CN112870186A - 一种治疗或预防人肝癌症的药物及制备方法和应用 - Google Patents
一种治疗或预防人肝癌症的药物及制备方法和应用 Download PDFInfo
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Abstract
一种治疗或预防人肝癌症的药物及制备方法和应用,属于医药技术领域,具体涉及一种基于p53蛋白靶点机制的,用于治疗或预防人肝癌症的药物,同时又提供该药物的制备方法和应用。化合物1,5,6‑三甲氧基‑2,7‑二羟基菲具有抑制人肝癌HepG‑2细胞生长的作用。在0‑100μM浓度范围内其抑制作用随药物浓度的增高和作用时间的延长而增大,呈明显的剂量依赖性。作用HepG‑2细胞48h的IC50为0.20μM。
Description
技术领域
本发明属于医药技术领域,具体涉及一种治疗或预防人肝癌症的药物及制备方法和应用。
背景技术
据世界卫生组织(WTO)报告,到本世纪末,癌症将成为全球头号杀手,也是人类预期寿命延长的最大障碍。2018年全球有近1810万新增癌症病例,因癌症死亡人数达960万。我国有关部门统计每年有130万人死于癌症,新发病例约为160万人,每年的经济损伤达千亿元。据全国肿瘤防治研究办公室提供《中国人口死因最新排行表》表明,恶性肿瘤死亡率居各种死因第二位,由于地球环境的严重污染及饮食生活形态的变化,恶性肿瘤有进一步上升的趋势。中国城市居民癌症发病数,居城市死因第一名,排名依次为:肺癌、肝癌、胃癌、结肠癌、食管癌。
癌症的发病率和死亡率仅次于心血管疾病。随着癌基因、抑癌基因发现、细胞凋亡学说形成,对其了解也从细胞水平深入到分子水平。癌症与许多癌基因和抑癌基因的改变有关,研究与细胞凋亡有关信息传递、蛋白酶活性,有望为癌症治疗提供新手段。近年来抑癌基因p53在研究上取得一些进展,以该靶点作为研究治疗癌症的靶点药物受到广泛关注。但基于P53蛋白靶点的抗肿瘤药物作用机制研究却鲜有报道。
发明内容
本发明的目的在于提供一种基于p53蛋白靶点机制的,用于治疗或预防人肝癌症的药物,同时又提供该药物的制备方法和应用。
为了实现上述目的,采用以下技术方案:
一种治疗或预防人肝癌症的药物,所述药物的组成包括:1,5,6-三甲氧基-2,7-二羟基菲、淀粉、滑石粉、硬脂酸镁、微晶纤维素、交联聚乙烯吡咯烷酮;其中,主要成分化合物1,5,6-三甲氧基-2,7-二羟基菲的英文名为:1,5,6-trimethoxy-2,7-Phenanthrenediol,分子式为C17H16O5,分子量为300.31,在药物中其纯度≥90%。
进一步的,所述药物的组成为1,5,6-三甲氧基-2,7-二羟基菲1-100重量份、淀粉0-200重量份、硬脂酸镁0-5重量份、滑石粉0-10重量份、微晶纤维素0-250重量份、交联聚乙烯吡咯烷酮0-50重量份、羧甲基淀粉钠0-10重量份、甘露醇0-150重量份。
所述药物的主成分化合物1,5,6-三甲氧基-2,7-二羟基菲的结构如式(I)所示:
所述的化合物1,5,6-三甲氧基-2,7-二羟基菲是从含有该化合物成分的植物、中药材或中药饮片中提取得到或者采用化学方法制备得到的。所述的植物、中药材或中药饮片为:兰科植物铁皮石斛Dendrobium officinale Kimura et Migo的干燥茎,兰科植物金钗石斛Dendrobium nobile Lindl、霍山石斛Dendrobium huoshanense C Z Tang et S.JCheng、鼓槌石斛Dendrobiumchrysotoxum Lindl或流苏石斛Dendrobium fimbriatumHook.的栽培品及其同属植物近似种的新鲜或干燥茎。所述的化学制备方法,为各种化学方法均可合成该化合物或者以该化合物为母核采用化学方法进行改善该化合物的溶解度或者生物利用度而进行的不改变母核结构的结构修饰,包括各种成盐、酸化、碱化、酯化。
一种治疗或预防人肝癌症的药物的制备方法,包括以下步骤:
将化合物1,5,6-三甲氧基-2,7-二羟基菲、淀粉细粉、微晶纤维素、交联聚乙烯吡咯烷酮、羧甲基淀粉钠、滑石粉、硬脂酸镁混匀,制粒,干燥,得所述药物;
或者:
将化合物1,5,6-三甲氧基-2,7-二羟基菲和甘露醇混合,加注射用水,搅拌溶解,调节pH至9.60~10.0,溶解,滤过,滤液按1%溶液体积量加入活性炭,在70~80℃下加热30分钟,过滤,得所述药物。
上述制备方法中,1,5,6-三甲氧基-2,7-二羟基菲1-100重量份、淀粉0-200重量份、硬脂酸镁0-5重量份、滑石粉0-10重量份、微晶纤维素0-250重量份,交联聚乙烯吡咯烷酮0-50重量份、羧甲基淀粉钠0-10重量份、甘露醇0-150重量份;1,5,6-三甲氧基-2,7-二羟基菲纯度≥90%。
一种治疗或预防人肝癌症的药物在可应用于治疗或预防人肝癌症。应用方式为该药物单独或与其它药物或与药学上可接受的赋形剂联合使用,制成各种临床上使用的药物剂型。所述的药物剂型为口服给药的制剂、腔道给药的凝胶剂或栓剂、肌肉或静脉给药的注射剂;其中,腔道给药的途径为阴道、肛门或鼻腔,口服给药的制剂为片剂、胶囊剂、颗粒剂、缓释制剂、靶向制剂或滴丸。所述的赋形剂包括药学上可接受的黏合剂、填充剂、崩解剂、润滑剂、防腐剂、抗氧剂、矫味剂、芳香剂、助溶剂、乳化剂、增溶剂、渗透压调节剂、着色剂或它们的组合。
所述药物在制备用于治疗或预防人肝癌症的药物中的应用,其作用机制为p53蛋白靶点机制。具体为,因p53蛋白能够识别肿瘤细胞,化合物1,5,6-三甲氧基-2,7-二羟基菲小分子抑制剂可以与p53蛋白竞争性结合MDM2蛋白位点,释放野生型p53蛋白并通过乙酰化、磷酸化激活和稳定p53,发挥诱导凋亡等功能,实现靶向性抑癌作用。
所述药物能作为治疗或预防人肝癌症的药物对照品使用。
化合物1,5,6-三甲氧基-2,7-二羟基菲采用体外培养法筛选实验,结果表明:化合物1,5,6-三甲氧基-2,7-二羟基菲对人肝癌HepG-2细胞的IC50值为0.20μM,阳性对照药顺铂的IC50值为2.27μM及紫杉醇的IC50值为0.20μM。与阳性对照药相比,化合物1,5,6-三甲氧基-2,7-二羟基菲对人肝癌HepG-2细胞具有非常好的杀伤作用。因此,化合物1,5,6-三甲氧基-2,7-二羟基菲为一种抗癌活性成分,以此制成抗肿瘤新药制剂。
本发明的有益效果:
化合物1,5,6-三甲氧基-2,7-二羟基菲具有抑制人肝癌HepG-2细胞生长的作用。其明显抑制HepG-2细胞的生长,在0-100μM浓度范围内其抑制作用随药物浓度的增高和作用时间的延长而增大,呈明显的剂量依赖性。化合物1,5,6-三甲氧基-2,7-二羟基菲作用HepG-2细胞48h的IC50为0.20μM。
化合物1,5,6-三甲氧基-2,7-二羟基菲具有基于p53蛋白靶点抑制人肝癌HepG-2细胞生长的作用并可以用于治疗人肝癌的用途。
附图说明
图1本发明实施例5中化合物1,5,6-三甲氧基-2,7-二羟基菲抑制人肝癌HepG-2细胞实验结果;其中,A:化合物1,5,6-三甲氧基-2,7-二羟基菲对HepG-2细胞的抑制结果;B:不同浓度的化合物1,5,6-三甲氧基-2,7-二羟基菲对HepG-2细胞的抑制作用。
图2本发明实施例6中蛋白表达情况。
具体实施方式
下面结合实施例来更详细的说明本发明,但本发明并不受这些实施例的限制。
本发明具体实施例中采用的BCA工作液和超敏发光液均由上海碧云天生物技术有限公司提供,产品编号分别为P0012S和P0018S;分离胶和浓缩胶均由北京达科为公司提供的蛋白电泳凝胶试剂盒。
实施例1
一种治疗或预防人肝癌症的药物的制备方法,具体为:
取化合物1,5,6-三甲氧基-2,7-二羟基菲50g,加入淀粉细粉150g,用等量递增法混匀,加入滑石粉5g,硬脂酸镁2g,混匀,用85%乙醇制粒,干燥,整粒,压制成1000片,每日3次,每次2片。
实施例2
一种治疗或预防人肝癌症的药物的制备方法,具体为:
取化合物1,5,6-三甲氧基-2,7-二羟基菲50g,加入淀粉细粉200g,滑石粉10g,硬脂酸镁5g,混匀,制粒,干燥,装入胶囊,制成1000粒,每日3次,每次2片。
实施例3
一种治疗或预防人肝癌症的药物的制备方法,具体为:
取化合物1,5,6-三甲氧基-2,7-二羟基菲100g,加入微晶纤维素250g,交联聚乙烯吡咯烷酮50g,混匀,加入90%乙醇制粒,干燥,整粒,加入羧甲基淀粉钠10g,硬脂酸镁5g,混匀,压制成1000片,每日服用3次,每次1片。
实施例4
一种治疗或预防人肝癌症的药物的制备方法,具体为:
取化合物1,5,6-三甲氧基-2,7-二羟基菲50g,甘露醇150g,加注射用水2000ml,搅拌溶解,用1M NaOH溶液调pH至9.60~10.0,搅拌溶解,滤过,滤液按1%溶液体积量加入活性炭,在70~80℃下加热30分钟,粗滤过,管道及容器用400ml注射用水洗涤,加水到2500ml,药液经0.22μm无菌过滤器过滤,灌装,冻干,压塞,轧盖,制成1000瓶。
实施例5
MTT体外抗肿瘤活性的筛选
1.1实验方法
选取对数生长期状态良好的人肝癌细胞(HepG-2),用0.25%的胰酶消化液制成单细胞悬液,细胞计数调整细胞密度为0.5×104个/ml,接种于96孔板中,药物浓度组、阳性对照组顺铂和紫杉醇,浓度设定为3.125μM,6.25μM,12.5μM,25μM,50μM,100μM,并设计好0.2%(v:v)的DMSO对照组,每组设5个复孔,各组均加入细胞悬液100μl,将接种好的96孔板置于37℃、5%的CO2培养箱中培养过夜,待细胞贴壁后给药处理。弃旧的培养基,加药组加入100μl不同浓度的药物,阳性对照组加入100μl不同浓度的顺铂,空白对照组加入100μl的培养基。置37℃、5%的CO2培养箱中继续培养24h、48h后,在倒置显微镜下观察细胞形态,每孔加入10μl的MTT原液,置37℃、5%的CO2培养箱中继续培养2h后,弃旧的培养基,加入150μl的DMSO溶解甲瓒结晶,用酶标仪检测其490nm波长处的OD值。
1.2实验结果
抗肿瘤活性筛选结果显示,化合物1,5,6-三甲氧基-2,7-二羟基菲对人肝癌细胞(HepG-2)具有非常强的抑制作用,如表1所示,其48h的IC50值为0.20μM。如图1所示,在人肝癌细胞(HepG-2)加药干预48h,显微镜下形态学观察发现,化合物1,5,6-三甲氧基-2,7-二羟基菲引起细胞明显的皱缩,细胞数量下降,化合物1,5,6-三甲氧基-2,7-二羟基菲能显著地抑制人肝癌细胞(HepG-2)增殖,并呈浓度、时间依赖性关系。
表1化合物1,5,6-三甲氧基-2,7-二羟基菲对人肝癌细胞(HepG-2)的活性的影响
1.3结论
化合物1,5,6-三甲氧基-2,7-二羟基菲具有抑制人肝癌细胞(HepG-2)生长的作用,其作用HepG-2细胞48h的IC50为0.20μM。
实施例6
蛋白质印记法(Western Blot analysis)
1实验方法
1.1细胞总蛋白的提取
(1)细胞培养:取对数期状态良好的人肝癌细胞(HepG-2),用胰酶消化制成单细胞悬液,以15×104个/孔接种于六孔板中,放入培养箱中培养过夜。待细胞长至60%-70%加药,药物浓度设定为3.125μM,6.25μM,12.5μM,对照组为等体积的DMSO。
(2)收集细胞:药物干预48h后,取出六孔板,弃上清,冷PBS洗2遍,弃PBS,加入500μl胰酶消化,加入培养基停止消化,转移至15ml离心管中,4℃1000rpm离心5min,弃上清,加入冷PBS吹打混匀,4℃1000rpm离心5min,弃上清,加入1mlPBS,吹匀,转移至1.5mlEP管中,4℃7.0×G离心15min。
(3)裂解细胞:离心后弃上清,根据细胞数,预先配好细胞裂解液总体积,每个样品加入100:1:1的细胞裂解液(体积比RIPA:PMSF:磷酸酶抑制剂=100:1:1),磁力搅拌器混匀,冰上裂解。裂解完成后用超声仪70%的能量进行超声,使蛋白完全裂解。超声后进行离心,4℃12×G离心30min。
1.2 BCA测浓度
(1)5mg/ml蛋白标准品BSA预先稀释为0.5mg/ml。
(2)标准品准备:8个EP管,将配制的0.5mg/ml蛋白标准品按以下梯度稀释:
(3)待测蛋白的稀释(40倍稀释):2μl蛋白样品加78μl去离子水。
(4)根据样品数,计算并配制BCA工作液,按体积比试剂A:试剂B=50:1,充分混匀,每孔200μl,现配现用。
(5)96孔板加样:每孔200μlBCA工作液+20μl标准品、待测蛋白稀释液。
(6)37℃孵育箱避光孵育30min。
(7)利用酶标仪测定A562nm下各孔吸光度,以蛋白含量(μg)为横坐标,吸光度为纵坐标,绘制标准曲线,并计算样品蛋白浓度,将所得浓度乘以40即为目前蛋白样品浓度。
1.3蛋白变性
在蛋白样品中加入5×上样缓冲液,加入量为蛋白样品的1/4,混合均匀后,变性仪中100℃恒温变性5min。
1.4配胶
(1)装板架,注意密封,加入去离子水,检测是否漏胶,后将水倒出,滤纸擦干。
(2)配胶,分离胶A液,B液按体积比1:1混匀,浓缩胶A液,B液按体积比1:1混匀,向分离胶溶液中加入10%的APS溶液,混匀后灌入模具中,分离胶溶液加至距前玻璃板顶端1.5cm或距梳齿约0.5cm。向浓缩胶中加入10%的APS溶液,混匀后直接灌入分离胶溶液的上层。将梳子插入凝胶内,静置15-20min,等待凝胶聚合。
1.5电泳准备及上样
(1)安装装置,配1×电泳液500ml并加入,拔梳子排气泡,设计上样孔道。
(2)Marker孔上样:加入与蛋白体积相同的Marker。
(3)蛋白样品孔上样:按上样量确定上样体积,上样量40μg(计算方法:40/原液浓度),用相同体积1×loading补齐空白孔道。
(4)电泳,恒压80V,待溴酚蓝跑过分离胶后,电压调为120V,至溴酚蓝跑出为止。
1.6转膜
预先配好转膜液,电泳结束后,取出胶板,放入装有1×转膜液的白色空盘里,用翘板除去不含蛋白的浓缩胶,准备转膜夹子,黑色在下,白色在上,黑色和白色夹子各铺一层海绵,浸湿,铺平,各加4层滤纸,浸湿,铺平,将裁剪好的凝胶小心放到黑色夹子上,裁剪好相应大小的PVDF膜,PVDF膜放入甲醇中激活60s,转移至凝胶上,铺平,避免有气泡,组装转膜夹,(黑对黑,白对红),于冰浴中200V转膜2h。
1.7牛奶封闭
配制5mg/ml的脱脂牛奶封闭液,称取5g脱脂牛奶,加入100ml洗膜液,混匀。转膜结束,取出PVDF膜,转移至牛奶封闭液中,于摇床上室温封闭2h。
1.8洗膜
牛奶封闭结束后,将PVDF膜放入洗膜液中,于摇床上洗膜3次,每次10min。
1.9一抗孵育
洗膜结束后,将抗体进行稀释,根据膜的大小加入相应体积的一抗,用塑封膜封口,放入4℃中孵育过夜。
1.10洗膜
将膜从一抗中取出,回收一抗,将PVDF膜放入洗膜液中,于摇床上洗膜3次,每次10min。
1.11二抗孵育
洗膜结束后,将抗体进行稀释,根据膜的大小加入相应体积的二抗,用塑封膜封口,室温摇床孵育2h。
1.12洗膜
将膜从二抗中取出,回收二抗,将PVDF膜放入洗膜液中,于摇床上洗膜3次,每次10min。
1.13显影
将超敏发光液A液B液,等体积混合,轻轻滴加到膜上,使显影液覆盖需要显影的表面,上机,显影。
2实验结果
如图2所示,加入药物作用48h后,p53蛋白上调,Bax蛋白变化不明显,Bcl-2变化不明显,表明化合物1,5,6-三甲氧基-2,7-二羟基菲通过激活p53蛋白的表达抑制细胞增殖。
3结论
化合物1,5,6-三甲氧基-2,7-二羟基菲具有基于p53蛋白靶点抑制人肝癌HepG-2细胞生长的作用并可以用于治疗人肝癌的用途。
Claims (9)
2.根据权利要求1所述的一种治疗或预防人肝癌症的药物,其特征在于,所述药物中化合物1,5,6-三甲氧基-2,7-二羟基菲是从含有该化合物成分的植物、中药材或中药饮片中提取得到或者采用化学方法制备得到;所述的植物、中药材或中药饮片为:兰科植物铁皮石斛Dendrobium officinale Kimura et Migo的干燥茎,兰科植物金钗石斛Dendrobiumnobile Lindl、霍山石斛Dendrobium huoshanense C Z Tang et S.J Cheng、鼓槌石斛Dendrobium chrysotoxum Lindl或流苏石斛Dendrobium fimbriatum Hook.的栽培品及其同属植物近似种的新鲜或干燥茎;所述的化学制备方法,为各种化学方法均可合成该化合物或者以该化合物为母核采用化学方法进行改善该化合物的溶解度或者生物利用度而进行的不改变母核结构的结构修饰,包括各种成盐、酸化、碱化、酯化。
3.根据权利要求1所述的一种治疗或预防人肝癌症的药物,其特征在于,所述药物中的化合物1,5,6-三甲氧基-2,7-二羟基菲作用于对人肝癌HepG-2细胞的IC50值为0.20μM,阳性对照药顺铂的IC50值为2.27μM、紫杉醇的IC50值为0.20μM。
4.根据权利要求1所述的一种治疗或预防人肝癌症的药物,其特征在于,所述药物治疗或预防人肝癌症的作用机制为p53蛋白靶点机制。
5.根据权利要求1所述的一种治疗或预防人肝癌症的药物,其特征在于,所述药物能作为治疗或预防人肝癌症的药物对照品使用。
6.权利要求1~5任一项所述的一种治疗或预防人肝癌症的药物的制备方法,其特征在于,包括以下步骤:
将化合物1,5,6-三甲氧基-2,7-二羟基菲、淀粉细粉、微晶纤维素、交联聚乙烯吡咯烷酮、羧甲基淀粉钠、滑石粉、硬脂酸镁混匀,制粒,干燥,得所述药物;
或者:
将化合物1,5,6-三甲氧基-2,7-二羟基菲和甘露醇混合,加注射用水,搅拌溶解,调节pH至9.60~10.0,溶解,滤过,滤液按1%溶液体积量加入活性炭,在70~80℃下加热30分钟,过滤,得所述药物。
7.根据权利要求6所述的一种治疗或预防人肝癌症的药物的制备方法,其特征在于,其中所述的1,5,6-三甲氧基-2,7-二羟基菲1-100重量份、淀粉0-200重量份、硬脂酸镁0-5重量份、滑石粉0-10重量份、微晶纤维素0-250重量份,交联聚乙烯吡咯烷酮0-50重量份、羧甲基淀粉钠0-10重量份、甘露醇0-150重量份;1,5,6-三甲氧基-2,7-二羟基菲纯度≥90%。
8.权利要求1所述的一种治疗或预防人肝癌症的药物可应用于治疗或预防人肝癌症。
9.根据权利要求8所述的应用,其特征在于,所述的应用方式为该药物单独或与其它药物或与药学上可接受的赋形剂联合使用,制成各种临床上使用的药物剂型;所述的药物剂型为口服给药的制剂、腔道给药的凝胶剂或栓剂、肌肉或静脉给药的注射剂;其中,腔道给药的途径为阴道、肛门或鼻腔,口服给药的制剂为片剂、胶囊剂、颗粒剂、缓释制剂、靶向制剂或滴丸;所述的赋形剂包括药学上可接受的黏合剂、填充剂、崩解剂、润滑剂、防腐剂、抗氧剂、矫味剂、芳香剂、助溶剂、乳化剂、增溶剂、渗透压调节剂或着色剂中的一种或它们的组合。
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