技术领域
本发明属于药物化学技术领域，具体涉及查耳酮类似物作为活性物质在制备抗肿瘤药物中的应用。
背景技术
在过去的几十年里，由于环境污染、不健康的生活方式和高压力等各种原因，癌症的发病率急剧上升。据国际癌症研究中心（International Agency for Research onCancer，IARC）最新统计结果显示，2020年全球估计新发癌症 19292789例，估计死亡9958133例。其中结直肠癌、胃癌导致的患者死亡人数仅次于肺癌，分别为9.4%和7.7%，女性中最常被诊断出的癌症是宫颈癌，并且发病率呈逐年升高的态势，越来越受到人们的关注。
化疗是目前治疗癌症的基础手段，其临床发展依赖于更多抗癌药物的研发。但大多数化疗药物因严重的副作用、耐药性以及疾病的转移和侵袭在一定程度上限制了其临床应用。因此，寻找新的高效、低毒抗肿瘤药物极为迫切。由于天然产物具有良好的生物活性及较弱的毒副作用，对其进行衍生化作为发现新型肿瘤化疗药物的有效策略引起了广泛的关注。
肿瘤细胞通过自身无限增殖，获得形成集落的能力，而高度分化成熟的细胞不具备这种增殖能力，因此，肿瘤细胞集落形成效率的差异反映着肿瘤细胞体外独立生存能力的强弱。
细胞迁移是其维持生长发育的基本生理功能之一，而相比于正常的细胞，肿瘤细胞通常具有过高的迁移能力，这也是肿瘤细胞能够快速扩散增殖的主要原因。细胞创伤愈合实验主要是模拟细胞在体内受到创伤之后愈合过程中的实际迁移情况，能够较为真实的测定细胞的迁移运动和修复能力。
细胞周期属于细胞生命活动的基本过程之一，用以维持细胞正常增殖和发育，其可分为间期与分裂期（M期）两个阶段；其中间期包括有丝分裂完成到DNA复制前的一段时间G1期）、DNA复制期（S期）以及 DNA 复制到有丝分裂准备开始的时间（G2期）。但肿瘤细胞通常表现为周期调节受阻，细胞分化和凋亡过程被破坏，因此能够无限增殖。
微管蛋白抑制剂在肿瘤治疗中发挥重要作用，其能够组织和破坏肿瘤血管，快速切断肿瘤血流供应，代表性的药物有秋水仙碱（Colchicine）。此外CA-4（Combretastain A-4）是一种高效的秋水仙碱结合位点的微管蛋白抑制剂，其以可逆性结合方式结合微管蛋白，并且显著降低微管蛋白二聚体之间的聚合效率，进而阻滞细胞周期于G2/M期，其有效剂量是自身最大耐受剂量的1/10，能够有效降低临床用药毒性；鬼臼毒素（Podophyllotoxin）及其类似物也被用于治疗恶性肿瘤，研究表明依托泊苷（Etoposide）在治疗支气管小细胞癌，绒毛膜癌等均具有较好的效果；ZD6126作为N-乙酰基秋水仙醇（N-acetylcolchinol,NAC）水溶性前药，主要用于治疗转移性肾细胞癌，其代谢产物NAC可以选择性破坏肿瘤细胞的内皮骨架，达到切断肿瘤的血流供应的目的。比较这些经典微管蛋白抑制的基本化学结构发现，三甲氧基苯基是它们共有的一种化学结构。这些结果进一步说明三甲氧基苯基是微管蛋白抑制剂发挥抗肿瘤活性的药效基团。
黄酮类化合物是广泛分布于高等植物的次生代谢物，泛指两个苯环之间通过三个碳相连的一系列C6-C3-C6化合物。研究发现黄酮类化合物具有抗癌作用、心脏保护作用、抗氧化作用、抗炎作用、抗病毒作用、抗真菌作用、神经突生长刺激作用及预防心血管疾病等多种生物学作用。由于黄酮类化合物结构多样性，又具有较低的毒性及广泛的生物活性，从而使其在新药的合成中占有极其重要的地位，成为当前的研究热点。
查尔酮类化合物（1,3-diaryl-2-propen-1-ones）是黄酮类化合物生物合成的前体，相对于黄酮的A/B环之间的吡喃酮的连接方式，查尔酮的A/B环之间以丙烯酮连接，在分子结构上具有较大的柔性，能与不同的受体结合，具有广泛的靶点效应，表现出明显的生物活性。
发明内容
本发明的目的是提供一种查耳酮类似物的医药新用途，即作为活性物质在制备抗肿瘤药物中的应用。
本发明鉴于查耳酮类化合物因结构柔性表现出的广泛的靶点效应，在掌握了查耳酮类化合物与抗肿瘤活性关系的基础上，基于药效团拼合原理将具有抑制微管蛋白聚合活性的三甲氧基苯基药效团引入查耳酮类化合物结构中的A环。同时，在B环引入具有不同电负性的取代基，可望通过这种结构优化方式提高药物抗肿瘤活性，筛选具有良好抗肿瘤活性的查尔酮类化合物。
一、查耳酮类似物的结构：
本发明的查耳酮类似物，其结构式如下：
其中，取代基R选自三氟甲基、咪唑基、氯离子、氟离子、甲氧基、甲基、吡啶基、喹啉基、吗啉基、四氢吡咯基和4-甲基哌嗪基中的一种或几种。
二、查尔酮类似物的合成：
将1.2 mmol氢氧化钾和苯甲醛类化合物（2.1 mmol）混合，充入惰性气体保护，将2.2 mmol 2,3,4-三甲氧基-6-羟基苯乙酮溶于10 mL无水乙醇溶液中，缓慢滴加到氢氧化钾和苯甲醛类化合物混合溶液中，置于电热套中80℃加热搅拌反应2h，TLC检测反应进程，待反应完毕后，冷却至室温，减压蒸发取出多余溶剂，剩余物用无水乙醇溶解，通过洗脱剂石油醚/乙酸乙酯（v/v=10:1）体系进行洗脱纯化，获得查耳酮类产物。
为了进一步实现本发明，上述苯甲醛类化合物的取代基采用三氟甲基、咪唑基、氯离子、氟离子、甲氧基、甲基、吡啶基、喹啉基、吗啉基、四氢吡咯基和4-甲基哌嗪基中的一种或几种。
三、查尔酮类似物的抑制肿瘤细胞活性：
本发明查尔酮类似物经体外抗肿瘤活性筛选结果表明，对人宫颈癌细胞（HeLa）、人结肠癌细胞（HCT-116）及人胃癌细胞（MGC-803）表现出较强的抑制活性，且一些化合物的抑制活性高于目前临床药物顺铂，因此本发明的化合物可用于制备抗肿瘤的药物。本发明所述的查耳酮类化合物结构新颖、原料廉价易得、合成工艺简单、产品纯度高，对肿瘤细胞表现出较强的抑制作用，具有优良的应用前景。
本发明通过平板细胞克隆技术测定查尔酮类化合物对HGC-27细胞集落检测细胞增殖能力，本发明通过集落实验测定查尔酮类化合物对MGC-803细胞增殖能力的影响，发现随着加药浓度的不断增加，培养皿中结晶紫的面积越来越少，并且颜色也逐渐变浅直至结晶紫几乎完全消失，结果表明查尔酮类化合物能够以剂量依赖性方式显著地抑制胃癌MGC-803细胞的体外生长。
本发明通过细胞创伤愈合实验测定查尔酮类化合物对于MGC-803细胞迁移及修复能力的影响，发现一方面加药组划痕愈合程度显著低于未加药的空白对照组，另一方面发现随着加药浓度的增加，细胞迁移率逐渐降低，结果表明查尔酮类化合物对MGC-803细胞迁移及修复能力的抑制作用具有剂量依赖性。
本发明采用流式细胞术测定查尔酮类化合物对MGC-803细胞周期的改变，发现随着查尔酮类化合物加药浓度的增加，分布于G2期的MGC-803细胞比例也逐渐增加，结果表明查尔酮类化合物能够以剂量依赖性方式阻滞MGC-803细胞于G2/M期，从而具备抗肿瘤活性。
附图说明
图1为查尔酮类似物合成产物Ic抑制MGC-803细胞的集落形成情况；
图2为查尔酮类似物合成产物Ic抑制MGC-803细胞的迁移情况：
（A）不同加药浓度划痕伤口愈合程度的倒置显微成像；
（B）统计来自三个独立的划痕愈合率的平均值±SD，***P<0.001；
图3为查尔酮类似物合成产物Ic处理MGC-803细胞48 h周期分布的情况：
（A）采用流式细胞仪分析显示的经PI染色细胞周期分布，通过FlowJo统计细胞周期不同阶段的细胞比量；
（B)统计来自三个独立的周期分布比例的平均值±SD，与对照相比，*P<0.05，**P<0.01。
具体实施方式
下面结合具体实施例及附图对本发明查尔酮类化合物的合成及其抑制肿瘤细胞活性做进一步说明。应理解，这些实施例用于说明本发明，但不限制本发明的范围。
一、查尔酮类似物的结构及合成
实施例1-13中，查尔酮类似物的结构如下：
其合成方法根据不同的构型，将2,3,4-三甲氧基-6-羟基苯乙酮与不同取代苯甲醛类化合物，在有机溶剂和碱作用下，进行缩合反应后得到目标化合物，反应式如下：
具体方法为：将苯甲醛类化合物与氢氧化钾混合，在氮气保护下，缓慢滴加到溶解有2,3,4-三甲氧基-6-羟基苯乙酮的无水乙醇溶液中，置于电热套中80℃加热搅拌反应2h，TLC检测反应进程，待反应完毕后，冷却至室温，减压蒸发取出多余溶剂，剩余物用无水乙醇溶解，通过洗脱剂石油醚/乙酸乙酯体系进行洗脱纯化，获得查耳酮类产物。
其中苯甲醛类化合物的取代基采用三氟甲基、咪唑基、氯离子、氟离子、甲氧基、甲基、吡啶基、喹啉基、吗啉基、四氢吡咯基和4-甲基哌嗪基中的一种或几种。
实施例1、2-三氟甲基-2´-羟基-4´,5´,6´-三甲氧基查尔酮（Ia）的合成
本实施例中的苯甲醛类化合物采用2-三氟甲基苯甲醛。
合成步骤：将1.2 mmol氢氧化钾和2.1 mmol 2-三氟甲基苯甲醛置于带有回流冷凝管的双口烧瓶中，充入惰性气体进行保护。将2.2 mmol2,3,4-三甲氧基-6-羟基苯乙酮溶于无水乙醇后逐滴加入双口烧瓶中，置于80℃温水浴中搅拌反应回流2h，TLC检测反应进程，待反应完毕后，冷却至室温，减压蒸发去除多余溶剂，剩余物用无水乙醇溶解，通过洗脱剂石油醚/乙酸乙酯（v/v=10:1）体系进行洗脱纯化，得到目标化合物2-三氟甲基-2´-羟基-4´,5´,6´-三甲氧基查尔酮，产物的结构式如下：
反应式如下：
产物的检测数据如下：
产率: 75%；熔点: 128-129 ℃；
1 H NMR (400 MHz, CDCl3): δ (ppm) 13.53 (s, 1H), 8.00 (d, J = 15.6 Hz,1H), 7.79 (d, J = 16 Hz, 1H), 7.73 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 8.4 Hz,2H), 6.29 (s, 1H), 3.93 (s, 3H), 3.90 (s, 3H), 3.83 (s, 3H).
13C NMR (100 MHz, CDCl3): δ (ppm) 192.5, 162.8, 160.6, 154.9, 140.7,138.8, 135.3, 131.7, 131.4, 129.0, 128.4, 125.9, 125.9, 108.6, 96.6, 61.9,61.3, 56.2.
HRMS, 计算值: C19H17F3NaO5: 405.0920 [M + Na]+; 检测值: 405.0916 [M +Na]+。
实施例2、4-(1H-咪唑-1-基)-2´-羟基-4´,5´,6´-三甲氧基查尔酮（Ib）的合成
本实施例中的苯甲醛类化合物采用4-(1H-咪唑-1-基)苯基。
合成步骤与实施例1相同，仅以4-(1H-咪唑-1-基)苯基替代2-三氟甲基苯基。
产物的结构式如下：
产物的检测数据如下：
产率: 62%, 熔点: 146-147 ℃；
1H NMR (400 MHz, CDCl3): δ (ppm) 13.59 (s, 1H), 7.92 (d, J = 6.8 Hz,2H), 7.80 (d, J = 16.0 Hz, 1H), 7.73 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.4Hz, 2H), 7.31 (s, 1H), 7.21 (s, 1H), 6.28 (s, 1H), 3.92 (s, 3H), 3.88 (s,3H), 3.82 (s, 3H).；
13C NMR (100 MHz, CDCl3): δ (ppm) 192.5, 162.7, 160.4, 154.9, 141.2,135.3, 135.3, 134.5, 129.8, 121.4, 117.8, 108.6, 96.6, 61.9, 61.3, 56.1.；
HRMS, 计算值: C21H21N2O5: 381.1445 [M + H]+; 检测值: 381.1446 [M + H]+。
实施例3、2, 6-二氯-2´-羟基-4´,5´,6´-三甲氧基查尔酮（Ic）的合成
本实施例中的苯甲醛类化合物采用2, 6-二氯苯基。
合成步骤与实施例1相同，仅以2, 6-二氯苯基替代2-三氟甲基苯基。
产物的结构式如下：
产物的检测数据如下：
产率: 51%, 熔点: 129-130 ℃；
1H NMR (400 MHz, CDCl3): δ (ppm) 13.56 (s, 1H), 8.05 (dd, J =48 16.0Hz, 1H), 7.39 (d, J =8.0 Hz, 1H), 7.33 (d, J =8.0 Hz, 1H), 7.21-7.16 (m, 2H),6.29 (s, 1H), 3.93 (s, 3H), 3.90 (s, 3H), 3.80 (s, 3H).
13C NMR (100 MHz, CDCl3): δ (ppm) 192.5, 162.9, 160.6, 155.1, 136.4,135.3, 134.5, 129.8, 129.7, 128.9, 128.5, 108.8, 96.5, 62.1, 61.2, 60.2.
HRMS, 计算值: C18H16Cl2NaO5: 405.0267 [M + Na]+; 检测值: 405.0276 [M +Na]+.。
实施例4、3-氟-4-氯-2´-羟基-4´,5´,6´-三甲氧基查尔酮（Id）的合成
本实施例中的苯甲醛类化合物采用3-氟-4-氯苯基。
合成步骤与实施例1相同，仅以3-氟-4-氯苯基替代2-三氟甲基苯基。
产物的结构式如下：
产物的检测数据如下：
产率: 53%, 熔点: 135-136 ℃；
1H NMR (400 MHz, CDCl3): δ (ppm) 13.52 (s, 1H), 7.90 (d, J =15.2 Hz,1H), 7.69 (d, J =15.6 Hz, 1H), 7.44 (d, J =8.0 Hz, 1H), 7.40 (d, J =9.6 Hz,1H), 7.34 (d, J =8.4 Hz, 1H), 6.29 (s, 1H), 3.92 (s, 3H), 3.90 (s, 3H), 3.83(s, 3H).
13C NMR (100 MHz, CDCl3): δ (ppm) 192.4, 162.8, 160.6, 154.9, 136.1,136.0, 135.3, 131.1, 128.3, 125.0, 124.9, 115.5, 115.3, 108.6, 96.6, 61.9,61.3, 56.2.
HRMS, 计算值: C18H16ClFNaO5: 389.0563 [M + Na]+; 检测值: 389.0582 [M +Na]+.。
实施例5、3-氟-4-甲氧基-2´-羟基-4´,5´,6´-三甲氧基查尔酮（Ie）的合成
本实施例中的苯甲醛类化合物采用3-氟-4-甲氧基苯基。
合成步骤与实施例1相同，仅以3-氟-4-甲氧基苯基替代2-三氟甲基苯基。
产物的结构式如下：
产物的检测数据如下：
产率: 83%, 熔点: 127-128 ℃；
1H NMR (400 MHz, CDCl3): δ (ppm) 13.67 (s, 1H), 7.83 (dd, J =33.2 15.6Hz, 1H), 7.41 (dd, J =12.4 2.4 Hz, 1H), 7.35 (d, J =8.4 Hz, 1H), 6.98 (t, J =8.8 Hz, 1H), 6.28 (s, 1H), 3.93 (s, 6H), 3.90 (s, 3H), 3.83 (s, 3H).
13C NMR (100 MHz, CDCl3): δ (ppm) 192.6, 162.7, 160.2, 155.0, 153.7,151.2, 142.0, 135.3, 128.8, 126.0, 125.4, 114.8, 113.2, 108.7, 96.6, 61.9,61.3, 56.3, 56.1.
HRMS, 计算值: C19H20FO6: 363.1238 [M + H]+; 检测值: 363.1230 [M + H]+.。
实施例6、3,4-二甲基-2´-羟基-4´,5´,6´-三甲氧基查尔酮（If）的合成
本实施例中的苯甲醛类化合物采用3,4-二甲基苯基。
合成步骤与实施例1相同，仅以3,4-二甲基苯基替代2-三氟甲基苯基。
产物的结构式如下：
产物的检测数据如下：
产率: 84%, 熔点: 125-126 ℃；
1H NMR (400 MHz, CDCl3): δ (ppm) 13.73 (s, 1H), 7.93 (dd, J =43.6 15.6Hz, 2H), 7.40 (d, J =7.6 Hz, 2H), 7.18 (d, J =7.6 Hz, 1H), 6.30 (s, 1H), 3.93(s, 3H), 3.90 (s, 3H), 3.84 (s, 3H), 2.30 (d, J =2.8 Hz, 1H).
13C NMR (100 MHz, CDCl3): δ (ppm) 193.0, 162.7, 160.0, 155.0, 143.7,139.7, 137.2, 135.3, 133.0, 130.3, 129.8, 126.1, 125.3, 108.8, 96.6, 62.0,61.3, 56.1, 19.9, 19.8.
HRMS, 计算值: C20H23O5: 343.1540 [M + H]+; 检测值: 343.1530 [M + H]+.。
实施例7、4-(2-吡啶基)-2´-羟基-4´,5´,6´-三甲氧基查尔酮（Ig）的合成
本实施例中的苯甲醛类化合物采用4-(2-吡啶基)苯基。
合成步骤与实施例1相同，仅以4-(2-吡啶基)苯基替代2-三氟甲基苯基。
产物的结构式如下：
产物的检测数据如下：
产率: 61%, 熔点: 145-146 ℃；
1H NMR (400 MHz, CDCl3): δ (ppm) 13.61 (s, 1H), 8.65 (d, J =5.2 Hz,1H), 8.01 (d, J =8.0 Hz, 2H), 7.96 (d, J =15.6 Hz, 1H), 7.82 (d, J =15.6 Hz,1H), 7.71-7.67 (m, 4H), 7.19 (s, 1H), 6.23 (s, 1H), 3.88 (s, 3H), 3.84 (s,3H), 3.78 (s, 3H).
13C NMR (100 MHz, CDCl3): δ (ppm) 192.9, 162.8, 160.3, 156.5, 155.0,149.9, 142.6, 141.1, 136.9, 135.9, 135.4, 128.9, 127.4, 127.0, 122.6, 120.6,108.8, 96.6, 62.0, 61.4, 56.2.
HRMS, 计算值: C23H22NO5: 392.1492 [M + H]+; 检测值: 392.1496 [M + H]+.。
实施例8、6-喹啉-2´-羟基-4´,5´,6´-三甲氧基查尔酮（Ih）的合成
本实施例中的苯甲醛类化合物采用6-喹啉苯基。
合成步骤与实施例1相同，仅以6-喹啉苯基替代2-三氟甲基苯基。
产物的结构式如下：
产物的检测数据如下：
产率: 60%, 熔点: 150-151 ℃；
1H NMR (400 MHz, CDCl3): δ (ppm) 13.64 (s, 1H), 8.90 (dd, J =4.0 1.6Hz, 1H), 8.17 (d, J =8.0 Hz, 1H), 8.08 (t, J =8.8 Hz, 1H), 8.02-7.98 (m, 2H),7.95-7,94 (d, J =2.8 Hz 1H), 7.42 (dd, J =8.0 4.0 Hz, 1H), 6.27 (s, 1H), 3.94(s, 3H), 3.88 (s, 3H), 3.83 (s, 3H).
13C NMR (100 MHz, CDCl3): δ (ppm) 192.6, 162.7, 160.3, 154.9, 151.2,149.0, 142.0, 136.4, 135.3, 133.5, 130.2, 129.8, 128.3, 127.7, 127.3, 121.8,108.7, 96.5, 61.9, 61.3, 56.1.
HRMS, 计算值: C21H20NO5: 366.1336 [M + H]+; 检测值: 366.1330 [M + H]+.。
实施例9、4-(4-吗啉基)-2´-羟基-4´,5´,6´-三甲氧基查尔酮（Ii）的合成
本实施例中的苯甲醛类化合物采用4-(4-吗啉基)苯基。
合成步骤与实施例1相同，仅以4-(4-吗啉基)苯基替代2-三氟甲基苯基。
产物的结构式如下：
产物的检测数据如下：
产率: 73%, 熔点: 151-152 ℃；
1H NMR (400 MHz, CDCl3): δ (ppm) 13.85 (s, 1H), 7.83 (s, 2H), 7.58 (d, J =8.8 Hz, 2H), 6.91 (d, J =9.2 Hz, 2H), 6.29 (s, 1H), 3.92 (s, 3H), 3.90 (s,3H), 3.88 (t, J =4.8 Hz, 4H), 3.83 (s, 3H), 3.28 (t, J =4.8 Hz, 4H).
13C NMR (100 MHz, CDCl3): δ (ppm) 192.7, 162.6, 159.8, 155.0, 152.7,143.9, 135.3, 130.2, 126.3, 122.9, 114.7, 108.9, 96.6, 66.7, 62.0, 61.3,56.1, 48.0.
HRMS, 计算值: C22H26NO6: 400.1755 [M + H]+; 检测值: 400.1747 [M + H]+.。
实施例10、4-（1-四氢吡咯基）-2´-羟基-4´,5´,6´-三甲氧基查尔酮（Ij）的合成
本实施例中的苯甲醛类化合物采用4-（1-四氢吡咯基）苯基。
合成步骤与实施例1相同，仅以4-（1-四氢吡咯基）苯基替代2-三氟甲基苯基。
产物的结构式如下：
产物的检测数据如下：
产率: 52%, 熔点: 147-148 ℃；
1H NMR (400 MHz, CDCl3): δ (ppm) 14.06 (s, 1H), 7.91 (d, J =15.2 Hz,1H), 7.80 (d, J =15.6 Hz, 1H), 7.56 (d, J =8.4 Hz, 2H), 6.57 (d, J =8.4 Hz,2H), 6.29 (s, 1H), 3.92 (s, 3H), 3.89 (s, 3H), 3.84 (s, 3H), 3.36 (s, 4H),2.03 (s, 4H).
13C NMR (100 MHz, CDCl3): δ (ppm) 192.5, 162.5, 159.4, 154.9, 149.6,145.4, 135.2, 130.8, 122.5, 120.1, 111.8, 108.9, 96.6, 61.9, 61.3, 56.0,47.6, 25.5.
HRMS, 计算值: C22H26NO5: 384.1805 [M + H]+; 检测值: 384.1807 [M + H]+.。
实施例11、4-(4-甲基哌嗪-1-基)-2´-羟基-4´,5´,6´-三甲氧基查尔酮（Ik）的合成
本实施例中的苯甲醛类化合物采用4-（1-四氢吡咯基）苯基。
合成步骤与实施例1相同，仅以4-（1-四氢吡咯基）苯基替代2-三氟甲基苯基。
产物的结构式如下：
产物的检测数据如下：
产率: 50%, 熔点: 156-157 ℃；
1H NMR (400 MHz, CDCl3): δ (ppm) 13.88 (s, 1H), 9.77 (s, 1H), 7.82 (s,1H), 7.75 (d, J =8.8 Hz, 1H), 6.92-6.89 (m, 2H), 6.28 (s, 1H), 3.91 (s, 3H),3.89 (s, 3H), 3.83 (s, 3H), 3.40 (t, J =5.2 Hz, 2H), 3.33 (t, J =5. 2Hz, 2H),2.57 (dd, J =11.2, 6.0 Hz, 2H), 2.34 (s, 1H).
13C NMR (100 MHz, CDCl3): δ (ppm) 190.4, 162.6, 159.7, 155.0, 144.1,135.3, 131.8, 130.2, 127.1, 125.7, 122.5, 114.8, 113.5, 108.9, 96.6, 61.9,61.31, 56.1, 54.8, 54.7, 47.7, 47.1, 46.2.
HRMS, 计算值: C23H29N2O5: 413.2071 [M + H]+; 检测值: 413.2088 [M + H]+.。
实施例12、2-氟-4-甲氧基-2´-羟基-4´,5´,6´-三甲氧基查尔酮（Il）的合成
本实施例中的苯甲醛类化合物采用2-氟-4-甲氧基苯基。
合成步骤与实施例1相同，仅以2-氟-4-甲氧基苯基替代2-三氟甲基苯基。
产物的结构式如下：
产物的检测数据如下：
产率: 68%, 熔点: 124-125 ℃；
1H NMR (400 MHz, CDCl3): δ (ppm) 12.34 (s, 1H), 7.81 (t, J =8.8 Hz,1H), 7.67 (dd, J =28.8 16 Hz, 2H), 7.00 (dd, J =13.2 2.4 Hz, 1H), 6.91 (dd, J =8.8 2.8 Hz, 1H), 6.39 (s, 1H), 3.85 (d, J =2.8 Hz, 3H), 3.70 (s, 3H), 3.34(s, 3H), 2.51 (s, 1H).
13C NMR (100 MHz, CDCl3): δ (ppm) 192.6, 162.7, 160.2, 155.0, 153.7,151.2, 142.0, 135.3, 128.8, 126.0, 125.4, 114.8, 113.2, 108.7, 96.6, 61.9,61.3, 56.3, 56.1.
HRMS, 计算值: C19H19FNaO6: 385.1058 [M + Na]+; 检测值: 385.1005 [M +Na]+.。
实施例13、2-氟-2´-羟基-4´,5´,6´-三甲氧基查尔酮（Im）的合成
本实施例中的苯甲醛类化合物采用2-氟苯基。
合成步骤与实施例1相同，仅以2-氟苯基替代2-三氟甲基苯基。
产物的结构式如下：
产物的检测数据如下：
产率: 60%, 熔点: 117-118 ℃；
1H NMR (400 MHz, CDCl3): δ (ppm) 13.63 (s, 1H), 7.89 (dd, J =38.4,15.6 Hz, 2H), 7.63 (dd, J =8.8, 5.6 Hz, 2H), 7.12 (t, J =8.8 Hz, 2H), 6.29(s, 1H), 3.92 (s, 3H), 3.89 (s, 3H), 3.83 (s, 3H).
13C NMR (100 MHz, CDCl3): δ (ppm) 192.7, 165.2, 162.7, 160.3, 155.0,141.9, 135.3, 131.6, 130.3, 126.3, 116.2, 108.7, 96.6, 61.9, 61.3, 56.1.
HRMS, 计算值: C18H17FNaO5: 355.0952 [M + Na]+; 检测值: 355.0884 [M +Na]+.。
二、查尔酮类似物的抗肿瘤活性实验
1、实施例14-26为通过MTT法检测查尔酮类似物对HeLa细胞、MGC-803细胞和HCT-116细胞的毒性实验。
实验中采用四甲基偶氮唑盐（MTT）比色法。培养肿瘤细胞选用培养基：HeLa细胞与HCT-116细胞使用含10% FBS，1%青链霉素混合液的DMEM培养基；MGC-803细胞使用含10%FBS，1%青链霉素混合液的RPMI-1640培养基。
将肿瘤细胞接种于96孔板，每个孔培养3-5×103个细胞，加入不同浓度的待测试查尔酮类似物合成产物溶液。培养48h后，每孔加入20 μL MTT测试液，MTT测试液为微黄色，注意避光，然后放入培养箱中静置4 h。之后取出96 孔板，吸出孔中液体，每孔加入150 μLDMSO溶液，溶解结晶，将96孔板放置于微量震荡器上充分震荡10分钟，观察结晶是否完全溶解，溶解完毕后置于酶标仪上检测吸光度，酶标仪波长设置为570nm，测OD值。
最后计算抑制率：抑制率%=1-（给药组-空白孔OD平均值）/（control组OD值-空白孔OD平均值）×100%。
所有实验设三个平行组或重复三次。
查尔酮类似物合成产物Ⅰa-Ⅰm的细胞毒性实验结果见表1。
体外实验表明，本发明合成的查尔酮类似物Ia-Im对人宫颈癌细胞（HeLa）、人胃癌细胞（MGC-803）、人结肠癌细胞（HCT-116）表现出较好的抑制活性，大多数化合物其抗肿瘤活性高于对照药CA-4及cis-Platin，尤其是Ic、Im对受试的三种细胞株显示了较高的抑制活性，表现出较好的应用前景。
2、实施例27为通过平板细胞克隆实验检测查尔酮类似物Ic对MGC-803细胞集落形成的影响
将细胞用PBS清洗、胰酶消化、新鲜完全培养基终止、离心机离心后重悬，用细胞计数板进行计数，接着将 MGC-803 细胞按照每孔 1500 个的细胞密度接种在6孔培养板中，加入适量新鲜培养液，然后在37℃、含5% CO2的培养箱中孵育24 h；次日，更换含有不同浓度化合物Ic（0.25μM、0.5 μM、1 μM、2 μM）的新鲜培养液，设置空白组、仅含0.1% DMSO 的新鲜培养液为DMSO对照组，置于 37 ℃、5% CO2细胞培养箱中孵育。每三天更换一次培养液，共孵育 9 天。当培养皿底部中出现肉眼可见集落群体时，弃去培养液，用1 mL PBS 洗涤2次，以4%多聚甲醛（Paraformaldehyde, POM）固定15分钟，然后在室温下以0.1%结晶紫染色15 min，之后再次用PBS洗涤多次，菌落干燥后在光照良好条件下用相机拍照。
通过平板细胞克隆实验成功测定了查尔酮类似物Ic对MGC-803细胞增殖能力的影响，结果如图1所示，加药组中不同浓度的查尔酮类似物合成产物Ic（0.25μM、0.5μM、1μM、2μM）与空白组和DMSO对照组比较，发现随着加药浓度的不断增加，培养皿中结晶紫的面积越来越少，并且颜色也逐渐变浅，甚至当查尔酮类似物合成产物Ic加药浓度为2 μM时，结晶紫几乎完全消失。结果表明查尔酮类似物合成产物Ic能够以剂量依赖性方式显著地抑制胃癌MGC-803细胞的体外生长。
3、实施例28为查尔酮类似物合成产物Ic对MGC-803细胞迁移及修复能力的抑制作用
将生长状态良好且处于对数生长期的MGC-803细胞进行细胞铺板操作。将细胞用PBS清洗、胰酶消化、新鲜完全培养基终止、离心机离心后重悬，接着将MGC-803细胞按照2×105个细胞于6孔培养板中，每组设3个复孔，培养至形成单层细胞后换无血清培养液于37℃、5% CO2细胞培养箱中饥饿培养4 h，用10 μL无菌移液器头沿培养板底部正中间划“一”字型划痕，用PBS洗涤除去漂浮物，更换含有不同浓度查尔酮类似物合成产物Ic（0.5 μM、1μM、2 μM、4 μM）的新鲜培养液，加药后继续培养48 h，使用显微镜观测划线区域愈合程度，拍照，计算细胞迁移率。
通过细胞创伤愈合实验成功测定了查尔酮类似物合成产物Ic对于MGC-803细胞迁移及修复能力的影响，结果如图2所示，一方面，由直观的倒置显微成像图2A观察明显可知，加药组划痕愈合程度显著低于未加药的空白对照组；另一方面由直观数据统计图2B所示，通过比较受创伤的MGC-803细胞0 h和48 h之间划痕宽度值的差别，准确计算得到各个加药浓度的细胞迁移率可知（空白组：34.38%；DMSO对照组：37.57%；加药组：0.5 μM：20.14%、1 μM：14.78%、2 μM：6.32%、4 μM：3.02%），随着加药浓度的增加，细胞迁移率逐渐降低。表明查尔酮类似物合成产物Ic对MGC-803细胞迁移及修复能力的抑制作用具有剂量依赖性。
4、实施例29为查尔酮类似物合成产物Ic阻滞MGC-803细胞周期
通过流式细胞术检测查尔酮类似物合成产物Ic诱导MGC-803细胞凋亡的同时是否也能阻滞肿瘤细胞周期。
将指数生长的MGC-803细胞进行细胞铺板操作。将细胞用PBS清洗、胰酶消化、新鲜完全培养基终止、离心机离心后重悬，用细胞计数板进行计数，接着将计数过的细胞稀释到适宜浓度，按照每孔约1×105细胞浓度以2 mL细胞悬液注射到6孔板上，记得左右摇匀，使得细胞分散均匀再放入细胞培养箱中过夜。24 h后，更换含有不同浓度查尔酮类似物合成产物Ic（0.5μM、1μM、2μM、4 μM、8 μM）的新鲜培养液，设置无药物contral组，置37 ℃、5%CO2细胞培养箱中培养48 h。细胞数量控制在1×105-1×106个。小心吸除细胞培养液，用胰酶消化细胞，制备成单细胞悬液。1000 g离心5 min，沉淀细胞，弃上清，用1 mL预冷的PBS润洗细胞一次，离心收集细胞。细胞沉淀用1 mL预冷的70%乙醇轻轻混匀，4 ℃固定2 h以上或者过夜。接下来1000 g，离心5 min沉淀细胞后，用1 mL预冷的PBS重悬。然后再次1000 g离心5 min沉淀细胞。在0.5 mL染色缓冲液（40301-C）中加入10 μL碘化丙啶储液（40301-B）和10 μL RNaseA（40301-A）溶液，混匀待用。每个细胞样品加入0.5 mL配制好的碘化丙啶染色液，轻轻混匀重悬细胞。37 ℃避光孵育30 min，就可以进行流式检测，流式检测最好在5 h内完成。配制好的PI染色液在短时间内可以4 ℃保存，宜当日使用。细胞用400目筛网过滤，用流式细胞仪进行检测，在激发波长488 nm波长处检测，同时检测光散射情况。采用分析软件进行细胞DNA含量分析和光散射分析。所有实验组均平行操作进行3次。
结果如图3所示，其中，细胞核中的DNA经与PI结合被染色，并且PI经一定波长的光刺激后显示荧光，其强度与DNA含量成正相关，图3A为不同浓度的查尔酮类似物合成产物Ic（0、0.5、1、2、4、8 μM）处理MGC-803细胞48 h后（其中0μM在图3A中标注为空白组），不同阶段细胞实际周期分布情况；图3B为细胞周期分布比例直观统计图，分别表示空白组（G1:74.18%，S: 20.94%，G2: 4.88%），加药浓度为0.5 μM时，（G1: 65.29%，S: 24.69%，G2:10.02%）；加药浓度为1 μM时，（G1: 52.18%，S: 32.15%，G2: 15.67%）；加药浓度为2 μM时，（G1: 48.72%，S: 33.26%，G2: 18.01%）；加药浓度为4 μM时，（G1: 43.66%，S: 39.26%，G2:17.08%）；加药浓度为8 μM时，（G1: 43.22%，S: 35.05%，G2: 21.73%）。比较发现，随着查尔酮类似物合成产物Ic加药浓度的增加，分布于G2期的MGC-803细胞比例也逐渐增加，表明查尔酮类似物合成产物Ic能够以剂量依赖性方式阻滞MGC-803细胞于G2/M期，从而具备抗肿瘤活性。
Claims (7)
1.查耳酮类似物作为活性物质在制备抗肿瘤药物中的应用，其特征在于，所述查耳酮类似物的结构式如下：
其中，R为苯基，选自三氟甲基、咪唑基、氯离子、氟离子、甲氧基、甲基、吡啶基、喹啉基、吗啉基、四氢吡咯基和4-甲基哌嗪基中的一种或几种。
2.权利要求1所述查耳酮类似物的合成方法，其特征在于：将氢氧化钾和苯甲醛类化合物混合，充入惰性气体保护，将2,3,4-三甲氧基-6-羟基苯乙酮溶于无水乙醇溶液中，缓慢滴加到氢氧化钾和苯甲醛类化合物混合溶液中，置于电热套中80℃加热搅拌反应2h，TLC检测反应进程，待反应完毕后，冷却至室温，减压蒸发取出多余溶剂，剩余物用无水乙醇溶解，通过洗脱剂石油醚/乙酸乙酯体系进行洗脱纯化，获得查耳酮类产物。
3.如权利要求2中所述查耳酮类似物的合成方法，其特征在于：所述苯甲醛类化合物的取代基为三氟甲基、咪唑基、氯离子、氟离子、甲氧基、甲基、吡啶基、喹啉基、吗啉基、四氢吡咯基和4-甲基哌嗪基中的一种或几种。
4.权利要求1所述查耳酮类似物作为活性物质在制备抗肿瘤药物中的应用，其特征在于：所述类似物用于制备抗肿瘤的药物。
5.权利要求1所述查耳酮类似物作为活性物质在制备抗肿瘤药物中的应用，其特征在于：所述类似物用于制备治疗宫颈癌的药物。
6.权利要求1所述查耳酮类似物作为活性物质在制备抗肿瘤药物中的应用，其特征在于：所述类似物用于制备治疗结肠癌的药物。
7.权利要求1所述查耳酮类似物作为活性物质在制备抗肿瘤药物中的应用，其特征在于：所述类似物用于制备治疗胃癌的药物。
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