CN113045399B - 查尔酮衍生物及其用途 - Google Patents

查尔酮衍生物及其用途 Download PDF

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CN113045399B
CN113045399B CN202110302392.7A CN202110302392A CN113045399B CN 113045399 B CN113045399 B CN 113045399B CN 202110302392 A CN202110302392 A CN 202110302392A CN 113045399 B CN113045399 B CN 113045399B
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姚宏亮
李刚
潘文俊
关文
王华敏
张亚莉
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Abstract

本发明公开了查尔酮衍生物及其用途。查尔酮衍生物的化学结构如式(a)或式(b)所示。本发明所述的查尔酮衍生物可以有效抑制肿瘤细胞的增殖，这为发展抗肿瘤药物提供一种新的先导化合物。

Description

查尔酮衍生物及其用途
技术领域：
本发明属于有机化合物领域，具体涉及查尔酮衍生物及其用途。
背景技术：
恶性肿瘤是危害人类健康最严重的一类疾病，它的发病率仅次于心脑血管疾病，是人类健康的第二大“杀手”，而其死亡率甚至超过心脑血管疾病，居于所有疾病的首位。因此，寻找和开发治疗肿瘤的新药是当前面临的重大课题。
查尔酮虽然有一定的抗肿瘤活性，但是如何经过修饰或改造使得其衍生物具有更强的抗肿瘤活性是技术人员所努力的。
发明内容：
本发明的第一个目的是提供一种能够抑制肿瘤细胞增殖的查尔酮衍生物。
本发明的查尔酮衍生物，其化学结构如(a)或(b)所示，
Figure BDA0002986839830000011
经过实验发现，上述查尔酮衍生物能够抑制肿瘤增殖，可用于制备肿瘤增殖抑制剂，该抑制剂的抗肿瘤效果显著。
因此，本发明的第二个目的是提供上述查尔酮衍生物在制备抗肿瘤药物中的应用。
本发明的第三个目的是提供一种抗肿瘤药物，其包括上述查尔酮衍生物作为活性成分。
所述的抗肿瘤药物为抗宫颈癌、结肠癌、乳腺癌、肺癌、肝癌或黑色素瘤的药物。
优选，所述的抗肿瘤药物包括查尔酮衍生物和医学上可接受的辅料。
本发明的查尔酮衍生物可以有效抑制肿瘤细胞的增殖，这为发展抗肿瘤药物提供一种新的先导化合物。
具体实施方式
以下实施例是对本发明的进一步说明，而不是对本发明的限制。
实施例1化合物7的合成
Figure BDA0002986839830000021
称量2-羟基-4,6-二甲氧基苯乙酮(970.8mg,5mmol)，置于100mL圆底烧瓶中，加入50mL无水乙醇和Ba(OH)2·8H2O(3.1546g,10mmol)，搅拌10min后缓慢加入苯甲醛(0.77mL,7.5mmol)，按上述温度和时间进行反应，TLC检测反应进行情况。反应完成后加入CH3COOH乙醇溶液(CH3COOH：EtOH＝1:10)至溶液pH＝6，旋干溶剂。得到的固体加入20mL水，用20mL乙酸乙酯萃取三次，合并有机相，然后再用Brine溶液洗涤，无水硫酸钠干燥，过滤，旋干溶剂，过柱，得到黄色固体粉末(化合物7)，产量：0.82g，产率：58％。1H NMR(400MHz,Chloroform-d)δ14.26(s,1H),7.90(d,J＝15.6Hz,1H),7.78(d,J＝15.6Hz,1H),7.63-7.57(m,2H),7.43-7.38(m,3H),6.11(d,J＝2.4Hz,1H),5.97(d,J＝2.4Hz,1H),3.92(s,3H),3.84(s,3H).13C NMR(100MHz,Chloroform-d)δ192.79,168.54,166.39,162.67,142.44,135.75,130.17,129.00(2C),128.48(2C),127.72,106.53,93.99,91.44,56.00,55.72.
实施例2化合物8的合成
Figure BDA0002986839830000031
称量2,6-二羟基-4-(2-(甲基(苯基)氨基)乙基)苯乙酮(5mmol)，置于100mL圆底烧瓶中，加入50mL无水乙醇和Ba(OH)2·8H2O(10mmol)，搅拌10min后缓慢加入对羟基苯甲醛(7.5mmol)，按上述温度和时间进行反应，TLC检测反应进行情况。反应完成后加入CH3COOH乙醇溶液(CH3COOH：EtOH＝1:10)至溶液pH＝6，旋干溶剂。得到的固体加入20mL水，用20mL乙酸乙酯萃取三次，合并有机相，然后再用Brine溶液洗涤，无水硫酸钠干燥，过滤，旋干溶剂，过柱，得到黄色固体粉末(化合物8)，产率：47％。1H NMR(400MHz,Chloroform-d)δ10.07(s,1H),7.96–7.76(m,2H),7.55(d,J＝8.0Hz,2H),6.87(d,J＝8.2Hz,2H),6.77(t,J＝8.3Hz,3H),5.96(s,2H),5.37(s,1H),4.17(q,J＝7.2,6.5Hz,2H),3.77(t,J＝6.0Hz,2H),3.05(s,3H).
实施例2查尔酮衍生物对肿瘤细胞抑制效果研究
本发明化合物的对肿瘤抑制效果采用如下方法测试所证明。
这些效果表明本发明化合物对肿瘤细胞抑制效果明显，其可用于治疗癌症。具体测试方法如下：
一、实验目的及原理
实验目的：采用MTT法检测合成的查尔酮衍生物对肿瘤细胞增殖的抑制效果。
实验原理：MTT比色法是一种检测细胞存活和生长的方法，其原理为活细胞线粒体中的琥珀酸脱氢酶能使外源性MTT还原为水不溶性蓝紫色结晶甲瓒，并沉积在细胞中，而死细胞缺少这一功能。二甲基亚砜(DMSO)可以溶解活细胞中的甲瓒，用酶联免疫检测仪检测570nM下的吸光度值(OD值)，可以根据吸光度值反应活细胞的数量，在一定范围内，OD值越小，则表明细胞活性越弱，药物的抑制增殖效果越好。
二、试剂基本信息
试剂名称 品牌
RPMI-1640培养基粉末 Gibco
胎牛血清 Capricorn Scientific
二甲基亚砜(DMSO) Sigma
四甲基偶氮唑蓝(MTT) Sigma
三、试剂配制
1、RPMI-1640完全培养基
配置1L的RPMI-1640培养基，取相应量的RPMI-1640粉末，溶于含有800ml三蒸水的烧杯中，搅拌4h，直至粉末完全溶解。加入2g NaHCO3，搅拌至完全溶解。用浓度为1mol/L的盐酸调节PH，使其PH在7.2-7.4范围内，定容至1L。用装有0.22μm孔径的滤膜，并提前高压好的滤器过滤，分装，保存于4℃备用。使用时加入5％的血清，使其成完全培养基，即可用于细胞培养。
2、MTT
将50ml的离心管用锡箔纸包裹避光，精密称取MTT粉末250mg，加入到离心管中，加入50ml的PBS，使MTT粉末完全溶解，用0.22μm孔径的滤膜过滤除菌并分装，在-20℃条件下避光保存。
3、化合物配置
取高压灭菌后的EP管用于称取化合物，向EP管中加入对应量的DMSO，使液体成100mM的母液，并分别按比例稀释到30mM，10mM，3mM，1mM。使用时用相应量的培养基稀释1000倍，即可配成浓度为0.1μM，0.3μM，1μM，10μM，30μM，100μM的工作液。
四、实验过程
(1)取对数生长期的宫颈癌细胞(Hela)、乳腺癌细胞(MCF-7)、肺癌细胞(NCI-H292)、黑色素瘤细胞(B16-F10)，结肠癌细胞(HCT-116)，肝癌细胞(HepG2)，消化，调整细胞数浓度为2.5×104个/mL，按100μl/孔接种到96孔板中。在37℃，5％CO2细胞培养箱中培养过夜，待细胞贴壁。
(2)吸出原有培养基，每组加入不同浓度的查尔酮衍生物系列化合物，每个化合物梯度浓度分别为0.1μM，0.3μM，1μM，10μM，30μM，100μM，每个处理3个重复。以0.1％的DMSO设为对照组，以柚皮素作为阳性对照，以不加细胞和化合物作为空白对照，在细胞培养箱中继续培养72h。
(3)每孔加入10μl MTT液，在培养箱中孵育4h。
(4)弃去培养基，每孔加入100μl DMSO，振荡15min充分溶解甲瓒结晶。
(5)用酶联免疫检测仪测定570nm下的吸光度值。
(6)按以下公式计算细胞生长抑制率：
抑制率＝[(As-Ab)/(Ac-Ab)]×100％
As：实验孔的吸光度(含细胞、MTT、化合物)
Ac：对照孔的吸光度(含细胞、MTT，无化合物)
Ab：空白孔的吸光度(不含细胞和化合物，含MTT)
结果见下表1。
表1化合物对肿瘤细胞生长的半数抑制浓度
Figure BDA0002986839830000061
从表1可以看出，合成的查尔酮衍生物可以有效抑制肿瘤细胞的生长，比柚皮素对照组活性有显著提高。另外，针对该类化合物的衍生化及对Hela作用的研究调研发现，化合物7其活性比目前文献报道的更优。

Claims (4)

1.查尔酮衍生物，其化学结构如式(b)所示：
Figure FDA0003476483670000011
2.权利要求1所述的查尔酮衍生物在制备抗肿瘤药物中的应用；所述的抗肿瘤药物为抗宫颈癌、结肠癌、乳腺癌、肺癌、肝癌或黑色素瘤的药物。
3.一种抗肿瘤药物，其特征在于，包括权利要求1所述的查尔酮衍生物作为活性成分；所述的抗肿瘤药物为抗宫颈癌、结肠癌、乳腺癌、肺癌、肝癌或黑色素瘤的药物。
4.根据权利要求3所述的抗肿瘤药物，其特征在于，所述的抗肿瘤药物包括查尔酮衍生物和医学上可接受的辅料。
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Address after: 528306, 4th Floor, Building 19, Shengyue Garden, No. 33 Shunye East Road, Xingtan Town, Shunde District, Foshan City, Guangdong Province

Patentee after: Guangdong Andao Medical Instrument Co.,Ltd.

Address before: No.105, Xingang West Road, Guangzhou, Guangdong 510000

Patentee before: Institute of zoology, Guangdong Academy of Sciences