CN103127112A - 一类喹啉酮衍生物在肿瘤治疗中的应用 - Google Patents
一类喹啉酮衍生物在肿瘤治疗中的应用 Download PDFInfo
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- CN103127112A CN103127112A CN2013100622147A CN201310062214A CN103127112A CN 103127112 A CN103127112 A CN 103127112A CN 2013100622147 A CN2013100622147 A CN 2013100622147A CN 201310062214 A CN201310062214 A CN 201310062214A CN 103127112 A CN103127112 A CN 103127112A
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Abstract
本发明公开了结构如式（I）所示的一类喹啉酮化合物用于抑制MUC1阳性肿瘤细胞活性的药物中的用途。
Description
技术领域
本发明涉及一类喹啉酮类化合物在肿瘤治疗中的应用。
背景技术
MUCl属黏蛋白家族成员，成熟的MUC1蛋白由α和β两个亚基组成。其中，α亚基完全位于胞外，β亚基则分为胞外区、跨膜区(28个氨基酸)和胞内区(72个氨基酸)。跨膜区和胞内区在不同种属间的结构是高度保守的。MUC1α亚基的序列则存在多个转录剪切本，并且被高度糖基化修饰。
早期对MUCl生物学功能的认识主要局限于其润滑、保护及凋节细胞同的黏附等机械作用。正常情况下，MUCl广泛分布于机体正常各黏膜表面，另外骨髓造血细胞中也有表达。
近年来的研究发现，MUC1与肿瘤的发生和进展密切相关，具体体现在以下3个方面：(1)肿瘤细胞中MUC1的表达量增高，常常达正常细胞的10倍以上，且增加的程度与肿瘤的恶性程度成正比；(2)MUC1在细胞上的极性分布消失；(3)糖链的糖基化不全，糖链变短，分支变少，结构变简单。
进一步的研究显示MUC1参与了多个信号传导通路（图1）。例如，MUCl与多个酪氨酸激酶信号通路均有相互作用，这些相互作用促进了肿瘤的生长、浸润以及转移。另外，MUCl参与调节erbB家族成员的功能。MUCl的表达抑制了erbBl的降解，使细胞中EGFR的总量增加，这可能也是细胞发生癌变的机制之一。有趣的是，MUCl还可通过Wnt信号通路中APC、β-catenin等的功能影响肿瘤的发展及转移潜能。在乳腺癌中，MUCl与APC相互作用，使乳腺癌发生时间提前，并增强乳腺癌细胞系的侵袭性。同时，MUCl通过胞内段与β-catenin结合，阻断GSK一3β对β-catenin的磷酸化，使之无法被蛋白酶体降解，引起β-Catenin在胞浆和细胞核内的堆积，从而激活Wnt途径。另一个有力的证据是过表达MUC1胞内片段MUC1-CD可诱导细胞增殖和癌变，进一步支持了MUC1的癌基因的特性。
关于MUCI与肿瘤的转移和恶性程度间联系的证据也十分丰富。多种研究表明，MUCl的mRNA或蛋白表达升高常常提示肿瘤侵袭转移，且与患者的预后相关。其机制可能是：(1)癌细胞膜表面高密度表达的MUCl分子阻碍了其它膜表面蛋白间或蛋白与细胞间基质的相互作用。有证据显示MUCl的表达使E-Cadherin下调，从而使肿瘤相互问的黏附力下降；(2)肿瘤细胞MUCl的糖基化不完全，导致空间位阻增大，抑制了肿瘤细胞之间的黏附，使肿瘤细胞的侵袭性增强；(3)MUCl上的某些表位可与损伤或有炎症的血管内皮细胞上的E-Cadherin作用，使瘤细胞与血管内皮细胞黏附，易于穿过血管壁，从而利于瘤细胞转移。此外，有文献报道MUCl抗黏附作用可通过与黏附分子如ICAM-1，E-选凝素等相互作用而引起。
鉴于MUC1与癌症之间的密切联系，目前已有多种基于MUCl的免疫疗法用于肿瘤生物治疗研究。部分临床试验给出了较为乐观的结果。然而目前所有的免疫疗法都是针对胞外的MUC1α亚基，而由于MUC1本身的结构特点，临床试验中的免疫疗法疗效存在一定的不确定性。这些问题包括：（1）MUC1(alpha)亚基上的糖基化修饰的多变性影响了免疫应答；（2）MUC1(alpha)亚基本身的多态性影响了免疫应答；（3）MUC1的内化（internalization）削弱了抗体介导的免疫反应；（4）动物实验结果不能在临床试验重现。
近两年，基于对MUC1的功能机制研究逐渐深入，出现了以MUC1β亚基胞内区段为靶标的策略。由于MUC1与其它胞内蛋白的相互作用是通过其胞内片段MUC1-CD实现的，因此一种策略是人工合成MUC1-CD的某一特定区段，导入肿瘤细胞内竞争性的抑制MUC1与其它蛋白的结合。如PMIP，其MUC1相关序列为PYEKVSAGNGGSSLS，对应与MUC1-CD与EGFR和beta-catenin结合的区域。
另一种策略是合成MUC1-CD的近膜端片段，如已进入临床的GO-203-2C，其序列为CQCRRKNYGQCDIFP。这一区域是MUC1-CD二聚体化的关键序列，而MUC1-CD的二聚体化对MUC1的特定功能及胞内循环至关重要。将GO-203-2C导入肿瘤细胞内后，胞内的MUC1二聚体化受到抑制，且MUC1表达量也受到下调。
上述两类小肽类分子在临床前研究中均取得了明显的肿瘤抑制功能。
最近，出现了第三种针对MUC1-CD的治疗策略。有研究发现黄酮类化合物可以在体外和细胞水平实验中抑制MUC1-CD的二聚体化和蛋白表达。这为开发MUC1的小分子抑制剂提供了方向。
喹啉酮骨架是一类重要的杂环结构，具有广泛的生物活性，特别是应用于许多小分子抗肿瘤药物中。
发明内容
本发明提供了一种采用结构如（I）所示的喹啉酮化合物或其药学上可接受的盐在制备用于抑制MUC1阳性肿瘤细胞活性的药物中的用途，其中：
R1选自氢、C1-6烷基、-OR3或-NR4R5；
R2选自氢、C1-6烷基、卤代甲基及或C6-10芳基；
R3、R4、R5独立选自氢、C1-6烷基、C6-10芳基亚甲基。
此外，本发明涉及的化合物（I）可以参照本领域已有的文献报道制备。如Shuji,T.et al,Journal of Medicinal Chemistry(2003),46(14),3033-3044;Marc,M.et al，European Journal ofOrganic Chemistry(2004),(1),54-63;Yoshiyasu,K.et al,Heterocycles(1990),31(11),2085-90;Przemyslaw，R.et al,ChemMedChem(2010),5(1),103-117.以及他们所引用的相关文献。
更进一步地，所述通式（I）的化合物选自：
其中，化合物1-8可以分别参照本领域文献报道的方法制备，如Jun,T.et al,Chemical &Pharmaceutical Bulletin(2000),48(12),1854-1861；Tomohiko,Y. et al,Chemical&Pharmaceutical Bulletin(1992),40(5),1322-4;Eugene R.B.et al,Journal of Organic Chemistry(1980),45(12),2283-7;Pietro,V. et al,Journal of Heterocyclic Chemistry(1975),12(4),669-73;Pietro,V. et al,Gazzetta Chimica Italiana(1970),100(7),678-81;JP2003146972;Naiema,M.et al,Journal of Medicinal Chemistry(2004),47(25),6392-6400;Przemyslaw，R.et al,ChemMedChem(2010),5(1),103-117.以及他们所引用的相关文献。
发明详述
术语“C1-C6烷基”是指具有直链或支链部分并含有1至6个碳原子的饱和一价烃基。此类基团的实例包括但不限于甲基、乙基、丙基、异丙基、正丁基、异丁基和叔丁基。
术语“C6-C10芳基”是指含有6至10个碳原子的衍生至芳烃的基团。此类基团的实例包括但不限于苯基、苄基、萘基。
术语“卤代”是指氟、氯、溴、碘。
术语“药学上可接受的盐”表示保留母体化合物的生物有效性和性质的那些盐。这类盐包括：
（1）与酸成盐，通过母体化合物的游离碱与无机酸或有机酸的反应而得，无机酸包括盐酸、氢溴酸、氢碘酸、硝酸、亚硝酸、磷酸、偏磷酸、硫酸、亚硫酸和高氯酸等，有机酸包括乙酸、丙酸、丙烯酸、草酸、（D）或（L）苹果酸、富马酸、马来酸、羟基苯甲酸、γ-羟基丁酸、甲氧基苯甲酸、邻苯二甲酸、甲磺酸、乙磺酸、萘-1-磺酸、萘-2-磺酸、对甲苯磺酸、水杨酸、酒石酸、柠檬酸、乳酸、扁桃酸、琥珀酸或丙二酸等。
（2）存在于母体化合物中的酸性质子被金属离子代替或者与有机碱配位化合所生成的盐，金属例子例如碱金属离子、碱土金属离子或铝离子，有机碱例如乙胺、二乙胺、二环己胺、三乙胺、丁胺、乙二胺、乙醇胺、二乙醇胺、三乙醇胺、哌嗪、苄胺、苯基苄胺、胆碱、葡甲胺、氨丁三醇、N-甲基葡糖胺等。
更优选的，本发明所述式（I）化合物在制备药物中的用途，该药物用作癌症疗法的辅助手段或者用于强化电离放射或化学治疗剂对肿瘤细胞的治疗。
进一步优选的，本发明所述式（I）化合物在制备药物中的用途，该药物用于治疗个体的癌症。
所述MUC1-阳性肿瘤细胞可以是癌细胞、白血病细胞或骨髓瘤细胞，癌细胞可以是，例如，乳腺癌、肺癌、结肠癌、胰腺癌、肾癌、胃癌、肝癌、骨癌、血液癌、神经组织癌、黑色素瘤、卵巢癌、睾丸癌、前列腺癌、宫颈癌、阴道癌或膀胱癌细胞。更典型地，所述癌细胞选自前列腺癌或乳腺癌。抑制可包括诱导所述肿瘤细胞的生长停滞，所述肿瘤细胞的凋亡和/或包含所述肿瘤细胞的肿瘤组织的坏死。
采用生化水平结合试验、细胞水平MUC1表达量测试和抑制肿瘤细胞增殖活性测试来确定本发明的各种化合物对MUC1阳性肿瘤细胞的抑制活性和作用水平。
在生化水平结合试验中，采用纯化的GST-Muc1-CD(1-72)蛋白，可测定不同的本发明化合物对MUC1蛋白二聚体化的抑制能力。
在细胞水平MUC1表达量测试中，测定按常规采用Westernblot法，可测定不同的本发明化合物对MUC1蛋白表达的抑制能力。
在抑制肿瘤细胞增殖活性测试中，测定按常规采用Cell Counting Kit-8（CCK8）法。在电子载体1-甲氧基-5-甲基吩嗪鎓硫酸二甲酯（1-Methoxy PMS）的作用下，活细胞线粒体中的琥珀酸脱氢酶能使外源性黄色的2-(2-甲氧基-4-硝基苯基)-3-(4-硝基苯基)-5-(2,4-二磺酸苯)-2H-四唑单钠盐（WST-8）还原为具有高度水溶性的黄色甲瓒产物（Formazan）。生成的甲瓒物的数量与活细胞的数量成正比。用酶联免疫检测仪在450nm波长处测定其光吸收值，可间接反映活细胞数量。因而甲瓒生成量在通常情况下与活细胞数成正比，可根据OD值推测出活细胞的数目，了解药物抑制或杀伤细胞的能力。该测定方法可以用于测定不同的本发明化合物对一种或多种癌细胞增殖的抑制能力，利用本领域熟知的方法，可以对任意癌细胞使用相似的测定方法。
附图说明
图1为Westernblot法检测化合物对肿瘤细胞MCF7和MDA-MB-468的MUC1蛋白表达的抑制活性。
具体实施方式
下面用实施例来进一步说明本发明，但本发明不受其限制。
实施例1：体外生化水平抑制MUC1二聚体化活性实验
将纯化的GST-Muc1-CD(1-72)蛋白（100ug/mL）溶于PBS中，加入至高蛋白吸附96孔板(Thermo Fisher Scientific,Waltham,MA)中，37°孵育过夜。第二天，加入5%BSA封闭1小时，TPBS清洗三遍后加入不同浓度的化合物（DMSO含量为1%），后加入His-Muc1-CD（1-16）小肽，继续与37°孵育2h。TPBS清洗三遍后，加入Anti-His-HRP（MBL,MA）抗体，继续于37°孵育1h，TPBS清洗三遍。后加入TMB(Thermo Fisher Scientific)显色，2M浓H2SO4终止显色后于562nM处检测吸光度值。
实施例2：体外细胞水平抑制MUC1蛋白表达活性实验（Westernblot法）
收集不同浓度化合物处理的细胞，加入1XLoading裂解细胞。裂解液进行SDS-PAGE电泳后，转印至PVDF膜。然后使用Muc1-C抗体（Epitomic，2900-1）和b-Actin抗体（SantaCruz，SC81178）杂交目的蛋白。
实施例3：肿瘤细胞增殖抑制活性实验（CCK8法）
收集对数期生长的MCF7和MDA-MB468细胞，以5×103/孔接种于96孔板中，37°CO2培养箱孵育培养过夜。第二天，待细胞贴壁生长后给予不同浓度的化合物：化合物配置，以150μM开始，三倍梯度稀释，设8个梯度浓度组，DMSO为0.1%。空白对照组设置为不含细胞的全培养基。继续培养于37°CO2培养箱培养72h。然后各孔加入CCK8（DOJINDO，CK04）于37°CO2培养箱培养2h后于450nM处检测吸光度值。
细胞生长抑制率以及IC50的计算：
同时根据各浓度的生长抑制率，采用以化合物浓度的对数同Logit线性回归，求出抑制生长率为50％时的待测化合物浓度即IC50，取三次平均值。
表1化合物对肿瘤细胞增殖的半数抑制浓度范围（IC50）
试验结果：本发明所述的具有式I结构的化合物1-8对MCF7和MDA-MB-468肿瘤细胞的增殖具有抑制作用，经统计分析，效果显著（P<0.05），其IC50均在2×10-5mol/L以下。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (6)
1.结构如（I）所示的喹啉酮化合物或其药学上可接受的盐在制备用于抑制MUC1阳性肿瘤细胞活性的药物中的用途，其中：
R1选自氢、C1-6烷基、-OR3或-NR4R5；
R2选自氢、C1-6烷基、卤代甲基及或C6-10芳基；
R3、R4、R5独立选自氢、C1-6烷基或C6-10芳基亚甲基。
2.根据权利要求1所述的用途，其中所述的化合物选自：
3.权利要求1的化合物在制备药物中的用途，该药物用作癌症疗法的辅助手段或者用于强化电离放射或化学治疗剂对肿瘤细胞的治疗。
4.权利要求1的化合物在制备药物中的用途，该药物用于治疗个体的癌症。
5.权利要求4或5的用途，其中所述癌症选自乳腺癌、肺癌、结肠癌、胰腺癌、肾癌、胃癌、肝癌、骨癌、血液癌、神经组织癌、黑色素瘤、卵巢癌、睾丸癌、前列腺癌、宫颈癌、阴道癌或膀胱癌细胞。
6.权利要求3至5的用途，其中所述癌症选自前列腺癌或乳腺癌。
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