CN114044764B - 中草药小分子化合物及其应用、药物组合物 - Google Patents
中草药小分子化合物及其应用、药物组合物 Download PDFInfo
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Abstract
本发明公开了一种作为雌激素受体激动剂的中草药小分子化合物，包括上述的中草药小分子化合物以及中草药小分子化合物的应用。结合说明书实施例部分的内容，这种中草药小分子化合物对乳腺癌细胞MCF‑7(雌激素受体阳性细胞)具有促增殖效果，此外结合图1和图2，通过分子对接计算方法验证了中草药小分子化合物与雌激素受体具有很强的亲和力，从而说明中草药小分子化合物可作为雌激素受体的激动剂。
Description
技术领域
本发明涉及医药领域，尤其是涉及一种作为雌激素受体激动剂的中草药小分子化合物及其应用、药物组合物。
背景技术
雌激素是负责雌性生殖系统和第二雌性性征的发育和调节的主要雌性激素。雌激素也特别地在蛋白质合成、凝血、脂质平衡、液体平衡、黑色素、胃肠道功能、肺功能、认知、免疫反应和心脏疾病中发挥作用。
雌激素受体是配体激活的转录调节蛋白，其通过与内源雌激素的相互作用来介导多种生物学效应的诱导。
雌激素在体内可与雌激素受体结合，通过激活雌激素受体而发挥重要的生理作用，在生殖系统、内分泌系统、骨骼系统、神经系统和心血管系统等多系统的功能维持方面扮演着重要的角色。当机体雌激素水平下降，雌激素受体不能正常激活时，容易导致骨质疏松、月经不调、不孕症、更年期综合征、老年痴呆等疾病。雌激素受体是重要的核受体超家族成员，能够与雌激素应答元件结合调控DNA转录过程，在机体生长发育和代谢过程中发挥重要的调控作用，也是治疗骨质疏松、妇产科疾病、神经退行性疾病、心脑血管疾病、自身免疫性疾病、皮肤病、脱发、癌症等疾病以及抗衰老的重要药物作用靶标。
近年来，中草药小分子化合物因具有功效显著、毒副作用小等特点，逐渐被应用于中成药制剂、保健品和化妆品等行业。现有技术中并没有中草药小分子化合物是否可以作为雌激素受体激动剂的相关报导。
发明内容
基于此，有必要提供一种可以作为雌激素受体激动剂的中草药小分子化合物。
此外，还有必要提供一种包括上述中草药小分子化合物的药物组合物以及中草药小分子化合物的应用。
一种作为雌激素受体激动剂的中草药小分子化合物，所述中草药小分子化合物的结构通式如下：
其中，-R1为-CH(CH3)2或-OH；
-R2为-OH或-CH(CH3)2；
-R3处稠合了一个2(5H)-呋喃酮，或者，-R3为连接到同一个碳原子上的两个-CH3。
在一个实施例中，所述中草药小分子化合物为具有如下结构式的雷酚内酯或桃拓酚：
在一个实施例中，所述雷酚内酯的有效作用浓度为0.0016μM～0.2μM，所述桃拓酚的有效作用浓度为0.0016μM～1μM。
一种药物组合物，包括上述的中草药小分子化合物、其立体异构体、其药学上可接受的盐、其溶剂化物或其前药。
在一个实施例中，所述药物组合物用于预防和治疗骨质疏松、妇产科疾病、神经退行性疾病、心脑血管疾病、自身免疫性疾病、皮肤病、脱发以及癌症。
一种上述的中草药小分子化合物、其立体异构体、其药学上可接受的盐、其溶剂化物或其前药，在药物领域、保健食品领域和化妆品领域的应用。
结合说明书实施例部分的内容，这种中草药小分子化合物对乳腺癌细胞MCF-7(雌激素受体阳性细胞)具有促增殖效果，此外结合图1和图2，通过分子对接计算方法验证了中草药小分子化合物与雌激素受体具有很强的亲和力，从而说明中草药小分子化合物可作为雌激素受体的激动剂。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案，下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本发明的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他的附图。
其中：
图1为雷酚内酯与雌激素受体间的成键形式图。
图2为桃拓酚与雌激素受体间的成键形式图。
图3为实施例1中雷酚内酯对MCF-7细胞增殖的影响图。
图4为实施例2中桃拓酚对MCF-7细胞增殖的影响图。
具体实施方式
下面将结合本发明实施例中的附图，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
本发明公开了一种作为雌激素受体激动剂的中草药小分子化合物，中草药小分子化合物的结构通式如下：
其中，-R1为-CH(CH3)2或-OH；
-R2为-OH或-CH(CH3)2；
-R3处稠合了一个2(5H)-呋喃酮，或者，-R3为连接到同一个碳原子上的两个-CH3。
优选的，中草药小分子化合物为具有如下结构式的雷酚内酯或桃拓酚：
具体来说，雷酚内来源于酯雷公藤，桃拓酚来源于罗汉松，二者均为性质相对温和的中草药小分子化合物。
结合说明书实施例部分的内容，这种中草药小分子化合物对乳腺癌细胞MCF-7(雌激素受体阳性细胞)具有促增殖效果。
为研究中草药小分子化合物的雌激素活性，本发明通过分子对接软件分析雌激素受体与中草药小分子化合物之间结合的构象，并进一步分析了小分子与雌激素受体相互作用的构象。
结合图1和图2，雷酚内酯的氧原子与雌激素受体的关键氨基酸残基Arg394的氢原子形成氢键，说明其能与雌激素受体通过氢键相互作用结合，而桃拓酚主要通过共轭效应与雌激素受体结合。
需要说明的是，氢键是指氢原子与电负性大、半径小的原子X以一种特殊的分子间作用力结合形成X-H形式的化学键；共轭效应是指共轭体系中由于原子间的相互影响而使体系内的π电子(或p电子)分布发生变化的一种电子效应。
由此，结合实施例部分的数据以及分子对接计算方法验证了中草药小分子化合物与雌激素受体具有很强的亲和力，从而说明中草药小分子化合物可作为雌激素受体的激动剂。
优选的，雷酚内酯的有效作用浓度为0.0016μM～0.2μM，桃拓酚的有效作用浓度为0.0016μM～1μM。中草药小分子化合物的作用浓度温和。
本发明还公开了一种药物组合物，包括上述的中草药小分子化合物、其立体异构体、其药学上可接受的盐、其溶剂化物或其前药。
当机体雌激素水平下降，雌激素受体不能正常激活时，容易导致骨质疏松、月经不调、不孕症、更年期综合征、老年痴呆等疾病。
基于此，可以作为雌激素受体的激动剂的中草药小分子化合物在理论上可以用于预防和治疗上述相关的疾病。
具体来说，药物组合物用于预防和治疗骨质疏松、妇产科疾病、神经退行性疾病、心脑血管疾病、自身免疫性疾病、皮肤病、脱发以及癌症。
本发明还公开了一种上述的中草药小分子化合物、其立体异构体、其药学上可接受的盐、其溶剂化物或其前药，在药物领域、保健食品领域和化妆品领域的应用。
以下为具体实施例。具体实施例中，乳腺癌细胞MCF-7购于中科院细胞库，胎牛血清为中国杭州四季青生物股份有限公司产品，双抗为美国Gibco产品。
实施例1
雷酚内酯对乳腺癌细胞MCF-7生长的影响试验
(1)活性炭处理四季青胎牛血清：
1)在装有100mL胎牛血清的烧杯中加入1g活性炭，置于56℃水浴条件下持续搅拌2小时后，超速离心机17000rpm离心20min；2)将上清液收集在一个新的烧杯中，加入1g活性炭，置于37℃水浴条件下持续搅拌2小时后，超速离心机17000rpm离心20min；3)将上清液收集在一个新的烧杯中，加入1g活性炭，置于4℃冰浴条件下持续搅拌3小时后，超速离心机在17000rpm离心30min；
4)最后将收集到的上清液用0.22μm的无菌滤膜过滤，并分装保存于-80℃冰箱备用。
(2)雷酚内酯对乳腺癌细胞MCF-7增殖的测定(结晶紫染色法)：
1)采用无酚红的RPMI1640培养基(内含10％活性炭处理过的胎牛血清和1％双抗)培养MCF-7细胞3天；2)将细胞消化，按照5×104个/mL的MCF-7细胞悬液100μL加入96孔板中，培养24h，吸去培养板中的细胞培养液，加入用细胞培养液稀释的不同浓度的雷酚内酯，每个稀释浓度包含6个复孔，置于37℃二氧化碳培养箱中培养72h，弃细胞培养液，加入新配置的不同浓度的雷酚内酯的细胞培养液，置于37℃二氧化碳培养箱中再培养72h；3)弃细胞培养液，加入1％戊二醛100μL固定30min，用PBS清洗细胞3次，置于室温下彻底干燥后，0.5％的结晶紫溶液50μL染色15min，弃染液并用清水清洗多余的结晶紫，置于室温下彻底干燥，0.5％的100X-Triton溶液100μL过夜溶解后，通过酶标仪检测405nm、560nm的OD值。
计算雷酚内酯对乳腺癌细胞MCF-7的增殖效果：细胞的密度＝OD值(650)-OD值(405)，结果图3所示。
由图3可以看出，雷酚内酯对乳腺癌细胞MCF-7具有明显的促增殖效果。
具体来说，雷酚内酯的有效作用浓度为0.0016μM～0.2μM，作用浓度温和。
实施例2
桃拓酚对乳腺癌细胞MCF-7生长的影响试验
(1)活性炭处理四季清胎牛血清：
1)在装有100mL胎牛血清的烧杯中加入1g活性炭，置于56℃水浴条件下持续搅拌2小时后，超速离心机17000rpm离心20min；2)将上清液收集在一个新的烧杯中，加入1g活性炭，置于37℃水浴条件下持续搅拌2小时后，超速离心机17000rpm离心20min；3)将上清液收集在一个新的烧杯中，加入1g活性炭，置于4℃冰浴条件下持续搅拌3小时后，超速离心机在17000rpm离心30min；
4)最后将收集到的上清液用0.22μm的无菌滤膜过滤，并分装保存于-80℃冰箱备用。
(2)桃拓酚对乳腺癌细胞MCF-7增殖的测定(结晶紫染色法)：
1)采用无酚红的RPMI1640培养基(内含10％活性炭处理过的胎牛血清和1％双抗)培养MCF-7细胞3天；2)将细胞消化，按照5×104个/mL的MCF-7细胞悬液100μL加入96孔板中，培养24h，吸去培养板中的细胞培养液，加入用细胞培养液稀释的不同浓度的桃拓酚，每个稀释浓度包含6个复孔，置于37℃二氧化碳培养箱中培养72h，弃细胞培养液，加入新配置的不同浓度的桃拓酚的细胞培养液，置于37℃二氧化碳培养箱中再培养72h；3)弃细胞培养液，加入1％戊二醛100μL固定30min，用PBS清洗细胞3次，置于室温下彻底干燥后，0.5％的结晶紫溶液50μL染色15min，弃染液并用清水清洗多余的结晶紫，置于室温下彻底干燥，0.5％的100X-Triton溶液100μL过夜溶解后，通过酶标仪检测405nm、560nm的OD值。
计算桃拓酚对乳腺癌细胞MCF-7的增殖效果：细胞的密度＝OD值(650)-OD值(405)，结果图4所示。
由图4可以看出，桃拓酚对乳腺癌细胞MCF-7具有明显的促增殖效果。
具体来说，桃拓酚的有效作用浓度为0.0016μM～1μM，作用浓度温和。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对申请专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。
Claims (3)
1.一种中草药小分子化合物作为雌激素受体激动剂的应用，其特征在于，所述中草药小分子化合物的结构通式如下：
其中，-R1为-CH(CH3)2或-OH；
-R2为-OH或-CH(CH3)2；
-R3处稠合了一个2(5H)-呋喃酮，或者，-R3为连接到同一个碳原子上的两个-CH3。
2.根据权利要求1所述的应用，其特征在于，所述中草药小分子化合物为具有如下结构式的雷酚内酯或桃拓酚：
3.根据权利要求1或2所述的应用，其特征在于，所述雷酚内酯的有效作用浓度为0.0016μM～0.2μM，所述桃拓酚的有效作用浓度为0.0016μM～1μM。
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