CN116549455A - PLK4抑制剂Centrinone在制备治疗包虫病药物中的应用 - Google Patents
PLK4抑制剂Centrinone在制备治疗包虫病药物中的应用 Download PDFInfo
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- CN116549455A CN116549455A CN202310540713.6A CN202310540713A CN116549455A CN 116549455 A CN116549455 A CN 116549455A CN 202310540713 A CN202310540713 A CN 202310540713A CN 116549455 A CN116549455 A CN 116549455A
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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Abstract
本发明公开了一种PLK4抑制剂Centrinone在制备治疗包虫病药物中的应用。所述的PLK4抑制剂Centrinone可作为活性成分,单独用药或者联合用药,为制备治疗包虫病药物提供了新选择。本发明所述PLK4抑制剂Centrinone消除细粒棘球囊泡的增殖性细胞并阻止囊泡的生长和发育。本发明PLK4抑制剂Centrinone联合塞利尼索、吉西他滨和5‑氟尿嘧啶,或者联合塞利尼索和MALAT1‑N‑12,对细粒棘球蚴囊泡生长均具有显著的抑制效果,能够用于制备治疗包虫病药物。
Description
技术领域
本发明属于医药技术领域,涉及一种PLK4抑制剂Centrinone在制备治疗包虫病药物中的应用。
背景技术
包虫病是由棘球绦虫寄生于人体或宿主动物而引起的严重人兽共患寄生虫疾病,呈世界性分布,我国是高发区。包虫病包括细粒棘球蚴引发的囊性包虫病和多房棘球蚴引发的泡状包虫病,我国以囊性包虫病(CE)为主。目前对CE的治疗手段主要包括手术和药物治疗。手术治疗局限性较大,术中易发生囊肿破裂造成继发性感染。目前使用最广泛的抗CE药物是苯并咪唑类药物,包括阿苯达唑和甲苯咪唑。但由于该类药的肠道吸收率很低、服药依从性差、只能抑制寄生虫生长而不能彻底有效杀灭寄生虫,致使大量患者必须长期大量服用该药物,但仍然具有较高的术后复发率。与此同时,研究发现该类药作用靶点β-微管蛋白在寄生虫和宿主之间非常相似,可引起多系统的严重药物不良反应。因此,寻找或开发疗效显著且副作用小的包虫病治疗新药物具有重大的意义。
Centrinone是一种可逆的Polo样激酶4(PLK4)抑制剂,它可以破坏癌细胞中心粒(centriole)的活性,抑制癌细胞生长和增殖。其分子式为C26H25F2N7O6S2,分子量为633.65。其结构式如式(1)所示。该药物用于治疗乳腺癌、肝癌、黑色素瘤等,但未见Centrinone用于治疗囊性包虫病的报道。
塞利尼索(Selinexor)是一种口服有效的XPO1抑制剂,导致肿瘤抑制蛋白在细胞核内积累,这将重新启动并放大它们的肿瘤抑制功能,导致癌细胞选择性凋亡,同时不会对正常细胞造成显著影响。其分子式为C17H11F6N7O,分子量为443.31。该药物多用于多发性骨髓瘤的研究,但未见塞利尼索用于治疗囊性包虫病的报道。
MALAT1-N-1是一种有效且特异性的Malat1抑制剂。MALAT1-IN-1以剂量依赖性方式调节Malat1下游基因。其分子式为C19H21N3O2,分子量为323.39。MALAT1-N-1被报道用于治疗腹主动脉瘤,但未见MALAT1-N-1用于治疗囊性包虫病的报道。
吉西他滨(Gemcitabine),为一种新的胞嘧啶核苷衍生物,化学式为C9H11F2N3O4,分子量为263.198。进入人体内后由脱氧胞嘧啶激酶活化,由胞嘧啶核苷脱氨酶代谢。在临床上,吉西他滨对多种实体肿瘤有效。5-氟尿嘧啶(5-fluorouracil)化学式为C4H3FN2O2,分子量为323.39130.077是一种嘧啶类似物,属于抗代谢药的一种,对多种肿瘤如消化道肿瘤、乳腺癌、卵巢癌、绒毛膜上皮癌、子宫颈癌、肝癌、膀胱癌等均有一定疗效。吉西他滨和5-氟尿嘧啶可以减少循环中的MDSCs的数量,促进更强大的抗肿瘤免疫反应,但这些药物对MDSCs没有特异性,影响所有快速增殖的细胞,包括抗肿瘤T细胞。与吉西他滨联合应用可以明显改善胰腺癌患者体能。目前未见吉西他滨和5-氟尿嘧啶用于治疗囊性包虫病。
发明内容
发明目的:本发明目的在于提供一种PLK4抑制剂Centrinone在制备治疗包虫病药物中的应用。所述PLK4抑制剂Centrinone消除细粒棘球囊泡的增殖性细胞并阻止囊泡的生长和发育。因此,PLK4抑制剂Centrinone可以单独使用或者与其它药物联合使用,用于制备治疗包虫病药物。
技术方案:本发明的目的通过下述技术方案实现:
本发明提供了一种PLK4抑制剂Centrinone在制备治疗包虫病药物中的应用。
所述PLK4抑制剂Centrinone可以作为药物的唯一活性成分,其结构式如下:
所述PLK4抑制剂Centrinone可以与其它化合物联合用药。
本发明还提供了PLK4抑制剂Centrinone、塞利尼索、吉西他滨和5-氟尿嘧啶联合用药在制备治疗包虫病药物中的应用。
本发明还提供了PLK4抑制剂Centrinone、塞利尼索和MALAT1-N-12联合用药在制备治疗包虫病药物中的应用。
所述药物还包括药学上可接受的载体或辅料。
所述辅料包含抗氧剂、乳化剂、稀释剂、防腐剂、增溶剂、崩解剂、润湿剂、黏合剂或润滑剂中的一种或几种。
所述药物的剂型为颗粒剂、片剂、胶囊剂、混悬剂、口服液、注射剂或输液剂。
本发明的药物可以采用各种已知的方式施用,例如口服、注射等方式施用。本发明的药物可单独给药也可与其他药物联合用药。口服组合物可以是任何口服可接受的剂型,包含但不限于颗粒剂、片剂、胶囊剂和混悬剂。
无菌可注射组合物可按照本领域已知的技术,使用适合的分散剂或润湿剂和助悬剂来配制。可以使用的药学上可接受的载体和溶剂包括水、氯化钠溶液等。
本发明药物可以制成普通制剂,也可以制成缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
可以改变本发明的药物中活性成分的实际剂量水平以获得对特定患者、组合物和施用方式而言可以有效实现所需治疗响应、对患者无毒的活性成分的量。所选择的剂量水平取决于多种因素,包括施用途径、施用时间、排泄速率、治疗的持续时间、与PLK4抑制剂Centrinone组合使用的其它药物、化合物和/或材料、所治疗的患者的年龄、性别、体重、一般健康状况和既往病史以及医学领域中公知的类似因素。
Polo样激酶4(PLK4)和核输出蛋白(XPO1)对于细粒棘球蚴囊泡生发层细胞的增殖和分化具有重要作用,Centrinone和塞利尼索分别作为PLK4和XPO1的靶向抑制剂,可以消除细粒棘球囊泡的增殖性细胞并阻止囊泡的生长和发育。
塞利尼索结构式如下:
Malat1抑制是CD4+T细胞激活的标志,并且Malat1的表达与Maf的表达呈正相关。Malat1的高表达,导致囊性包虫病小鼠中Th1与Th2免疫失衡,造成免疫失衡。活化的CD4+T细胞中抑制Malat1是对慢性感染的最佳免疫的关键决定因素。MALAT1-N-1作为有效且特异性的Malat1抑制剂,能够有效促进CD4+T细胞活化和防止免疫失衡,有效解决囊性包虫病免疫逃逸。
MALAT1-N-1结构式如下:
MDSCs是导致感染囊性包虫病小鼠发生免疫抑制重要原因。吉西他滨和5-氟尿嘧啶可以通过靶向抑制MDSCs的免疫抑制机制而发生功能性失活,以此防止MDSCs对CE小鼠免疫系统的抑制作用。
吉西他滨结构式如下:
5-氟尿嘧啶结构式如下:
有益效果:
本发明所述的PLK4抑制剂Centrinone可作为活性成分,单独用药或者联合用药,应用于治疗包虫病,开拓了Centrinone的新用途,为制备治疗包虫病药物提供了新选择。本发明所述PLK4抑制剂Centrinone消除细粒棘球囊泡的增殖性细胞并阻止囊泡的生长和发育。因此,PLK4抑制剂Centrinone可以单独使用或者与其它药物联合使用,用于制备治疗包虫病药物。
本发明PLK4抑制剂Centrinone联合塞利尼索、吉西他滨和5-氟尿嘧啶,或者联合塞利尼索和MALAT1-N-12,对细粒棘球蚴囊泡生长均具有显著的抑制效果,能够用于制备治疗包虫病药物。
本发明首次公开了Centrinone,塞利尼索,MALAT1-N-1以及吉西他滨和5-氟尿嘧啶在抗囊性包虫病中的应用,拓展了这几类药物的应用,同时开发了新的治疗囊性包虫病的药物。
附图说明
图1为药物治疗15天后各组囊湿重重量柱状图;
图2为药物治疗15天后各组的抑制结果柱状图;
图3为对照组给予CMC-Na 15天后囊泡状态图;
图4为Centrinone,塞利尼索,MALAT1-N-1以及吉西他滨和5-氟尿嘧啶分别治疗15天后囊泡状态图;
图5为阳性药物阿苯达唑治疗15天后囊泡状态图;
图6为联合用药组1和组2治疗15天后囊泡状态图。
具体实施方式
下面通过具体实施例对本发明技术方案进行详细说明,但是本发明的保护范围不局限于所述实施例。
实施例中未注明具体技术或条件者,按照本领域内的文献所描述的技术或条件,或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者,均为可通过正规渠道购买得到的常规产品。
下述实施例中的实验方法,如无特殊说明,均为常规方法。下述实施例中所用的试验材料,如无特殊说明,均为市售产品。
实施例1Centrinone,塞利尼索,MALAT1-N-1以及吉西他滨和5-氟尿嘧啶分别用药对小鼠细粒棘球蚴囊泡的影响
Centrinone,塞利尼索,MALAT1-N-1以及吉西他滨和5-氟尿嘧啶均购自上海阿拉丁生化科技股份有限公司。
实验动物:7~8周龄的昆明小鼠,体重约为25g左右。
实验方法:
Untreat组:给予0.4%CMC-Na水溶液,给药体积为0.1mL/10g×小鼠体重。作为对照组。
给药组:Centrinone用0.4%的CMC-Na溶解在研钵研磨后,按照每只小鼠每天摄入药物量为20mg/kg/天口服给药;
塞利尼索用0.4%的CMC-Na溶解在研钵研磨后,按照每只小鼠每天摄入药物量为15mg/kg/天口服给药;
MALAT1-N-1用0.4%的CMC-Na溶解在研钵研磨后,按照每只小鼠每天摄入药物量为15mg/kg/天口服给药;
吉西他滨用0.4%的CMC-Na溶解在研钵研磨后,按照每只小鼠每天摄入药物量为40mg/kg/天口服给药;
5-氟尿嘧啶,将其溶于DMSO溶剂中,按照每只小鼠每天摄入药物量为50mg/kg/天腹腔注射给药。
持续给药15天后,安乐死处死不同给药组的小鼠,从腹腔内将包囊收集,测量囊湿重,并计算药物对包囊的抑制率。
抑制率=(空白组囊湿重-治疗组囊湿重)/空白组囊湿重*100%。
实验结果见表1。
通过比较Untreat组和不同给药组小鼠体内囊泡的湿重可以观察不同药物对细粒棘球蚴囊泡的作用效果。Untreat组中小鼠囊泡结构完整,数量较多(见图3);而给药组小鼠体内囊泡数量较小,体积也明显减小(见图4)。相较于Untreat组,几个给药组小鼠囊泡湿重都有不同程度的减少(见图1,图2)。这一结果表明Centrinone,塞利尼索,MALAT1-N-1,吉西他滨和5-氟尿嘧啶单独给药对细粒棘球蚴包囊生长有较为明显的抑制作用。
实施例2阳性药阿苯达唑(ABZ)给药对小鼠细粒棘球蚴囊泡的影响
实验动物:7~8周龄的昆明小鼠,体重约为25g左右。
实验方法:
阿苯达唑药物用0.4%的CMC-Na溶解在研钵研磨后,按照每只小鼠每天摄入药物量为50mg/kg/天口服给药。
持续给药15天后,安乐死处死给药组的小鼠,从腹腔内将包囊收集,测量囊湿重,并计算药物对包囊的抑制率。抑制率=(空白组囊湿重-治疗组囊湿重)/空白组囊湿重*100%。实验结果见表1。
通过比较Untreat组和阿苯达唑药组小鼠体内囊泡的湿重可以观察不同药物对细粒棘球蚴囊泡的作用效果。Untreat组中小鼠囊泡结构完整,数量较多(见图3);而阿苯达唑给药组小鼠体内囊泡数量较小,囊壁变薄,体积也明显减小(见图5)。相较于Untreat组,阿苯达唑给药组小鼠囊泡湿重都有明显减少(见图1,图2)。这一结果表明阿苯达唑对细粒棘球蚴包囊生长有明显的抑制作用。
实施例3Centrinone,塞利尼索以及吉西他滨和5-氟尿嘧啶联合用药(联合用药组1)对小鼠细粒棘球蚴囊泡的影响
实验动物:7~8周龄的昆明小鼠,体重约为25g左右。
实验方法:
给药组按照实施例1中的方法,对小鼠依次进行Centrinone,塞利尼索以及吉西他滨和5-氟尿嘧啶联合给药治疗,持续给药15天后,安乐死处死的小鼠,从腹腔内将包囊收集,测量囊湿重,并计算药物对包囊的抑制率,抑制率=(空白组囊湿重-治疗组囊湿重)/空白组囊湿重*100%。
最后运用spss 20.0进行统计学分析,数据以平均值±标准差来进行表示,组间采用One-way ANOVA分析,p值小于0.05有统计学差异。实验结果见表1。
通过比较Untreat组和Centrinone,塞利尼索以及吉西他滨和5-氟尿嘧啶联合给药组小鼠体内囊泡的湿重可以观察联合用药对细粒棘球蚴囊泡的作用效果。Untreat组中小鼠囊泡结构完整,数量较多;而Centrinone,塞利尼索以及吉西他滨和5-氟尿嘧啶联合给药组小鼠体内囊泡数量很少,体积也明显减小,甚至出现一定程度的钙化(见图6)。联合用药组囊泡湿重明显减少(见图1,图2)。这一结果表明Centrinone,塞利尼索以及吉西他滨和5-氟尿嘧啶联合用药对细粒棘球蚴包囊生长有显著的抑制作用。
实施例4Centrinone,塞利尼索以及MALAT1-N-1联合用药(联合用药组2)对小鼠细粒棘球蚴囊泡的影响
实验动物:7~8周龄的昆明小鼠,体重约为25g左右。
实验方法:
按照实施例1中的给药方式对小鼠进行Centrinone,塞利尼索以及MALAT1-N-1联合给药,持续给药15天后,安乐死处死的小鼠,从腹腔内将包囊收集,测量囊湿重,并计算药物对包囊的抑制率,抑制率=(空白组囊湿重-治疗组囊湿重)/空白组囊湿重*100%。
实验结果见表1。
通过比较Untreat组和Centrinone,塞利尼索以及MALAT1-N-1联合给药组小鼠体内囊泡的湿重可以观察联合用药对细粒棘球蚴囊泡的作用效果。Untreat组中小鼠囊泡结构完整,数量较多(见图3);而联合给药组小鼠体内囊泡数量很少,体积也明显减小(见图6)。联合用药组囊泡湿重显著减少,这一结果表明Centrinone,塞利尼索以及MALAT1-N-1联合给药对细粒棘球蚴包囊生长有显著的抑制作用,但是抑制效果略低于联合给药组1(见图1,图2)。
如表1和图1所示,各类药治疗3周后各组小鼠包囊湿重与空白组(4.3255±2.7955)相比,联合用药组1(0.7344±0.2273)和联合用药组2(0.9334±0.3273)的小鼠包囊湿重下降显著,小鼠体内包囊几近消失(p=0.019,p=0.032)。同时,对比联合用药组1、2和阿苯达唑组可见:联合用药组1(抑制率达到83.0%)治疗效果显著优于联合用药组2(抑制率达到78.4%)(p=0.021,p=0.032),结果见图2。此外,阿苯达唑,Centrinone(2.3375±0.8558),塞利尼索Selinexor(3.1375±1.2564),MALATI-N-1(1.9765±0.7264),吉西他滨Gemcitabine(1.4436±0.6345),5-氟尿嘧啶5-fluorouracil(1.0233±0.4273)组中小鼠的包囊湿重也有明显降低,这些药物单独使用也可以减缓囊泡的生长,但效果不如联合用药组。
表1治疗3周后各组小鼠包囊湿重和抑制率
本发明Centrinone,塞利尼索,MALAT1-N-1以及吉西他滨和5-氟尿嘧啶以及两组联合用药可用于抗包虫药物的开发,体内药效学数据提示这些药物可以高效的治疗包虫病,可以作为细粒棘球蚴包虫病新型药物筛选的靶点。本发明可以为囊性包虫病的治疗提供新途径。
如上所述,尽管参照特定的优选实施例已经表示和表述了本发明,但其不得解释为对本发明自身的限制。在不脱离所附权利要求定义的本发明的精神和范围前提下,可对其在形式上和细节上作出各种变化。
Claims (9)
1.PLK4抑制剂Centrinone在制备治疗包虫病药物中的应用。
2.根据权利要求1所述的应用,其特征在于,所述PLK4抑制剂Centrinone作为药物的唯一活性成分,其结构式如下:
3.根据权利求1所述的应用,其特征在于,所述PLK4抑制剂Centrinone与其它化合物联合用药。
4.PLK4抑制剂Centrinone、塞利尼索、吉西他滨和5-氟尿嘧啶联合用药在制备治疗包虫病药物中的应用。
5.PLK4抑制剂Centrinone、塞利尼索和MALAT1-N-12联合用药在制备治疗包虫病药物中的应用。
6.根据权利要求1-5任一项所述的应用,其特征在于,所述药物还包括药学上可接受的载体或辅料。
7.根据权利要求6所述的应用,其特征在于,所述辅料包含抗氧剂、乳化剂、稀释剂、防腐剂、增溶剂、崩解剂、润湿剂、黏合剂或润滑剂中的一种或几种。
8.根据权利要求1-5任一项所述的应用,其特征在于,所述药物的剂型为颗粒剂、片剂、胶囊剂、混悬剂、口服液、注射剂或输液剂。
9.根据权利要求1-5任一项所述的应用,其特征在于,所述PLK4抑制剂Centrinone消除细粒棘球囊泡的增殖性细胞并阻止囊泡的生长和发育。
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