CN116370462A - 抗包虫的咔唑氨基醇类化合物的药物新用途 - Google Patents
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Abstract
本发明公开了抗包虫的咔唑氨基醇类化合物的药物新用途。所述咔唑氨基醇类化合物的结构式如式I所示。其药物新用途是其在制备下述至少一种产品中的应用:(1)预防和/或治疗肿瘤的产品;(2)抑制肿瘤细胞增殖或生长的产品;(3)促进肿瘤细胞凋亡的产品;(4)抑制肿瘤细胞迁移的产品。本发明通过细胞划痕、RTCA和流式细胞术凋亡检测实验数据证实,抗包虫化合物H1402对肿瘤细胞HepG2和A549的迁移和凋亡的影响优于或相当于临床常用的顺铂(DDP)干预肿瘤细胞的效果,说明抗包虫化合物H1402(咔唑氨基醇类)可干预肿瘤细胞的迁移和凋亡,即说明抗包虫化合物H1402(咔唑氨基醇类)能够作为新型的抗肿瘤药物,从而为肿瘤的治疗提供新途径。
Description
技术领域
本发明属于医药领域,具体涉及抗包虫的咔唑氨基醇类化合物的药物新用途。
背景技术
棘球蚴病(Echinococcosis)又称包虫病,一种呈世界性分布的人兽共患病。目前主要分为由细粒棘球绦虫(Echinococcus granulosus,E.g)感染引起的细粒棘球蚴病,俗称囊型包虫病(Cystic echinoccosis,CE)和由多房棘球绦虫(E.mulilocularis,E.m)引起的多房棘球蚴病,俗称泡型包虫病(Alevolar echinoccosis,AE)两种类型。我国23个省(自治区)有发现病例,发病面积占全国的86.9%,西北部农牧民深受其害,且在新疆、甘肃、宁夏、内蒙,四川,和西藏等省份为高流行区,对当地的经济和百姓的生活和健康都造成了困扰。两型包虫病的感染是通过吞食了细粒棘球绦虫和多房棘球绦虫虫卵经粪口传播途径而感染,人类作为中间宿主,囊型包虫病主要通过犬传播;泡型包虫病主要通过犬、狼和狐狸等传播。肝脏是包虫感染的主要脏器,大约占据70%,肺占20%,其它脏器占据10%。囊性包虫病多为占位性病变,压迫周围的组织和器官,有明显的界面和包膜;泡型包虫呈类癌样生长,有浸润性强且恶性程度高的特性,可经淋巴道和血管转移至腹腔、脑和肺脏等部位,故称“虫癌”,其病灶无明显的界限和包膜。临床治疗多以切除病变组织为主要治疗方案,对于早期干预、术后预防和无法进行手术治疗的患者可使用口服阿苯达唑片剂或者脂质体进行长期干预治疗。
阿苯达唑,是世界卫生组织唯一指定棘球蚴病的治疗药物,但在临床使用过程中出现许多不良反应,且阿苯达唑的治疗作用主要依赖抑虫发挥作用,导致阿苯达唑对棘球蚴病的治疗发挥作用受限。发明人所在的课题组前期工作中,通过对体外细粒棘球蚴及其培养包囊的杀伤发现一种咔唑氨基醇类化合物H1402具有良好的杀虫作用,通过对细粒棘球蚴病小鼠模型口服化合物H1402证实体外发现,显著增加病灶囊肿的死亡率,进一步表明其具有一定抑制细胞增殖活性的作用和较好的杀包虫功效。
原发性肝细胞瘤(hepatocellular carcinoma,HCC),简称肝癌,是指自肝细胞或肝内胆管上皮细胞发生的恶性肿瘤,是全球公认的严重的公共卫生问题之一,死亡率居中国恶性肿瘤排名第2位。其治疗方式包括根治性肝脏外科切除术、肝移植和姑息性的局部消融、肝动脉栓塞介入等,通过不断地优化和创新,肝癌的预后得到很大程度的改善,但依旧存在复发、转移及不良反应。肺癌也是我国常见的恶性肿瘤之一,其发病率和死亡率呈逐年升高态势,其中非小细胞肺癌(non-small-cell lung carcinoma,NSCLC)更是高居世界首位,治疗方法包括手术治疗、放射疗法、免疫治疗和靶向药物疗法,其中的药物应用存在严重的耐药性和毒副作用,严重危害公众的身心健康和生活质量。
因此,对于恶性程度较高且危害严重的肿瘤而积极寻找新药物的意义重大,近年来,治疗恶性肿瘤药物的研发从不同角度切入,随着各个研究领域中相关因子和机制的深入研究,都会促进抗肿瘤药物的发展。然而对于抗包虫化合物H1402(咔唑氨基醇类)干预肿瘤细胞的迁移和凋亡,用于肿瘤及其相关疾病的治疗尚未见报道。
发明内容
本发明的目的是提供抗包虫的咔唑氨基醇类化合物的药物新用途。
本发明所述咔唑氨基醇类化合物的结构式如式I所示:
式I中,R为NHR1,其中,R1可为C1-C8的烷基,进一步的R1可为C3-C6的烷基。具体的,R1可为丙基、丁基或己基。
当R1为丙基(即R为丙氨基)时,所对应的式I化合物命名为H1402。
本发明所提供的咔唑氨基醇类化合物的药物新用途是其在制备下述至少一种产品中的应用:
(1)预防和/或治疗肿瘤的产品;
(2)抑制肿瘤细胞增殖或生长的产品;
(3)促进肿瘤细胞凋亡的产品;
(4)抑制肿瘤细胞迁移的产品。
本发明还提供了所述咔唑氨基醇类化合物在下述至少一方面的应用:
(1)预防和/或治疗肿瘤;
(2)抑制肿瘤细胞增殖或生长;
(3)促进肿瘤细胞凋亡;
(4)抑制肿瘤细胞迁移。
本发明中所述肿瘤可为实体肿瘤或非实体肿瘤,包括肝癌、肺癌、乳腺癌、宫颈癌、结直肠癌、卵巢癌等。
本发明中所述肿瘤细胞包括肝癌细胞(如人肝癌细胞HepG2)、肺癌细胞(如人肺腺癌细胞A549细胞)、乳腺癌细胞、宫颈癌细胞、结直肠癌细胞、卵巢癌细胞。
示例性的,所述产品可为药物或药物制剂或试剂。
以式I所示的咔唑氨基醇类化合物为活性成分制备的预防和/或治疗肿瘤的药物也属于本发明的保护范围。
所述预防和/或治疗肿瘤的药物可通过注射、喷射、滴鼻、滴眼、渗透、吸收、物理或化学介导的方法导入机体如肌肉、皮内、皮下、静脉、粘膜组织;或是被其他物质混合或包裹后导入机体。
需要的时候,在上述药物中还可以加入一种或多种药学上可接受的载体。所述载体包括药学领域常规的稀释剂、赋形剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂、吸附载体、润滑剂等。
上述药物可以制成注射液、片剂、粉剂、颗粒剂、胶囊、口服液、膏剂、霜剂等多种形式。上述各种剂型的药物均可以按照药学领域的常规方法制备。
本发明首次公开了一种抗包虫化合物H1402(咔唑氨基醇类)干预肿瘤细胞的迁移和凋亡,用于肿瘤及其相关疾病的治疗的应用。本发明还首次公开了抗包虫化合物H1402(咔唑氨基醇类)干预肿瘤细胞HepG2和A549的迁移和凋亡,用于肿瘤及其相关疾病的治疗的应用,通过细胞划痕、RTCA和流式细胞术凋亡检测实验数据可知,抗包虫化合物H1402(咔唑氨基醇类)对肿瘤细胞HepG2和A549的迁移和凋亡的影响优于或相当于临床常用的顺铂(DDP)干预肿瘤细胞的效果,说明抗包虫化合物H1402(咔唑氨基醇类)可干预肿瘤细胞的迁移和凋亡,即说明抗包虫化合物H1402(咔唑氨基醇类)能够作为新型的抗肿瘤药物,从而为肿瘤的治疗提供新途径。
附图说明
图1为不同浓度H1402在不同时间对HepG2生长的影响;
图2为不同浓度H1402对HepG2在不同时间的抑制率;
图3为不同浓度H1402干预HepG2和A549细胞划痕愈合面积;
图4为RTCA检测不同浓度H1402和DDP对HepG2迁移的影响;
图5为RTCA检测不同浓度H1402和DDP对A549迁移的影响;
图6为不同浓度H1402对HepG2凋亡能力的影响;
图7为不同浓度H1402对A549凋亡能力的影响。
具体实施方式
下面结合具体实施例对本发明作进一步阐述,但本发明并不限于以下实施例。所述方法如无特别说明均为常规方法。所述原材料如无特别说明均能从公开商业途径获得。
下述实施例中使用的化合物H1402按照下述文献记载的方法制备得到:In vitroand in vivo efficacies of novel carbazole aminoalcohols in the treatment ofcystic echinococcosis。J Antimicrob Chemother.2017;72:3122-3130;doi:10.1093/jac/dkx250Advance Access publication 24July 2017.
实施例1、化合物H1402(咔唑氨基醇类)对肿瘤细胞HepG2、A549迁移和凋亡的影响。
1.实验内容
(一)MTT法检测抗包虫化合物H1402(咔唑氨基醇类)对HepG2细胞的抑制作用
收集对数期HepG2细胞,调整细胞悬液浓度,每孔加入200μl,铺板使待测细胞调密度至5000/孔,(边缘孔用无菌1×PBS填充),5%CO2,37℃孵育12h,至细胞单层铺满孔底(96孔平底板),细胞贴壁后即可加入不同浓度的H1402(2.5、5、10、20、40μM),5个梯度,每孔200ul,设5个复孔,5%CO2,37℃孵育24h和48h,每孔加入20μl MTT溶液(5mg/ml,即0.5%MTT),培养箱孵育培养4h。弃去孔内培养液。并加入150μl二甲基亚砜,置摇床上低速振荡10min,使结晶物充分溶解,在酶联免疫检测仪OD490nm处测量各孔的吸光值,并使用GraphPad Prism 8软件分析各组OD值,明确H1402干预肿瘤细胞的最佳时间和剂量。
(二)划痕实验检测抗包虫化合物H1402(咔唑氨基醇类)对肿瘤细胞的迁移作用
采用细胞划痕实验检测细胞划痕的愈合率。收集HepG2和A549细胞,调整细胞悬液,将其接种于6孔板,每孔约1×106个细胞,当细胞汇合度至90%;使用黄枪头在6孔板底部均匀划线,每孔2条平行线;使用无菌PBS多次洗涤去除漂浮细胞,加入不同浓度H1402(5、10、20μM)干预24h并设置顺铂(DDP)作为阳性对照干预细胞,显微镜下观察采图,计算划痕愈合百分率,使用Image J软件进行分析。
(三)RTCA检测抗包虫化合物H1402(咔唑氨基醇类)对肿瘤细胞的迁移作用
在CIM-Plate16检测板的下室中加入168μl 1640培养基(BISH1381)含1%胎牛血清,注意加液时不要产生气泡,使加入的培养基在下室的孔内形成凸出的弯月面。将CIM-Plate装配好后在上室中加入30μl 1640培养基,将检测板置于37℃,CO2浓度为5%的CO2培养箱平衡1h。RTCA DP监测台上,进行基线检测。收集不同浓度H1402和DDP(5、10、20μM)干预24h后的HepG2和A549细胞,制备细胞悬液,使得每孔接种细胞悬液100μl,每孔细胞数量为4×104个。细胞接种后CIM-Plate于室温静置30min待细胞沉降,待细胞沉降后将CIM-Plate放回RTCA DP检测台,进行细胞迁移的实时动态检测(每5min测量一次)。
(四)流式细胞术检测抗包虫化合物H1402(咔唑氨基醇类)对肿瘤细胞的凋亡作用
将不同浓度H1402和DDP(5、10、20μM)干预24h后的HepG2和A549细胞,使用细胞刮刀进行收集,进行Annexin V-FITC/PI染色,样品在1h内用流式细胞仪检测。
2.实验结果分析
MTT检测结果如图1和图2所示。由图1和图2可知,抗包虫化合物H1402(咔唑氨基醇类)干预HepG2细胞24h和48h,检测出其半数致死浓度(IC50)为6.79μM和8.95μM,根据其增殖抑制率可得出较好的干预时间为24h。依据MTT实验结果干预HepG2和A549细胞设定H1402干预浓度为5、10和20μM同时设置相同浓度的DDP为阳性对照,进行细胞划痕、RTCA检测迁移和流式细胞术检测凋亡实验。
细胞划痕实验结果如图3所示。由图3可知,H1402干预后两种细胞的划痕愈合率较DDP组明显降低(P<0.05),随着剂量的升高效果越明显;且H1402对于肝癌细胞(HepG2)的细胞愈合百分比影响大于肺腺癌细胞(A549)。
由图4和图5可知,通过RTCA实验,在实时监测下,对照组干预后的细胞随时间增加逐渐迁移并呈现上升趋势,抗包虫化合物H1402(咔唑氨基醇类)干预HepG2细胞迁移结果显示,细胞迁移能力减弱,高剂量20μM的迁移能力明显降低有显著性差异。干预A549细胞后,H1402干预后降低迁移能力但没有HepG2细胞明显。
由图6和图7可知,流式细胞术进行凋亡检测结果显示,抗包虫化合物H1402(咔唑氨基醇类)干预HepG2细胞24h后,细胞凋亡率较阳性对照组(DDP)明显增高,并呈现剂量依赖态势;但H1402干预A549细胞后对其凋亡无较大影响。
综上所述,本发明首次公开了一种抗包虫化合物H1402(咔唑氨基醇类)干预肿瘤细胞的迁移和凋亡,用于肿瘤及其相关疾病的治疗的应用。本发明还首次公开了抗包虫化合物H1402(咔唑氨基醇类)干预肿瘤细胞HepG2和A549的迁移和凋亡,用于肿瘤及其相关疾病的治疗的应用。通过细胞划痕、RTCA和流式细胞术凋亡检测实验数据可知,抗包虫化合物H1402(咔唑氨基醇类)对肿瘤细胞HepG2和A549的迁移和凋亡的影响优于或相当于临床常用的顺铂(DDP)干预肿瘤细胞的效果,说明抗包虫化合物H1402(咔唑氨基醇类)可干预肿瘤细胞的迁移和凋亡,即说明抗包虫化合物H1402(咔唑氨基醇类)能够作为新型的抗肿瘤药物,从而为肿瘤的治疗提供新途径。
以上技术特征构成了本发明的实施例,其具有较强的适应性和实施效果,可根据实际需要增减非必要的技术特征,来满足不同情况的需求。
Claims (10)
2.根据权利要求1所述的应用,其特征在于:所述R1为C3-C6的烷基。
3.根据权利要求2所述的应用,其特征在于:所述R1为丙基、丁基或己基。
4.根据权利要求1-3中任一项所述的应用,其特征在于:所述肿瘤为实体肿瘤或非实体肿瘤,包括肝癌、肺癌、乳腺癌、宫颈癌、结直肠癌、卵巢癌。
5.根据权利要求1-3中任一项所述的应用,其特征在于:所述肿瘤细胞包括肝癌细胞、肺癌细胞、乳腺癌细胞、宫颈癌细胞、结直肠癌细胞、卵巢癌细胞。
6.根据权利要求1-5中任一项所述的应用,其特征在于:所述产品为药物或药物制剂或试剂。
8.根据权利要求7所述的应用,其特征在于:所述R1为C3-C6的烷基;进一步的,所述R1为丙基、丁基或己基。
9.根据权利要求7所述的应用,其特征在于:所述肿瘤为实体肿瘤或非实体肿瘤,包括肝癌、肺癌、乳腺癌、宫颈癌、结直肠癌、卵巢癌。
10.根据权利要求7所述的应用,其特征在于:所述肿瘤细胞包括肝癌细胞、肺癌细胞、乳腺癌细胞、宫颈癌细胞、结直肠癌细胞、卵巢癌细胞。
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