CN113694073A - 一种化合物及其用途 - Google Patents
一种化合物及其用途 Download PDFInfo
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- CN113694073A CN113694073A CN202110948864.6A CN202110948864A CN113694073A CN 113694073 A CN113694073 A CN 113694073A CN 202110948864 A CN202110948864 A CN 202110948864A CN 113694073 A CN113694073 A CN 113694073A
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Abstract
本发明提供了一种化合物在制备治疗抗癌药物中的用途。本发明研究发现，上述化合物具备良好的抗癌活性，可将其作为新的具备抗癌活性的药物，为临床治疗癌症尤其是肺癌提供了一种新的可能。
Description
技术领域
本发明涉及天然植物化学领域。
背景技术
癌症是由于机体细胞失去正常调控,过度增殖而引起的疾病。过度增殖的细胞称癌细胞，癌细胞常可侵犯周围组织(浸润，invasion),甚至可经体内循环系统和/或淋巴系统转移到身体其他部分(癌症转移)。
肺癌是发病率和死亡率增长最快，对人群健康和生命威胁最大的恶性肿瘤之一。近50年来许多国家都报道肺癌的发病率和死亡率均明显增高，男性肺癌发病率和死亡率均占所有恶性肿瘤的第一位，女性发病率占第二位，死亡率占第二位。肺癌的病因至今尚不完全明确，大量资料表明，长期大量吸烟与肺癌的发生有非常密切的关系。已有的研究证明：长期大量吸烟者患肺癌的概率是不吸烟者的10～20倍，开始吸烟的年龄越小，患肺癌的几率越高。此外，吸烟不仅直接影响本人的身体健康，还对周围人群的健康产生不良影响，导致被动吸烟者肺癌患病率明显增加。城市居民肺癌的发病率比农村高，这可能与城市大气污染和烟尘中含有致癌物质有关。因此应该提倡不吸烟，并加强城市环境卫生工作。
发明内容
本发明提供了一种具备抗癌活性的药物，具体的，本发明提供了如式I所示化合物或其药学上可接受的盐在制备治疗抗癌药物中的用途：
其中，R1、R2分别独立选自O、Me、H或无，两者不同时为无；
R3选自H或OH；
R4选自H或糖基。
其中，当R1、R2其中之一为无时，另一个为H。
进一步地，所述化合物选自如下结构：
其中，所述糖基选自葡萄糖、半乳糖、鼠李糖、木糖、阿拉伯糖中的一种。
更进一步地，所述化合物选自如下结构：
其中，所述药物是抗肺癌的药物，所述肺癌包括非小细胞肺癌(NSCLC)和小细胞肺癌(SCLC)。
进一步地，所述肺癌选自非小细胞肺癌，包括但不限于肺腺癌(例如腺泡状腺癌、乳头状腺癌、细支气管肺泡癌(BAC)和实性腺癌及多种混合型)、肺鳞癌(例如乳头状鳞状细胞癌、透明细胞鳞状细胞癌、小细胞鳞状细胞癌、基底鳞状细胞癌)、大细胞癌(例如透明细胞大细胞癌、基底细胞样大细胞癌、肺淋巴上皮瘤样癌、肺大细胞神经内分泌癌)等。
本发明还提供了一种化合物，其结构式如下：
基于上述化合物，本发明还提供了一种药物，其活性成分包括上述式III化合物。
本发明所述抗癌，包括抑制癌细胞生长、促进癌细胞凋亡等等。
本发明研究发现，上述化合物具备良好的抗癌活性，可将其作为新的具备抗癌活性的药物，为临床治疗癌症尤其是肺癌提供了一种新的可能。
本发明所述化合物，可以通过从粉防己中提取纯化获得，也可以通过有机合成方法制备得到。例如，若R4部位为H，即该类化合物为糖苷配基，可以通过糖苷化合物水解获取。
所述粉防己为防己科(Menispermaceae)千金藤属植物粉防己(StephaniatetrandraS.Moore)的干燥根。
本发明药物中还可以使用药学上可接受的辅料或辅助性成分。
所述“药学上可接受的”是指包括任意不干扰活性成分的生物活性的有效性且对它被给予的宿主无毒性的物质。
“辅料”是药物制剂中除主药以外的一切附加材料的总称，辅料应当具备如下性质：(1)对人体无毒害作用，几无副作用；(2)化学性质稳定，不易受温度、pH、保存时间等的影响；(3)与主药无配伍禁忌，不影响主药的疗效和质量检查；(4)不与包装材料相互发生作用。
所述药学上可接受的辅助性成分，它具有一定生理活性，但该成分的加入不会改变上述药物组合物在疾病治疗过程中的主导地位，而仅仅发挥辅助功效，这些辅助功效仅仅是对该成分已知活性的利用，是医药领域惯用的辅助治疗方式。若将上述辅助性成分与本发明药物组合物配合使用，仍然应属于本发明保护的范围。
药学上可以接受的辅料，如纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
其中，所述药物组合物为经口给药制剂。
当然，本发明药物组合物的施用方式没有特别限制，除了经口给药外，也可以使用局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂、颗粒剂等，不限于上述剂型。在这些固体剂型中，原料或提取物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，原料或提取物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了原料或提取物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。除了原料或提取物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于局部给药的本发明组合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药，或者与其他药学上可接受的药物联合给药。
显然，根据本发明的上述内容，按照本领域的普通技术知识和手段，在不脱离本发明上述基本技术思想前提下，还可以做出其他多种形式的修改、替换或变更。
以下通过具体实施例的形式，对本发明的上述内容再做进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实施例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
图1：化合物1的质谱图
图2：化合物1的1H NMR谱
图3：化合物1的13C NMR谱
具体实施方式
实施例1
将10kg粉防己粉碎(5～10目)，用3.0L 70％乙醇水(盐酸调节pH＝3)常温浸提24小时。抽滤得总浸提液，真空浓缩除去大部分乙醇，氨水调节pH＝9～10，用氯仿萃取，得氯仿萃取物约90g。水相部分上D101型大孔树脂柱，依次用30％和70％的乙醇水洗脱，分别得到30％和70％乙醇水洗脱物约60g、30g。
将氯仿萃取物部分上硅胶柱(Φ12cm×60cm)，以氯仿-甲醇15：1到5：1梯度洗脱，每个梯度洗脱1.5L，每150mL洗脱物收集一瓶，真空浓缩回收溶剂，薄层追踪、合并相似组分，共得到10个组分(依次排序为STC-1到STC-10)。样品STC-1经过硅胶柱层析(石油醚-乙酸乙酯＝4：1)得到2(23.4mg)，样品STC-2经过硅胶柱(Φ4cm×45cm)层析得到化合物3(14.1mg)和4(18.3mg)，样品STC-3经过硅胶柱(Φ4cm×40cm)层析得到化合物5(8.3mg)、7(7.3mg)，样品STC-4经过硅胶柱层析(石油醚-丙酮＝1：1)得到化合物10(6.3g)、11(8.6g)。
将70％乙醇水洗脱物上Sephadex LH-20(Φ4cm×90cm)，以甲醇洗脱(每15mL收集1瓶，自然挥发溶剂)，薄层追踪、合并相似组分，共得到五个组分(依次排序为STC-701到STC-705)，STC-702在HPLC上以甲醇(45％)～水(55％)(水相中含氨水0.1％)等度洗脱，流速35mL/min，柱子规格为(C18,Φ30mm×250mm)，得到化合物6(tR＝23.7min,5.6mg)。
将30％乙醇水洗脱物上反相柱(ODS-C18，75μm)，分别以15％、75％甲醇水洗脱，分别得约20g STC301和约15g STC302，将样品STC-301上LH-20，以甲醇洗脱，控制流速约1滴/秒，每1/20个柱体积洗脱液收集1个馏分，点板合并相似组分，得到STC-3011(17.1g)、STC-3012(1.8g)，样品3011上硅胶柱(Φ8cm×60cm)，以氯仿甲醇3：1等度洗脱，每150mL收集一瓶，真空浓缩回收溶剂，薄层追踪、合并相似组分，得到10个组分(STC-3011-1到STC-3011-10)，样品STC-3011-6经HPLC梯度洗脱，甲醇-水35％到45％(0-50min)，流速35mL/min，柱子规格为(C18,Φ30mm×250mm)，得化合物9(tR＝32.2min,200mg)，样品STC-3011-10经HPLC梯度洗脱，甲醇-水5％到15％(0-50min)，流速35mL/min，柱子规格为(C18,Φ30mm×250mm)，得化合物1(tR＝8min,5.2mg)、8(tR＝31min,11.3g)。
化合物1：浅黄色粉末，
λmax＝282(0.938)，λmax＝234(1.191)，高分辨质谱HR-ESI-MS准分子离子峰m/z:494.20273[M+H]+(calculated 494.20262 for C24H32NO10)给出分子式为C24H32NO10。
1H and 13C NMR(Table 1,400MHz for the 1H NMR and 100MHz for the 13CNMR,CD3OD)。
表1化合物1的核磁共振氢谱和碳谱
对本发明的各化合物进行抗癌活性研究(人肺癌细胞株H1299,肺腺癌亚型)，检测方法：采用MTT法测试了部分化合物对人肺癌耐药细胞株H1299的IC50活性。细胞株用含10％胎牛血清的DMEM培养基(100U/mL青霉素、100μg/mL链霉素)在37℃、5％CO2培养箱中培养。
取对数期的细胞株，按大约3000细胞/孔的量接种于96孔板，置于37℃恒温培养箱中孵育24h。24h后，将不同浓度梯度的样品分别加入到培养孔中，并设置空白对照，置于细胞培养箱中继续培养72h。再向培养基中加入20μL MTT培养液(5mg/mL)染色4h。移去MTT溶液，每孔加入150μL DMSO，震荡10min后，用酶标仪检测在570nm波长下各孔的吸光值，并计算抑制率及IC50。
表2
吉非替尼，是一种口服表皮生长因子受体酪氨酸激酶(EGFR-TK)抑制剂(属小分子化合物)。对EGFR-TK的抑制可阻碍肿瘤的生长、转移和血管生成，并增加肿瘤细胞的凋亡。可用于治疗既往接受过化学治疗的局部晚期或转移性非小细胞肺癌(NSCLC)。
本发明研究表明，上述化合物能够有效抗癌，尤其是针对肺癌细胞；在同等试验条件下，上述化合物的IC50均低于吉非替尼，其中部分化合物甚至显著低于吉非替尼，例如化合物1、3、5、7、10等。说明上述天然化合物或可有效预防或治疗肺癌，尤其是非小细胞肺癌。
Claims (10)
1.如式I所示化合物或其药学上可接受的盐在制备治疗抗癌药物中的用途：
其中，R1、R2分别独立选自O、Me、H或无，两者不同时为无；
R3选自H或OH；
R4选自H或糖基。
2.根据权利要求1所述的用途，其特征在于：R1、R2其中之一为无时，另一个为H。
3.根据权利要求1所述的用途，其特征在于：所述化合物选自如下结构：
4.根据权利要求1或3任意一项所述的用途，其特征在于：所述糖基选自葡萄糖、半乳糖、鼠李糖、木糖、阿拉伯糖中的一种。
5.根据权利要求4所述的用途，其特征在于：所述化合物选自如下结构：
6.根据权利要求1-5任意一项所述的用途，其特征在于：所述药物是抗肺癌的药物。
7.根据权利要求6所述的用途，其特征在于：所述肺癌选自非小细胞肺癌。
8.根据权利要求6所述的用途，其特征在于：所述肺癌选自肺腺癌、肺鳞癌、大细胞癌。
9.一种化合物，其结构式如下：
10.一种药物，其特征在于：它包括权利要求9所述的化合物。
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