CN112168976B - 一种黄酮衍生物前药及合成和作为抗肿瘤药物的应用 - Google Patents
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Abstract
本发明涉及一种黄酮衍生物前药,具体是以人体的条件必需氨基酸酪氨酸为连接臂,利用酪氨酸三种不同化学性质的官能团:氨基、羧基和酚羟基,分别连接聚乙二醇单甲醚、黄酮衍生物和肿瘤相关糖抗原,将黄酮衍生物修饰为具有靶向性且理化性质更佳的前药。本发明提供的黄酮衍生物前药对多种肿瘤细胞,包括人白血病细胞K562、人肝癌细胞HepG2和人结肠癌细胞HCT‑116表现出很强的抗肿瘤活性,可望开发成新的抗肿瘤药物。
Description
技术领域
本发明属于新化合物合成和药物应用领域,尤其是一种具有靶向性且理化性质更佳的黄酮衍生物前药的合成及其在制备抗肿瘤药物中的应用。
背景技术
前药是活性药物分子的非活性、生物可逆衍生物,必须在体内进行酶和/或化学作用转化以释放活性母体药物,然后才能引发其所需的药理作用。旨在克服药物利用的制剂障碍、递送障碍和毒性障碍的多种前药已经批准上市,实际上,在2000年至2008年期间批准的所有小分子药物中,约有20%是前药。尽管前药的开发可能非常具有挑战性,但前药方法代表了一种改善在研药物或已上市药物不良性质的可行方法。
黄酮类化合物广泛存在于自然界,且被报导具有良好的抗肿瘤活性,但目前医药市场上黄酮类产品很少,分析其主要原因是大多数黄酮类化合物存在理化性质差、生物利用度低以及严重的毒副作用等原因。
聚乙二醇(PEG)是一类具有独特物理和化学性质的大分子聚合物,在水和许多有机溶剂中都具有较好的溶解度,由于其低毒性、低免疫原性和高生物相容性而被广泛使用。PEG修饰的前药不仅可以改善药物的水溶性,而且可以保持原有的生物学活性不变,被人体吸收后可以缓慢的释放药物活性分子,改善药物作用的半衰期。此外,大分子药物在肿瘤组织中的透过性增强和滞留效应(EPR效应)有助于PEG修饰的前药在实体瘤内的积累,从而实现肿瘤药物的靶向递送,降低药物对正常组织的毒副作用。
肿瘤相关糖抗原(Tumor-associated carbogydrate antigens,TACAs)是肿瘤细胞表面过度表达的一类特殊糖链结构,它是肿瘤细胞表面重要的标记分子,可以作为细胞膜表面的受体。因此将抗肿瘤药物与肿瘤相关糖抗原偶联,可以对药物起到主动靶向的作用。
发明内容
本发明的目的在于提供一种黄酮衍生物前药及合成和作为抗肿瘤药物的应用,具体是以人体的条件必需氨基酸酪氨酸为连接臂,利用酪氨酸三种不同化学性质的官能团:氨基、羧基和酚羟基,分别连接聚乙二醇单甲醚、黄酮衍生物和肿瘤相关糖抗原,将黄酮衍生物修饰为具有靶向性且理化性质更佳的前药,体外抗肿瘤活性研究证明,本发明的黄酮衍生物前药对多种肿瘤细胞,包括人白血病细胞K562、人肝癌细胞HepG2和人结肠癌细胞HCT-116具有很强的抗肿瘤活性,可望开发成新的抗肿瘤药物。
本发明的目的是通过以下技术方案实现的:
一种黄酮衍生物前药,所述前药由L-酪氨酸、黄酮衍生物I、聚乙二醇单甲醚和肿瘤相关糖抗原制得;
其中,所述聚乙二醇单甲醚的分子量为300~100000Da;所述肿瘤相关糖抗原为T抗原、Tn抗原、TF抗原、sTn抗原、sLex抗原等及它们的氟代衍生物。
而且,所述黄酮衍生物前药的结构式通式为:
其中,TACAs为肿瘤相关糖抗原;n=4~2000。
而且,所述的肿瘤相关糖抗原为Tn抗原,所述前药结构式为:
其中,n=4~2000。
而且,所述黄酮衍生物前药II的合成路线为:
其中,n=4~2000。
如上述的一种黄酮衍生物前药在制备具有靶向性抗肿瘤药物中的应用。
而且,所述的抗肿瘤药物为治疗人白血病细胞K562,或为人肝癌细胞HepG2,或为人结肠癌细胞HCT-116的药物。
黄酮衍生物前药II的体外抗肿瘤活性结果如表1所示。
表1体外抗肿瘤活性测试结果
从测试结果可以看出,在细胞水平上,前药保持了原药对肿瘤细胞抑制的高活性,且对正常细胞的毒性降低。
本发明取得的优点和积极效果为:
本发明的黄酮衍生物前药保持了原药对肿瘤细胞抑制的高活性,同时相对于阳性对照药物CPT,前药对正常细胞的毒性减弱。相比于原药黄酮衍生物I,由于引入了水溶性基团聚乙二醇单甲醚,前药II的理化性质得到了有效改善,可以促进药物在体内的吸收进而提高其生物利用度;具有肿瘤细胞靶向性的肿瘤相关糖抗原引入,可以使药物在体内对肿瘤细胞的抑制作用更具靶向性,降低治疗的毒副作用,可望开发成新的抗肿瘤药物。
附图说明
图1为本发明中化合物II的MALDI-TOF图谱;
图2为本发明中化合物II的高效液相色谱图,采用Diamonsil C18柱(4.6mm×250mm,5μmol/L),流动相甲醇/水(90/10 v/v)在25℃以0.5mL/min流速和254nm检测器波长;
具体实施方式
下面详细叙述本发明的实施例,需要说明的是,本实施例是叙述性的,不是限定性的,不能以此来限定本发明的保护范围。
本发明中所使用的原料,如无特殊说明,均为常规的市售产品;本发明中所使用的方法,如无特殊说明,均为本领域的常规方法。
一种黄酮衍生物前药,所述前药由L-酪氨酸、黄酮衍生物I、聚乙二醇单甲醚和肿瘤相关糖抗原制得;
其中,所述聚乙二醇单甲醚的分子量为300~100000Da;所述肿瘤相关糖抗原为T抗原、Tn抗原、TF抗原、sTn抗原、sLex抗原等及它们的氟代衍生物。
较优地,所述黄酮衍生物前药的结构式通式为:
其中,TACAs为肿瘤相关糖抗原;n=4~2000。
较优地,所述的肿瘤相关糖抗原为Tn抗原,所述前药结构式为:
其中,n=4~2000。
较优地,所述黄酮衍生物前药II的合成路线为:
其中,n=4~2000。
如上述的一种黄酮衍生物前药在制备具有靶向性抗肿瘤药物中的应用。
较优地,所述的抗肿瘤药物为治疗人白血病细胞K562,或为人肝癌细胞HepG2,或为人结肠癌细胞HCT-116的药物。
具体地,相关的制备步骤如下:
(1)化合物1b的合成
在圆底烧瓶中,将化合物1a(1.80g,5.64mmol)溶于N,N-二甲基甲酰胺(15mL)溶液中,在0℃搅拌条件下,依次加入化合物I(1.20g,3.76mmol)、EDCI(1.08g,5.64mmol)、DMAP(46.2mg,0.37mmol)和DIEA(1.26mL,7.52mmol),在25℃搅拌条件下反应12h;用乙酸乙酯(100mL)稀释后缓慢倾入水中,乙酸乙酯(3×100mL)萃取分离后合并有机相,饱和食盐水(3×100mL)洗涤,无水硫酸钠干燥后减压浓缩,经柱层析(石油醚∶乙酸乙酯=2∶1)纯化,得淡黄色油状产物1.34g,收率56%。
(2)化合物1c的合成
将化合物1b(300mg,0.34mmol)溶解于TFA/DCM(1∶1,v/v,6mL)中,将反应溶液在室温搅拌2小时。然后减压浓缩后得淡黄色油状产物,直接用于下一步。
(3)化合物1e的合成
将化合物1c(180mg,0.37mmol)溶于N,N-二甲基甲酰胺(5mL)、二氯甲烷(2mL)混合溶液中,在0℃搅拌条件下,依次加入化合物1d(900mg,0.18mmol)、EDCI(110mg,0.55mmol)、DMAP(4.5mg,0.037mmol)和DIEA(0.25mL,1.48mmol),在25℃搅拌条件下反应12h;TLC检测反应完全,用二氯甲烷(100mL)稀释后缓慢倾入水中,二氯甲烷(3×100mL)萃取分离后合并有机相,饱和食盐水(3×100mL)洗涤,无水硫酸钠干燥后减压浓缩,经柱层析(二氯甲烷∶甲醇=10∶1)纯化,得淡黄色固体产物0.44g,收率45%。
(4)黄酮衍生物前药II的合成
将化合物1e(400mg,0.14mmol)、化合物1f(26.02mg,0.17mmol)、无水硫酸铜(11.94mg,0.15mmol)和抗坏血酸钠(14.82mg,0.15mmol)溶于THF/H2O(2mL,v/v,1∶1)混合溶剂中,室温搅拌反应10h,TLC检测反应完全,减压旋蒸后柱层析(二氯甲烷∶甲醇=20∶1-10∶1)纯化,得白色固体产物260mg,收率62%。MALDI-TOF结果显示与理论分子量范围相符,图谱如图1所示;通过高效液相色谱法(HPLC)测定其纯度为97%,结果如图2所示。
(5)本发明氮杂黄酮衍生物的抗肿瘤活性测定
取对数生长期的细胞,调整细胞密度为5×104cells/mL接种于96孔板上,每孔100μL,同时设置空白孔和对照孔,每个化合物浓度设置3个平行孔。于37℃、5%CO2培养箱中培养(悬浮细胞培养2h,贴壁细胞培养24h)。分别加入终浓度为1.0、10μM的化合物,每孔0.5μL。空白孔为不含有细胞、DMSO以及化合物的纯培养基孔,对照孔为含相同浓度DMSO作用的细胞。按照以上方案处理后,将孔板置于37℃,5%CO2恒温培养箱中培养48h。此后,每孔加入5mg/mL的MTT溶液20μL(用PBS配制,0.22μm滤膜过滤除菌),置于37℃,5%CO2恒温培养箱中继续孵育4h,终止培养。悬浮细胞每孔直接加入100μL盐酸异丙醇,贴壁细胞小心移除孔内培养上清液,每孔加入100μL DMSO。37℃,培养箱内放置10min,使紫色结晶物充分溶解。用酶标仪(悬浮细胞选择580,620nm,贴壁细胞选择490,620nm)测定各孔的吸光度(OD)值。根据测出的OD值按照以下公式计算细胞存活率。
细胞存活率(%)=(实验组OD-空白组OD)/(对照组OD-空白组OD)×100%
尽管为说明目的公开了本发明的实施例,但是本领域的技术人员可以理解:在不脱离本发明及所附权利要求的精神和范围内,各种替换、变化和修改都是可能的,因此,本发明的范围不局限于实施例和附图所公开的内容。
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