CN110878065A - 一类含氟噻唑酰胺衍生物在制备抗癌药物中的用途 - Google Patents
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Abstract
本发明提供了一类含氟噻唑酰胺衍生物在制备抗宫颈癌药物中的用途,本发明涉及一类含氟噻唑酰胺衍生物,其化学结构见式I:
Description
技术领域
本发明的技术方案涉及含氟噻唑酰胺衍生物在制备抗癌药物中的制备方法和用途,具体涉及此类化合物的在抗宫颈癌药物的制备方法和用途。
背景技术
药物是保障大众健康的重要有效工具,新药创制是复杂的系统工程,正如对症治疗一样,新药的创制往往具有很强的靶向性,布鲁顿酪氨酸激酶(BTK)就是白血病的重要靶标之一,BTK在骨髓细胞、肥大细胞和B细胞等造血细胞中表达,但在T细胞、血浆细胞和NK细胞中不表达(Smith,C.I.;et al.,J Immunol 1994,152,557-65),已成为B细胞恶性肿瘤和自身免疫性疾病的热门靶点。近年来,仅基于布鲁顿酪氨酸激酶(BTK)就已创制出多个药物品种,ibrutinib更是这类药剂中的明星分子。然而,以BTK酶为重要靶标,开展ibrutinib的先导优化已有多项报道,其中,专利文献报道了一类三取代噻唑酰胺衍生物及其制备方法和用途(CN 201811414373.8):在医药领域,10微摩尔每升时,化合物7i对BTK酶的抑制活性为99.78±1.04%,IC50为0.86微摩尔每升,ibrutinib的抑制活性为99.76±1.0,IC50为0.002微摩尔每升,以IC50比较,化合物7i的活性是ibrutinib的约1/430。然而,在活体条件下,化合物7i对Ramos细胞增殖抑制活性的IC50为1.42微摩尔每升,ibrutinib的IC50为14.69微摩尔每升,以IC50比较,化合物7i对Ramos细胞的活性是ibrutinib的10.35倍;对Raji细胞增殖抑制活性的IC50为2.82微摩尔每升,ibrutinib的IC50为15.99微摩尔每升,以IC50比较,化合物7i对Ramos细胞的活性是ibrutinib的近5.67倍。化合物7i对B细胞淋巴癌细胞系的Ramos和Raji细胞系的细胞增殖具有很好的抑制活性。
实体癌瘤与淋巴癌具有很大的差异,子宫颈癌是世界各地女性生殖器官癌瘤中最常见的恶性实体癌瘤之一,在我国引发的死亡率占女性癌患者的第二位,其发病原因并不清楚。Hela细胞是一种人工培养条件下具有无限增殖能力的细胞,是人子宫颈癌组织分离出来的株细胞和研究宫颈癌的常用材料。
基于不同癌症之间生理生化的巨大差异,为了寻找更多高效抗宫颈癌的候选药物分子,本发明创造性的发现了对B细胞淋巴癌细胞增殖有很好抑制活性的含氟噻唑酰胺衍生物具有优异的抑制宫颈癌细胞Hela细胞的增殖活性。
发明内容
本发明的目的在于提供含氟噻唑酰胺衍生物的在制备抗宫颈癌药物的方法和用途,其化学结构式如I所示:
本发明式I目标化合物的试验代号为Gxf02-200-2,也就是背景技术里介绍的化合物7i,其抗宫颈癌活性测定的具体方法分为以下步骤:
抑制癌细胞增殖活性测定:
培养Hela细胞,取2000-3000个细胞均匀铺于96孔培养板中,利用CCK-8试剂盒测试细胞增殖抑制活性。本发明的化合物处理时间分别是48小时和72小时,每孔加入本发明的化合物母液10微升,CCK-8试剂10微升;然后测定450纳米下的吸光度值(OD值)。本发明的化合物每个化合物的测试浓度为10或5微摩尔每升。根据OD值计算活性化合物抑制细胞增殖活性,每个浓度至少设置三个重复。本发明的化合物的化学结构与ibrutinib最接近,因此,本发明选择ibrutinib为阳性对照药剂。
本发明通过特定制备和生物活性测定实施例更加具体说明含氟噻唑酰胺衍生物I的合成与抗宫颈癌细胞增殖的活性及应用,所述实施例仅用于具体说明本发明而非限制本发明,仅是举例说明,而非限制本专利,具体实施方式如下:
实施例1:本发明的含氟噻唑酰胺衍生物I对Hela细胞增殖抑制活性的测定结果:
按照说明书的使用方法对含氟噻唑酰胺衍生物I(Gxf02-200-2)进行抑制Hela细胞增殖活性的测试测试,测试结果见表1;原始数据见表2。如表所示,本发明的含氟噻唑酰胺衍生物I对宫颈癌Hela细胞有较好的抗细胞增殖活性,其48小时的细胞增殖抑制率为44.69%,高出阳性对照药剂ibrutinib(15.70%)的抑制率28.99%,72小时的细胞增殖抑制率为47.13%,高出阳性对照药剂ibrutinib(26.16%)的抑制率20.97%,对照药剂ibrutinib是化学结构与本发明的含氟噻唑酰胺衍生物I结构最接近的化合物。由此可见,ibrutinib对宫颈癌细胞Hela细胞增殖几乎没有抑制活性,为了进一步的验证ibrutinib对宫颈癌细胞Hela细胞增殖活性的影响,使用相同浓度的含氟噻唑酰胺衍生物I+相同浓度的ibrutinib组合物在同样条件下进行了测试,结果发现,48h时上述组合物的抑制率平均值为60.01%,与单独使用含氟噻唑酰胺衍生物I的抑制率相比较,活性提高了15%左右,在短时间内,ibrutinib对宫颈癌细胞Hela细胞的增殖抑制有增效作用,随着时间的延长,在72h时,上述组合物的抑制率平均值为51.96%,与单独使用含氟噻唑酰胺衍生物I的抑制率相比较,活性提高了不足5%;试验结果再次说明ibrutinib与本发明的含氟噻唑酰胺衍生物I组合使用对宫颈癌细胞Hela细胞增殖的活性仅仅表现了本发明的含氟噻唑酰胺衍生物I的活性,ibrutinib对宫颈癌细胞Hela细胞增殖的抑制没有贡献。本发明的结果说明:尽管本发明的含氟噻唑酰胺衍生物I对B细胞淋巴癌细胞系中的Ramos和Raji细胞系的细胞增殖有很好的抑制活性,对于同样引发其他癌症如宫颈癌的Hela细胞也具有很好的细胞增殖抑制活性,ibrutinib虽然结构类型与本发明的目标化合物相似,尽管其对B细胞淋巴癌细胞系中的Ramos和Raji细胞系的细胞增殖有很好的抑制活性,但对引发宫颈癌的Hela细胞的细胞增殖却没有抑制活性。因此,本发明的研究结果还说明,血液中的癌细胞(B细胞淋巴癌细胞)的研究结果不能推而广之到其他的实体癌(宫颈癌细胞Hela细胞)中。
实施例2:本发明的含氟噻唑酰胺衍生物I与药物的组合:
含氟噻唑酰胺衍生物I在制备抗宫颈癌药物中的方法和用途。
一种抗宫颈癌药物组合物,该组合物由含氟噻唑酰胺衍生物I及可用于制备药物的助剂或表面活性剂或增效剂组成,该组合物的活性成分为本发明的含氟噻唑酰胺衍生物I,活性成分的含量为0.1到99.9%质量,固体或液体助剂的含量为99.9到0.1%质量,表面活性剂或增效剂为任选0到25.0%质量;它们的含量之和为100%。
一种抗宫颈癌药物复配组合物,该复配组合物的活性成分为含氟噻唑酰胺衍生物I和任意一种或多种抗宫颈癌的商品药物,含氟噻唑酰胺衍生物I和抗宫颈癌的商品药物的比例为质量百分比1%∶99%到99%∶1%,活性成分的含量之和为1到99%质量,固体或液体助剂的含量为99.9到0.1%质量,以及表面活性剂或增效剂为任选0到25.0%质量;它们的含量之和为100%。
表1.本发明的含氟噻唑酰胺衍生物I(Gxf02-200-2)的抗宫颈癌细胞-Hela细胞增殖的活性
表2.本发明的含氟噻唑酰胺衍生物I(Gxf02-200-2)的抗Hela细胞增殖活性原始数据
Claims (4)
2.权利要求1所述的含氟噻唑酰胺衍生物I在制备抗宫颈癌药物中的用途。
3.一种药物组合物,该组合物由权利要求1所述的含氟噻唑酰胺衍生物I及可用于制备药物的助剂或表面活性剂或增效剂组成,该组合物的活性成分为权利要求1所述的含氟噻唑酰胺衍生物I,活性成分的含量为0.1到99.9%质量,固体或液体助剂的含量为99.9到0.1%质量,以及表面活性剂或增效剂为任选0到25.0%质量;它们的含量之和为100%。
4.一种药物复配组合物,该复配组合物的活性成分为权利要求1所述含氟噻唑酰胺衍生物I和任意一种或多种抗宫颈癌的商品药物,权利要求1所述含氟噻唑酰胺衍生物I和抗宫颈癌的商品药物的比例为质量百分比1%∶99%到99%∶1%,活性成分的含量之和为1到99%质量,固体或液体助剂的含量为99.9到0.1%质量,以及表面活性剂或增效剂为任选0到25.0%质量;它们的含量之和为100%。
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