CN102872017B - 6-(4-(二氟甲氧基)-3-甲氧基苯基)哒嗪-3(2h)-酮在制备抗肿瘤药物中的用途 - Google Patents
6-(4-(二氟甲氧基)-3-甲氧基苯基)哒嗪-3(2h)-酮在制备抗肿瘤药物中的用途 Download PDFInfo
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Abstract
本发明涉及式I所示的6-(4-(二氟甲氧基)-3-甲氧基苯基)哒嗪-3(2H)-酮在制备抗肿瘤药物,尤其是抗肝癌药物中的用途。
Description
技术领域
本发明属于药物学领域,涉及6-(4-(二氟甲氧基)-3-甲氧基苯基)哒嗪-3(2H)-酮的用途,具体涉及该化合物在制备抗肿瘤药物,尤其是抗肝癌药物中的用途。
背景技术
6-(4-(二氟甲氧基)-3-甲氧基苯基)哒嗪-3(2H)-酮,商品名:扎达维林(Zardaverine)为磷酸二酯酶PDE III及PDE IV的抑制剂,临床用作麻醉辅助药(骨骼肌松弛药)。与扎达维林相关的专利(WO 2001094319、DE 4310051、DE4207822、EP 523513、EP 163965、US4665074)主要涉及其抗炎或抗免疫方面的用途,而对其在抗肿瘤方面的应用未见报道。
众所周知,肝癌是第五大常见的男性肿瘤疾病,是第八大常见的女性肿瘤疾病。在2007年,估算的新增肝癌患者将有80%在发展中国家中产生,仅我国就占了总数的55%。而在发展中国家,59%的肝癌可归咎于HBV,33%的肝癌可归咎于HCV。尤其近年来,由于亚太国家乙肝病毒感染肆虐,肝癌发病率不断上升,对治疗肝癌药物有巨大的市场需求。
发明内容
本发明的一个目的是公开式I所示的6-(4-(二氟甲氧基)-3-甲氧基苯基)哒嗪-3(2H)-酮在制备抗肿瘤药物,尤其是抗肝癌药物中的用途。
本发明人通过体外和体内实验首次发现6-(4-(二氟甲氧基)-3-甲氧基苯基)哒嗪-3(2H)-酮在抗肿瘤方面的药理作用。具体而言,6-(4-(二氟甲氧基)-3-甲氧基苯基)哒嗪-3(2H)-酮在抗肝癌方面表现出很强的特异性,其对敏感细胞株BEL-7402及SMMC-7721的抑制活性与对不敏感细胞株(如HepG2、Hep3B或NCI-H460)的抑制活性相差近1000倍,同时其抗肿瘤作用在肝癌细胞BEL-7402体内裸鼠移植瘤模型中也得到了验证。
附图说明
图1为扎达维林对人肝癌细胞Bel-7402裸小鼠移植瘤的剂量依赖性抑制瘤体生长的活性;
图2为扎达维林对裸小鼠体重的影响。
具体实施方式
下面用实施例进一步说明本发明,但这些实施例并不限制本发明的保护范围。
实施例1:扎达维林的体外抗肿瘤活性
RPMI 1640培养基、最低基础培养基(Minimum essential medium,MEM)、Ham’s F12培养基、杜尔贝考氏改良伊格尔氏培养基(Dulbecco’s modifiedEagle’s medium,DMEM)培养基、M199培养基、胎牛血清(fetal bovine serum,FBS)均购自BRL(Gaithersburg,USA)公司。磺酰罗丹明B(sulforhodamine B,SRB)购自Sigma-Aldrich(St Louis,Mo,USA)公司。CO2细胞培养箱为美国Thermo Forma Scientific(Marietta,OH,United States)公司产品;倒置显微镜购自Olympus公司;CA-1390-1型超净工作台为上海净化设备有限公司产品;BT 124S型十万分之一天平为Sartorius公司产品;HF safe 1500型连续加样器为eppendorf公司产品;SPECTRA MAX 190酶标仪为MolecularDevices(Sunnyvale CA,U.S.A.)公司产品。人肝癌细胞BEL-7402以及SMMC-7721购自中国科学院上海生科院生化细胞所细胞库。其他人肿瘤细胞株HepG2、NCI-H460、Hep3B均购自美国典型培养物保藏中心库(American TypeCulture Collection Manassas,VA)。
实验方法:化合物体外抗肿瘤活性采用磺酰罗丹明B方法。肿瘤细胞用RPMI 1640或DMEM培养基(Gibco)培养,内含10%胎牛血清,培养条件为37℃,5%CO2。将BEL-7402、SMMC-7721、HepG2、Hep3B和NCI-H460细胞株分别接种于96孔板(0.4-1.0×104细胞/孔),24小时后,加入10倍稀释的目标化合物扎达维林;目标化合物至少含5个浓度。化合物处理72小时后,弃去培养液,用10%冷三氯醋酸固定细胞。然后用磺酰罗丹明B溶液染色。洗去未结合SRB后,用Tris溶解与蛋白结合的SRB,用酶标仪在515nm波长下测定OD值,按以下公式计算细胞生长抑制率:
抑制率=(OD值对照孔-OD值给药孔)/OD值对照孔×100%
根据各浓度抑制率,采用Logit法计算半数抑制浓度IC50。结果见表1。
表1.扎达维林的体外抗肿瘤作用
实施例2:扎达维林的体内抗肿瘤作用
实验方法:BALB/cA-nude裸小鼠,6-7周,♀,购自上海斯莱克实验动物有限责任公司。合格证号:SCXK(沪)2007-0005。饲养环境:SPF级。扎达维林及对照药物索拉非尼(sorafenib)均用含0.1%Tween-80的0.5%CMC配成所需浓度。裸小鼠皮下接种人肝癌Bel-7402细胞,待肿瘤生长至100-200mm3后,将动物随机分组(d0),溶剂对照组:n=12;扎达维林60mg/kg组、扎达维林200mg/kg组及阳性对照组:n=6,并开始给药,每天1次,连续灌胃14天,然后停药,观察持续37天,并测量肿瘤大小。每周测2-3次瘤体积,称鼠重,记录数据。
肿瘤体积(V)计算公式为:V=1/2×a×b2(其中a、b分别表示长、宽)。
相对肿瘤体积(RTV):最后1天肿瘤体积/开始给药时的肿瘤体积。
实验结果:见图1。图1显示了扎达维林对人肝癌细胞Bel-7402裸小鼠移植瘤的疗效。从图1中可以看出:扎达维林口服给药200mg/kg,表现出对BEL-7402移植瘤良好的抗肿瘤作用。同时,从图2中可以看出,高剂量时对老鼠的体重影响不大,说明毒性很小。
扎达维林在体内外均表现出有效的抗肿瘤活性,尤其是对肝癌具有较强的特异性,其可作为抗肿瘤药物在临床进行应用。
Claims (2)
1.式I所示的6-(4-(二氟甲氧基)-3-甲氧基苯基)哒嗪-3(2H)-酮在制备抗肝癌药物中的用途
2.根据权利要求1所述的用途,其中,所述抗肝癌药物特异性地抑制BEL-7402及SMMC-7721细胞株的活性。
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