CN106117188B - 用于治疗癌症的化合物 - Google Patents
用于治疗癌症的化合物 Download PDFInfo
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- CN106117188B CN106117188B CN201610302206.9A CN201610302206A CN106117188B CN 106117188 B CN106117188 B CN 106117188B CN 201610302206 A CN201610302206 A CN 201610302206A CN 106117188 B CN106117188 B CN 106117188B
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- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
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Abstract
Description
技术领域
本发明是关于一种新颖化合物及其应用,尤指用于制备治疗癌症的药剂的用途。
背景技术
癌症是源于细胞分裂增生的控制机制失控所引起的疾病。于正常状态下,个体的细胞增殖与细胞凋亡会达成平衡,并受到严谨的控制以保证组织与器官的完整性及正常运作,但调控细胞生长的基因发生突变或损坏时,细胞将失去控制,导致持续的增生分裂而产生肿瘤,随着病程的演进,癌细胞将侵犯周边组织,进而通过血管组织转移到远程。
在癌症的治疗上,目前已发展多种方法,其中化疗为主要的手段之一,然而目前临床使用的抗肿瘤化学治疗药物均有不同程度的毒副作用,如局部组织坏死、栓塞性静脉炎,或全身性反应,例如,消化道、造血系统、免疫系统、皮肤和粘膜反应、神经系统、肝功能损害、心脏反应、肺毒性反应、肾功能障碍及其他反应等,这些严重的毒副反应是限制药物剂量或使用的原因之一。
因此,仍需持续研发更为有效的癌症治疗方法或药物。
发明内容
本发明提供一种新颖化合物及其用于治疗癌症的用途,因此,本发明亦提供一种用于治疗癌症的医药组合物。
在一方面,本发明提供一种式(I)化合物:
其中
X为S或O;Z为H、OH或OAc;R1为H或O-(C1-6烷基);R2为H、NO2或O-(C1-6烷基);R3为H或O-(C1-6烷基);以及R4为H、OH、NO2或O-(C1-6烷基),或其医药上可接受的盐。
再一方面,本发明提供式(I)化合物用于制备治疗癌症的药剂的用途。
另一方面,本发明提供一种医药组合物,其包含式(I)化合物及医药上可接受的载剂。
又一方面,本发明提供一种治疗癌症的医药组合物,其包含式(I)化合物及其医药上可接受的盐。
本发明的此等及其他态样将可由下文的较佳具体实例叙述并结合附图时明显可见,但可在不偏离本揭示内容新颖概念的精神及范围的情形下对其进行变化及修饰。
附图说明
图1显示以本发明的化合物8及化合物14处理大肠癌细胞(DLD-1、 SW620)及乳癌细胞(MCF-7)24小时后的细胞存活率。
图2显示不同浓度的化合物对于SW620大肠癌细胞存活率的影响,化合物8及化合物14具降低癌症细胞存活率的功效。
图3显示本发明的化合物对于DLD-1大肠癌细胞存活率的影响,其中雷帕霉素可降低DLD-1存活率至80%,而化合物14可降低DLD-1存活率至 60%左右。
图4A和图4B为mTOR的西方墨点分析结果,显示雷帕霉素与化合物 14均可显著抑制mTOR的蛋白质表现。
具体实施方式
除非另外定义,本文中所用的所有技术及科学词汇具皆有熟习本文所属技艺者所通常明了的相同意义。如有冲突,则以本文件,包括其定义为主。
当用于此处时,本文所使用冠词「一」或「该」意指该冠词文法上的受词为一或一以上(亦即至少为一)。举例而言,「一组件」代表一组件或多于一组件。
本发明是提供一种式(I)化合物
在一方面,本发明提供一种式(I)化合物:
其中
X为S或O;Z为H、OH或OAc;R1为H或O-(C1-6烷基);R2为H、NO2或O-(C1-6烷基);R3为H或O-(C1-6烷基);以及R4为H、OH、NO2或O-(C1-6烷基)。
根据本发明的一具体实施例,本发明的新颖化合物具有如式(IA)的结构:
其中,X为S或O;Z为H、OH或OAc;R1为H或O-(C1-6烷基);R2为H、NO2或O-(C1-6烷基);R3为H或O-(C1-6烷基);以及R4为H、OH、NO2或O-(C1-6烷基)。
根据本发明的另一具体实施例,本发明的新颖化合物具有如式(IB)的结构:
其中X为S或O。
本发明的化合物的具体态样可选自以下组成的群组:
(E)-2-[2-(5-硝基呋喃-2-基)乙烯]苯并[d]恶唑;
(E)-2-[2-(5-硝基呋喃-2-基)乙烯]苯并[d]噻唑;
(E)-2-[2-(5-硝基噻吩-2-基)乙烯]苯并[d]噻唑;
(E)-1-{2-[2-(5-硝基噻吩-2-基)乙烯]-1H-苯并[d]咪唑-1-基}乙酮;
(E)-2-[2-(5-硝基噻吩-2-基)乙烯]-1H-苯并[d]咪唑;
(E)-2-[2-(5-硝基噻吩-2-基)乙烯]-苯并[d]恶唑;
(E)-2-[2-(5-硝基噻吩-2-基)乙烯]喹啉;
(E)-2-[2-(5-硝基噻吩-2-基)乙烯]喹啉酮;
(E)-2-[2-(5-硝基呋喃-2-基)乙烯]-8-羟基喹啉;
(E)-2-[2-(5-硝基噻吩-2-基)乙烯]-8-羟基喹啉;
(E)-6-硝基-2-[2-(5-硝基呋喃-2-基)乙烯]喹啉;
(E)-6-硝基-2-[2-(5-硝基呋喃-2-基)乙烯]喹啉酮;
(E)-8-硝基-2-[2-(5-硝基呋喃-2-基)乙烯]喹啉;
(E)-6-硝基-2-[2-(5-硝基噻吩-2-基)乙烯]喹啉;
(E)-2-[2-(5-硝基呋喃-2-基)乙烯]喹啉-4-基乙酸甲酯;
(E)-2-[2-(5-硝基噻吩-2-基)乙烯]喹啉-4-基乙酸甲酯;
(E)-2-[2-(5-硝基呋喃-2-基)乙烯]-4-羟基喹啉;
(E)-2-[2-(5-硝基噻吩-2-基)乙烯]-4-羟基喹啉;
(E)-6-甲氧基-2-[2-(5-硝基呋喃-2-基)乙烯]-4-羟基喹啉
(E)-6-甲氧基-2-[2-(5-硝基噻吩-2-基)乙烯]-4-羟基喹啉;
(E)-8-甲氧基-2-[2-(5-硝基呋喃-2-基)乙烯]-4-羟基喹啉;
(E)-8-甲氧基-2-[2-(5-硝基噻吩-2-基)乙烯]-4-羟基喹啉;
(E)-5,8-二甲氧基-2-[2-(5-硝基呋喃-2-基)乙烯]-4-羟基喹啉;
(E)-5,8-二甲氧基-2-[2-(5-硝基噻吩-2-基)乙烯]-4-羟基喹啉;
(E)-6,8-二甲氧基-2-[2-(5-硝基噻吩-2-基)乙烯]-4-羟基喹啉;
(E)-6,8-二甲氧基-2-[2-(5-硝基噻吩-2-基)乙烯]-4-羟基喹啉;
(E)-5,6,7-三甲氧基-2-[2-(5-硝基呋喃-2-基)乙烯]-4-羟基喹啉;以及
(E)-5,6,7-三甲氧基-2-[2-(5-硝基噻吩-2-基)乙烯]-4-羟基喹啉。
根据本发明,式(I)化合物具有抑制癌细胞增生及/或降低癌细胞存活率的功效,如实施例所示,例如(E)-2-[2-(5-硝基噻吩-2-基)乙烯]-1H-苯并[d]恶唑(化合物8)及(E)-6-硝基-2-[2-(5-硝基呋喃-2-基)乙烯]喹啉酮(化合物14),具有与临床使用的抗癌药物雷帕霉素相近或更为优异的抑制癌细胞功效,显示可做为医药组合物,用于癌症的治疗。因此,本发明化合物可用于制备治疗癌症药剂。再一方面,本发明提供一种治疗癌症的医药组合物,其包含治疗有效量的式(I)化合物及医药上可接受的载剂。
本文所用的术语「治疗」意指减少、减轻、改善、缓解、或控制一疾病或障碍的一或多个临床征兆,以及降低、停止或逆转一正在被治疗中的病况或症状的严重性的进展。
在治疗的应用上,本发明化合物可与药学上可接受载剂调配成医药组合物。此处所使用的「医药上可接受」意指该载剂是与包含于该组合物中的活性成分兼容,较佳能稳定该活性成分而不会对投予该医药组合物的对象产生伤害。该载剂可为该活性成分的稀释剂、载体、赋形剂或介质。适合载剂的实例包含生理兼容缓冲液,如汉克氏溶液、林格氏溶液、生理食盐水缓冲液、乳糖、右旋葡萄糖、蔗糖、山梨醇、甘露醇、淀粉、阿拉伯胶、磷酸钙、海藻胶、黄耆胶、明胶、硅酸钙、微晶型纤维素、聚乙烯咯啶酮、纤维素、无菌水、糖浆及甲基纤维素。该医药组合物可额外包含润滑剂,例如,滑石、硬脂酸镁及矿物油;润湿剂;乳化与悬浮剂;保存剂,例如,甲基-及丙基-羟基苯甲酸盐;甜味剂;以及调味剂。
本文所用的术语「医药上可接受的盐」意指保留化合物所需生物活性且具有最低不期望毒性的盐类。此等医药上可接受的盐可在最后单离或纯化化合物时制备,或另由呈其游离酸或游离碱型的纯化化合物再分别与合适碱或酸反应。代表性盐类包括医药上可接受的金属盐(如:钠、钾、锂、钙、镁、铝与锌)、医药上可接受的金属阳离子(如:钠、钾、锂、钙、镁、铝与锌)的碳酸盐与碳酸氢盐、医药上可接受的有机一级、二级与三级胺。亦可经合适酸处理形成医药上可接受的酸加成盐。合适酸包括医药上可接受的无机酸与医药上可接受的有机酸。代表性医药上可接受的酸加成盐包括盐酸盐、氢溴酸盐、硝酸盐、甲基硝酸盐、硫酸盐、硫酸氢盐、胺磺酸盐、磷酸盐、乙酸盐等。本文所用的术语「治疗有效量」是指相较于未接受此量的对应个体,药物或药剂的用量造成所欲的药理上的结果,或疾病、异常的治疗、治愈、或改善,或减少疾病或异常的扩散速度。药剂的有效量或有效剂量可根据所使用的特定有效成分、投药模式、年龄、体型、以及所欲治疗个体的条件而改变。药剂的精确用量是依医师的判断进行投药且依个体差异而异。
根据本发明的医药组合物可为片状、药丸、粉末、锭剂、囊袋、药包、药酒、悬浮液、乳化液、溶液、糖浆、软明胶胶囊与硬明胶胶囊、栓剂、无菌注射溶液及经包装的粉末的形式。
本发明的医药组合物可经由任何生理可接受途径传送。此些途径包含但不限于非经口服投药、系统性投药、口服投药、鼻腔投药、直肠投药、腹腔注射、血管注射、皮下注射、经皮投药、吸入投药及肌肉注射。
雷帕霉素(rapamycin)已知具有毒杀细菌、免疫抑制及抗肿瘤的作用,为目前临床上常用的抗癌药物。哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)为雷帕霉素(rapamycin)的标靶蛋白,已知mTOR于细胞的讯息传递扮演中心枢纽角色,细胞可透过控制mTOR路径来统整能量、养分、压力、刺激及生长讯号,而雷帕霉素可藉由抑制mTOR的表现来达到阻止细胞生长、增生、分化、分裂及合成细胞蛋白质,进一步抑制肿瘤的生长或促使癌症细胞自体凋亡,因此mTOR为抗癌药物标靶治疗的理想目标。
本发明的医药组合物可有效抑制癌细胞增生及/或降低癌细胞的存活率,而后附的实例证明,本发明的化合物具有与临床使用的抗癌药物雷帕霉素相近的抑制mTOR表现的功效,咸信本发明的医药组合物可透过哺乳动物雷帕霉素靶蛋白途径达成抑制癌症细胞的效果,因此本发明的医药组合物可用于治疗与哺乳动物雷帕霉素靶蛋白途径有关的癌症。
有丝分裂原活化蛋白激酶(MAPK)途径是细胞响应外界讯息的重要讯息传递系统,参与细胞生长、发育、分裂、死亡、以及细胞间的功能同步等多种生理反应,并在细胞发生恶性转化(例如癌细胞的产生)的病理过程中扮演重要角色。有丝分裂原活化蛋白激酶是一种丝氨酸/苏氨酸激酶,包括细胞外讯息调节蛋白激酶(ERK)、C-Jun N端激酶(JNK)与p38。另一种与细胞生理反应及病理机制有关的讯息传递系统为杰纳斯激酶-转录讯息转换子及活化子(JAK-STAT)途径,其主要是由各种细胞因子与受体结合而二聚体化,杰纳斯激酶接着靠近二聚体并磷酸化,使受体上的酪氨酸残基磷酸化,再透过转录讯息转换子及活化子形成二聚体后与受体分离,并转移到细胞核内结合至DNA序列,从而调控基因表现。
本发明的医药组合物可有效抑制癌细胞增生及/或降低癌细胞的存活率,而后附的实例证明,本发明的化合物的抑癌作用涉及有丝分裂原活化蛋白激酶(MAPK)途径及杰纳斯激酶-转录讯息转换子及活化子 (JAK-STAT)途径,咸信本发明组合物可透过上述途径至少其一达成抑制癌细胞的效果。因此,本发明医药组合物可用于治疗与JAK-STAT途径及MAPK途径的至少一者有关的癌症。
根据本发明的实施例,(E)-2-[2-(5-硝基噻吩-2-基)乙烯]-1H-苯并[d]恶唑 (化合物8)及(E)-6-硝基-2-[2-(5-硝基呋喃-2-基)乙烯]喹啉酮(化合物14)具有抑制癌细胞生长的功效,因此可用于治疗癌症,例如大肠癌与乳癌。
本发明将藉由下列范例进一步说明,此仅提供而用于展现而非限制的目的。由于本揭露,本领域具有通常知识者应可理解所揭露的特定具体实施例,并对该些具体实施例进行诸多修改而获得相似或类似的结果而仍未脱离本发明的精神与范畴。
实施例
1.化合物分析方法
以Electrothermal IA9100熔点分析仪测定化合物熔点。核磁共振(NMR) 光谱(1H及13C)是以Varian Gemini 200光谱仪或Varian-Unity-400光谱仪测量与纪录。化学位移以「δ」表示,并以四甲基硅烷(TMS)作为内标准。薄膜色层分析是于硅胶60F-254板(购自E.Merck and Co.)上进行。元素分析是使用成功大学内的国家科学委员会仪器中心及国立中兴大学的Heraeus CHN-O Rapid EA元素分析仪进行分析,所有数值皆于±0.4%的理论组成内。
2.制备例
A.本发明式(IA)化合物是以如下流程所示的方法制备,下文将详细说明化合物的制备方法:
化合物9:(E)-2-[2-(5-硝基噻吩-2-基)乙烯]喹啉
将0.72克(5毫摩尔)的2-甲基喹啉、4.87克(20毫摩尔)的5-硝基-2-糠醛二乙酯及150毫升乙酸酐的混合物于150℃加热30小时(以薄层色层分析监控)。待混合物冷却后,于真空中浓缩以移除溶剂而获得一粗产物,接续以骤沸管柱色层分析(FC,硅胶,甲醇:二氯甲烷=1:20)进行纯化,制得 (E)-2-[2-(5-硝基噻吩-2-基)乙烯]喹啉(化合物9,0.64公克,产率48%)。
熔点:175-176℃;1H-NMR(400MHz,DMSO-d6):7.23(d,1H,J=4.0Hz, furanyl-H),7.58(d,1H,J=16.0Hz),7.70-7.93(m,2H),7.83(d,1H,J=16.0Hz), 7.94(d,1H,J=8.4Hz),7.99(d,1H,J=8.4Hz),8.03(d,1H,J=8.8Hz),8.43(d, 1H,J=8.8Hz);13C-NMR(100MHz,DMSO-d6):114.17,115.41,119.78,120.90, 126.95,127.48,127.91,128.91,130.21,133.13,136.96,147.63,150.06,153.80, 155.14;分析计算值:C15H10N2O3·0.1H2O:C 67.21,H 3.84,N 10.45;实际值: C 67.15,H 4.09,N 10.12。
化合物10:(E)-2-[2-(5-硝基噻吩-2-基)乙烯]喹啉酮
将0.72克(5毫摩尔)的2-甲基喹啉、3.14克(20毫摩尔)的5-硝基噻吩 -2-甲醛及150毫升乙酸酐的混合物于150℃加热30小时(以薄层色层分析监控)。待混合物冷却后,于真空中浓缩以移除溶剂而获得一粗产物,接续以骤沸管柱色层分析(FC,硅胶,甲醇:二氯甲烷=1:20)进行纯化,制得 (E)-2-[2-(5-硝基噻吩-2-基)乙烯]喹啉酮(化合物10,0.63公克,产率45%)。
熔点:191-192℃;1H-NMR(400MHz,DMSO-d6):7.59-7.63(m,2H),7.62 (d,1H,J=16.0Hz),7.77-7.81(m,1H),7.88(d,1H,J=8.4Hz),7.99(d,1H,J=8.0 Hz),8.03(d,1H,J=8.4Hz),8.08(d,1H,J=16.0Hz),8.16(d,1H,J=4.4Hz, thiophenyl-H),8.43(d,1H,J=8.8Hz);13C-NMR(100MHz,DMSO-d6):120.69, 125.60,126.86,127.38,127.89,128.80,130.17,131.03,133.20,136.88,147.64, 149.27,149.48,151.26,153.99;分析计算值:C15H10N2O2S·0.1H2O:C 63.41,H 3.62,N 9.86;实际值:C 63.40,H 3.67,N 9.79。
化合物11:(E)-2-[2-(5-硝基呋喃-2-基)乙烯]-8-羟基喹啉
将0.8克(5毫摩尔)的8-羟基-2-甲基喹啉、4.87克(20毫摩尔)的(5-硝基呋喃-2-基)二乙酸亚甲酯及150毫升乙酸酐的混合物于150℃加热30小时 (以薄层色层分析监控)。待混合物冷却后,于真空中浓缩以移除溶剂而获得一粗产物,接续将该粗产物溶于吡啶/水(体积比4:1)溶液中于100℃加热1小时(以薄层色层分析监控)。待混合物冷却后,于真空中浓缩以移除溶剂而获得一粗产物,以骤沸管柱色层分析(FC,硅胶,甲醇:二氯甲烷=1:20)进行纯化,制得(E)-2-[2-(5-硝基呋喃-2-基)乙烯]-8-羟基喹啉(化合物11,0.75公克,产率50%)。
熔点:186-187℃;1H-NMR(400MHz,DMSO-d6):7.21(m,2H),7.38(dd,1H, J=8.0,1.6Hz),7.45(t,1H,J=8.0Hz),7.62(d,1H,J=16.0Hz),7.82(m,2H), 8.18(d,1H,J=16.0Hz),8.34(d,1H,J=8.4Hz),9.78(br s,1H,OH);13C-NMR (100MHz,DMSO-d6):111.47,113.62,115.51,117.57,120.10,121.74,127.97, 128.17,132.80,136.85,138.28,151.32,151.55,153.26,155.54;分析计算值: C15H10N2O4:C 63.83,H 3.57,N 9.92;实际值:C 63.58,H 3.70,N 9.83。
化合物12:(E)-2-[2-(5-硝基噻吩-2-基)乙烯]-8-羟基喹啉
将0.8克(5毫摩尔)的8-羟基-2-甲基喹啉、3.14克(20毫摩尔)的5-硝基噻吩-2-甲醛及150毫升乙酸酐的混合物于150℃加热30小时(以薄层色层分析监控)。待混合物冷却后,于真空中浓缩以移除溶剂而获得一粗产物,接续将该粗产物溶于吡啶/水(体积比4:1)溶液中于100℃加热1小时(以薄层色层分析监控)。待混合物冷却后,于真空中浓缩以移除溶剂而获得一粗产物,以骤沸管柱色层分析(FC,硅胶,甲醇:二氯甲烷=1:10)进行纯化,制得(E)-2-[2-(5-硝基噻吩-2-基)乙烯]-8-羟基喹啉(化合物12,0.97公克,产率65%)。
熔点:182-183℃;1H-NMR(400MHz,DMSO-d6):7.13(dd,1H,J=7.6,1.6 Hz),7.37-7.49(m,3H),7.62(d,1H,J=16.0Hz),7.78(d,1H,J=8.4Hz),8.16(d, 1H,J=4.4Hz,thiophenyl-H),8.35(d,1H,J=8.4Hz),8.41(d,1H,J=16.0Hz), 9.70(br s,1H,OH);13C-NMR(100MHz,DMSO-d6):111.39,117.58,121.68, 125.79,127.28,127.84,128.08,131.14,132.64,136.81,138.25,149.25,149.63, 151.64,153.14;分析计算值:C15H10N2O3S:C60.39,H 3.38,N 9.39;实际值: C 60.07,H 3.45,N 9.35。
化合物13:(E)-6-硝基-2-[2-(5-硝基呋喃-2-基)乙烯]喹啉
此化合物是自2-甲基-6-硝基喹啉及(5-硝基呋喃-2-基)二乙酸亚甲酯由化合物9所述的方法制得,并自乙醇中再结晶,产率53%。
熔点:258-260℃;1H-NMR(400MHz,DMSO-d6):7.31(d,1H,J=4.0Hz, furanyl-H),7.67(d,1H,J=16.4Hz),7.84(d,1H,J=4.0Hz,furanyl-H),7.96(d, 1H,J=16.4Hz),8.13(d,1H,J=8.4Hz),8.20(d,1H,J=9.2Hz),8.49(dd,1H,J= 9.2,2.8Hz),8.76(d,1H,J=8.4Hz),9.06(d,1H,J=2.8Hz);13C-NMR(100MHz, DMSO-d6):115.16,115.24,121.91,122.67,123.43,124.96,126.36,130.60,132.06, 139.22,144.89,149.67,151.59,154.55,157.34;分析计算值:C15H9N3O5:C 57.88, H 2.91,N 13.50;实际值:C 57.65,H3.01,N 13.46。
化合物14:(E)-6-硝基-2-[2-(5-硝基呋喃-2-基)乙烯]喹啉酮
此化合物是自2-甲基-6-硝基喹啉及5-硝基噻吩-2-甲醛由化合物10所述的方法制得,并自乙醇中再结晶,产率60%。
熔点:249-250℃;1H-NMR(400MHz,DMSO-d6):6.03(m,2H),8.02(d,1H, J=8.8Hz),8.14-8.18(m,3H),8.46(dd,1H,J=9.2,2.8Hz),8.73(d,1H,J=8.8 Hz),9.03(d,1H,J=2.8Hz);13C-NMR(100MHz,DMSO-d6):122.43,123.41, 124.95,126.26,127.83,128.69,130.49,130.96,132.23,139.14,144.82,148.51, 149.69,150.11,157.55;分析计算值:C15H9N3O4S:C 55.04,H 2.77,N 12.84;实际值:C 54.89,H 2.83,N 12.79。
化合物15:(E)-8-硝基-2-[2-(5-硝基呋喃-2-基)乙烯]喹啉
此化合物是自2-甲基-8-硝基喹啉及(5-硝基呋喃-2-基)二乙酸亚甲酯由化合物9所述的方法制得,并自乙醇中再结晶,产率45%。
熔点:230-232℃;1H-NMR(400MHz,DMSO-d6):7.32(d,1H,J=4.0Hz, furanyl-H),7.58(d,1H,J=16.4Hz),7.72-7.78(m,2H),7.81(d,1H,J=4.0Hz, furanyl-H),8.11(d,1H,J=8.4Hz),8.26-8.30(m,2H),8.61(d,1H,J=8.4Hz);13C-NMR(100MHz,DMSO-d6):114.98,115.29,121.51,122.70,124.02,125.92, 128.06,131.89,132.02,137.53,138.34,147.63,151.54,154.54,155.79;分析计算值:C15H9N3O5:C 57.89,H 2.91,N 13.50;实际值:C 57.98,H 3.18,N 13.89。
化合物16:(E)-6-硝基-2-[2-(5-硝基噻吩-2-基)乙烯]喹啉
此化合物是自2-甲基-8-硝基喹啉及5-硝基噻吩-2-甲醛由化合物10所述的方法制得,并自乙醇中再结晶,产率63%。
熔点:227-228℃;1H-NMR(400MHz,DMSO-d6):7.59(d,1H,J=16.0Hz), 7.64(d,1H,J=4.0Hz,thiophenyl-H),7.76(t,1H,J=8.0Hz),8.02(d,1H,J=16.0 Hz),8.06(d,1H,J=8.8Hz),8.15(d,1H,J=4.0Hz,thiophenyl-H),8.25-30(m, 2H),8.61(d,1H,J=8.4Hz);13C-NMR(100MHz,DMSO-d6):122.31,123.98, 125.87,127.46,127.98,128.59,130.95,131.87,132.21,137.45,138.39,147.60, 148.46,150.04,156.08;分析计算值:C15H9N3O4S:C 55.04,H 2.77,N 12.84;实际值:C 54.93,H 2.78,N 12.87。
化合物19:(E)-2-[2-(5-硝基呋喃-2-基)乙烯]喹啉-4-基乙酸甲酯
将0.8克(5毫摩尔)的4-羟基-2-甲基喹啉、4.87克(20毫摩尔)的(5-硝基呋喃-2-基)二乙酸亚甲酯及150毫升乙酸酐的混合物于150℃加热28小时 (以薄层色层分析监控)。待混合物冷却后,于真空中浓缩以移除溶剂而获得一粗产物,接续以骤沸管柱色层分析(FC,硅胶,甲醇:二氯甲烷=1: 5)进行纯化,制得(E)-2-[2-(5-硝基呋喃-2-基)乙烯]喹啉-4-基乙酸甲酯(化合物19,0.73公克,产率45%)。
熔点:>320℃;1H-NMR(400MHz,DMSO-d6):2.53(s,3H,CH3),7.23(d,1H, J=4.0Hz,furanyl-H),7.57(d,1H,J=16.4Hz),7.66(m,1H),7.78-7.87(m,3H), 8.01(d,1H,J=8.4Hz),8.07(d,1H,J=8.8Hz);13C-NMR(100MHz,DMSO-d6): 20.78,113.12,114.50,115.33,120.43,121.60,127.45,129.05,130.91,132.51, 149.15,151.44,154.53,154.79,154.86,168.65;分析计算值:C17H12N2O5:C 62.97, H 3.73,N 8.64;实际值:C62.98,H 4.12,N 8.46。
化合物20:(E)-2-[2-(5-硝基呋喃-2-基)乙烯]喹啉-4-基乙酸甲酯
将0.8克(5毫摩尔)的4-羟基-2-甲基喹啉、3.14克(20毫摩尔)的5-硝基噻吩-2-甲醛及150毫升乙酸酐的混合物于150℃加热26小时(以薄层色层分析监控)。待混合物冷却后,于真空中浓缩以移除溶剂而获得一粗产物,接续以骤沸管柱色层分析(FC,硅胶,甲醇:二氯甲烷=1:20)进行纯化,制得(E)-2-[2-(5-硝基呋喃-2-基)乙烯]喹啉-4-基乙酸甲酯(化合物20,0.82公克,产率48%)。
将0.8克(5毫摩尔)的4-羟基-2-甲基喹啉、3.14克(20毫摩尔)的5-硝基噻吩-2-甲醛及150毫升乙酸酐的混合物于150℃加热26小时(以薄层色层分析监控)。待混合物冷却后,于真空中浓缩以移除溶剂而获得一粗产物,接续以骤沸管柱色层分析(FC,硅胶,甲醇:二氯甲烷=1:20)进行纯化,制得(E)-2-[2-(5-硝基呋喃-2-基)乙烯]喹啉-4-基乙酸甲酯(化合物20,0.82公克,产率48%)。
化合物21:(E)-2-[2-(5-硝基呋喃-2-基)乙烯]-4-羟基喹啉
将0.8克(5毫摩尔)的4-羟基-2-甲基喹啉、4.87克(20毫摩尔)的(5-硝基呋喃-2-基)二乙酸亚甲酯及150毫升乙酸酐的混合物于150℃加热30小时 (以薄层色层分析监控)。待混合物冷却后,于真空中浓缩以移除溶剂而获得一粗产物,接续将该粗产物溶于吡啶/水(体积比4:1)溶液中于100℃加热1小时(以薄层色层分析监控)。待混合物冷却后,于真空中浓缩以移除溶剂而获得一粗产物,以骤沸管柱色层分析(FC,硅胶,甲醇:二氯甲烷=1:20)进行纯化,制得(E)-2-[2-(5-硝基呋喃-2-基)乙烯]-4-羟基喹啉(化合物21,0.92公克,产率65%)。
熔点:305-307℃;1H-NMR(400MHz,DMSO-d6):6.47(d,1H,J=1.6Hz), 7.15(d,1H,J=3.6Hz,furanyl-H),7.25(d,1H,J=16.4Hz),7.31-7.35(m,1H), 7.61-7.70(m,3H),7.81(d,1H,J=3.6Hz,furanyl-H),8.05(dd,1H,J=8.0,1.2 Hz),11.69(br s,1H,OH);13C-NMR(100MHz,DMSO-d6):107.93,114.75,115.22, 118.34,120.79,123.37,124.79,125.31,126.49,132.22,140.17,145.25,151.64, 153.88,177.07;分析计算值:C15H10N2O4:C63.83,H 3.57,N 9.92;实际值:C 63.47,H 3.69,N 9.73。
化合物22:(E)-2-[2-(5-硝基噻吩-2-基)乙烯]-4-羟基喹啉
将0.8克(5毫摩尔)的4-羟基-2-甲基喹啉、3.14克(20毫摩尔)的5-硝基噻吩-2-甲醛及150毫升乙酸酐的混合物于150℃加热30小时(以薄层色层分析监控)。待混合物冷却后,于真空中浓缩以移除溶剂而获得一粗产物,接续将该粗产物溶于吡啶/水(体积比4:1)溶液中于100℃加热1小时(以薄层色层分析监控)。待混合物冷却后,于真空中浓缩以移除溶剂而获得一粗产物,以骤沸管柱色层分析(FC,硅胶,甲醇:二氯甲烷=1:20)进行纯化,制得(E)-2-[2-(5-硝基噻吩-2-基)乙烯]-4-羟基喹啉(化合物22,0.89公克,产率60%)。
熔点:240-241℃;1H-NMR(400MHz,DMSO-d6+TFA):6.42(d,1H,J=1.6 Hz),7.27(d,1H,J=16.4Hz),7.31-7.35(m,1H),7.50(d,1H,J=4.4Hz, thiophenyl-H),7.63-7.71(m,2H),7.87(d,1H,J=16.4Hz),8.01(d,1H,J=8.4Hz), 8.17(d,1H,J=4.4Hz,thiophenyl-H),11.63(br s,1H,OH);13C-NMR(100MHz, DMSO-d6+TFA):104.97,119.54,121.90,124.12,124.81,126.51,129.79,130.45, 131.06,134.21,139.89,146.96,149.26,151.23,172.26;分析计算值:C15H10N2O3S: C 60.40,H 3.38,N 9.39;实际值;C 60.27,H 3.49,N9.31。
化合物23:(E)-6-甲氧基-2-[2-(5-硝基呋喃-2-基)乙烯]-4-羟基喹啉
此化合物是自6-甲氧基-2-甲基喹啉及(5-硝基呋喃-2-基)二乙酸亚甲酯由化合物21所述的方法制得,并自乙醇中再结晶,产率40%。
熔点:285-286℃;1H NMR(400MHz,DMSO-d6+TFA):3.96(s,3H,6-OMe), 7.29(d,1H,J=3.6Hz,furanyl-H),7.42(s,1H),7.48(d,1H,J=16.4Hz),7.58(d, 1H,J=2.8Hz),7.69(dd,1H,J=9.2,2.8Hz),7.83(d,1H,J=3.6Hz,furanyl-H), 7.87(d,1H,J=16.4Hz),7.98(d,1H,J=9.2Hz);13C NMR(100MHz,DMSO-d6+ TFA):56.03,101.92,102.66,115.00,116.93,121.79,121.99,123.41,124.82, 126.48,134.80,148.09,152.13,152.92,158.37,168.47;分析计算值: C16H12N2O5·0.5H2O:C 59.81,H 4.08,N 8.72;实际值:C59.99,H 3.95,N 8.55。
化合物24:(E)-6-甲氧基-2-[2-(5-硝基噻吩-2-基)乙烯]-4-羟基喹啉
此化合物是自6-甲氧基-2-甲基4-羟基喹啉及5-硝基噻吩-2-甲醛由化合物22所述的方法制得,并自乙醇中再结晶,产率53%。
熔点:>320℃;1H NMR(400MHz,DMSO-d6+TFA):4.00(s,3H,6-OMe), 7.33(s,1H),7.55(d,1H,J=16.4Hz),7.63(d,1H,J=2.8Hz),7.68(d,1H,J=4.4 Hz,thiophenyl-H),7.72(d,1H,J=16.4Hz),8.25(d,1H,J=4.4Hz,thiophenyl-H);13C NMR(100MHz,DMSO-d6+TFA):55.94,102.04,103.61,121.64,122.20, 124.22,126.12,129.73,130.46,130.93,134.90,146.77,147.94,151.13,158.04, 168.98;分析计算值:C16H12N2O4S·0.8H2O:C56.07,H 4.00,N 8.17;实际值: C 55.96,H 4.25,N 8.30。
化合物25:(E)-8-甲氧基-2-[2-(5-硝基呋喃-2-基)乙烯]-4-羟基喹啉
此化合物是自8-甲氧基-2-甲基4-羟基喹啉及(5-硝基呋喃-2-基)二乙酸亚甲酯由化合物21所述的方法制得,并自乙醇中再结晶,产率45%。
熔点:295-296℃;1H-NMR(400MHz,DMSO-d6):4.02(s,3H,OMe),6.61(d, 1H,J=1.6Hz),7.03(d,1H,J=3.6Hz,furanyl-H),7.25-7.29(m,2H),7.59-7.71 (m,3H),7.78(d,1H,J=3.6Hz,furanyl-H),11.27(br s,1H,OH);13C-NMR(100 MHz,DMSO-d6):56.29,105.17,111.50,114.92,115.22,116.04,120.99,123.33, 126.33,130.85,145.54,148.73,149.63,151.63,154.19,176.51;分析计算值: C16H12N2O5·1.3H2O:C 57.24,H4.38,N 8.34;实际值:C 57.15,H 4.16,N: 8.39。
化合物26:(E)-8-甲氧基-2-[2-(5-硝基噻吩-2-基)乙烯]-4-羟基喹啉
此化合物是自8-甲氧基-2-甲基4-羟基喹啉及5-硝基噻吩-2-甲醛由化合物22所述的方法制得,并自乙醇中再结晶,产率60%。
熔点:>320℃;1H-NMR(400MHz,DMSO-d6):4.03(s,3H,OMe),6.59(s, 1H),7.26-7.29(m,2H),7.41(d,1-H,J=4.0Hz,thiophenyl-H),7.58(d,1H,J= 16.4Hz),7.61-7.65(m,1H),7.86(d,1H,J=16.4Hz),8.13(d,1H,J=4.0Hz, thiophenyl-H),11.01(s,1H,OH);13C-NMR(100MHz,DMSO-d6):56.30,105.39, 111.48,116.00,123.38,126.30,126.59,126.95,128.36,130.18,131.05,135.78, 145.72,148.56,149.91,186.02;分析计算值:C16H12N2O4S·0.3H2O:C 57.57,H 3.81,N 8.39;实际值:C 57.19,H 3.74,N 8.42。
化合物27:(E)-5,8-二甲氧基-2-[2-(5-硝基呋喃-2-基)乙烯]-4-羟基喹啉
此化合物是自5,8-二甲氧基-2-甲基4-羟基喹啉及(5-硝基呋喃-2-基)二乙酸亚甲酯由化合物21所述的方法制得,并自乙醇中再结晶,产率42%。
熔点:206-207℃;1H-NMR(400MHz,DMSO-d6):3.74(s,3H,OMe),3.94(s, 3H,OMe),6.46(s,1H),6.67(d,1H,J=8.4Hz),7.00(d,1H,J=3.6Hz,furanyl-H), 7.15(d,1H,J=8.4Hz),7.54(d,1H,J=16.4Hz),7.63(d,1H,J=16.4Hz),7.77(d, 1H,J=3.6Hz,furanyl-H),10.81(s,1H,OH);13C-NMR(100MHz,DMSO-d6): 56.13,56.41,104.15,107.78,111.96,114.70,115.23,116.78,1120.53,126.15, 132.95,142.06,143.71,151.56,152.58,154.28,176.68;分析计算值:C17H14N2O6·1.7H2O:C 54.74,H 4.71,N 7.51;实际值:C54.43,H 4.85,N 7.47。
化合物28:(E)-5,8-二甲氧基-2-[2-(5-硝基噻吩-2-基)乙烯]-4-羟基喹啉
此化合物是自5,8-二甲氧基-2-甲基4-羟基喹啉及5-硝基噻吩-2-甲醛由化合物22所述的方法制得,并自乙醇中再结晶,产率51%。
熔点:>320℃;1H-NMR(400MHz,DMSO-d6):3.78(s,3H,OMe),3.96(s,3H, OMe),6.62(s,1H),6.75(d,1H,J=8.4Hz),7.19(d,1H,J=8.8Hz),7.41(br s,1H, thiophenyl-H),7.55(d,1H,J=16.0Hz),7.86(d,1H,J=16.0Hz),8.13(d,1H,J= 3.6Hz,thiophenyl-H);13C-NMR(100MHz,DMSO-d6):56.20,56.40,104.43, 107.24,111.76,115.54,123.82,126.95,128.30,129.88,131.02,143.02,145.70, 148.59,149.87,151.94,167.38;分析计算值:C17H14N2O5S·1.0H2O:C 54.25,H 4.29,N 7.44;实际值:C 54.17,H 4.59,N 7.16。
化合物29:(E)-6,8-二甲氧基-2-[2-(5-硝基噻吩-2-基)乙烯]-4-羟基喹啉
此化合物是自6,8-二甲氧基-2-甲基4-羟基喹啉及(5-硝基呋喃-2-基)二乙酸亚甲酯由化合物21所述的方法制得,并自乙醇中再结晶,产率42%。
熔点:235-236℃;1H-NMR(400MHz,DMSO-d6):3.84(s,3H,OMe),3.99(s, 3H,OMe),6.58(s,1H),6.88(d,1H,J=2.4Hz),7.01(d,1H,J=3.6Hz,furanyl-H), 7.05(d,1H,J=2.4Hz),7.55(d,1H,J=16.4Hz),7.64(d,1H,J=16.4Hz),7.77(d, 1H,J=3.6Hz,furanyl-H),11.29(s,1H,OH);13C-NMR(100MHz,DMSO-d6): 55.40,56.41,95.26,102.78,104.06,114.66,115.25,120.43,126.01,126.41,144.49, 149.97,151.54,154.32,156.18,175.69;分析计算值:C17H14N2O6·1.5H2O:C 55.27,H 4.64,N 7.59;实际值:C 55.33,H4.60,N 7.66。
化合物30:(E)-6,8-二甲氧基-2-[2-(5-硝基噻吩-2-基)乙烯]-4-羟基喹啉
此化合物是自6,8-二甲氧基-2-甲基4-羟基喹啉及5-硝基噻吩-2-甲醛由化合物22所述的方法制得,并自乙醇中再结晶,产率55%。
熔点:284-285℃;1H-NMR(400MHz,DMSO-d6):3.84(s,3H,OMe),4.01(s, 3H,OMe),6.55(s,1H),6.91(d,1H,J=2.0Hz),7.06(d,1H,J=2.0Hz),7.39(d, 1H,J=4.0Hz,thiophenyl-H),7.54(d,1H,J=16.4Hz),7.84(d,1H,J=16.4Hz), 8.13(d,1H,J=4.0Hz,thiophenyl-H),11.12(s,1H,OH);13C-NMR(100MHz, DMSO-d6):55.42,56.51,95.37,102.87,104.33,125.87,126.51,126.58,127.09, 128.22,131.08,144.53,148.69,149.79,149.94,156.14,175.67;分析计算值: C17H14N2O5S·2.0H2O:C 51.76,H 4.61,N7.10;实际值:C 51.86,H 4.60,N 6.98。
化合物31:(E)-5,6,7-三甲氧基-2-[2-(5-硝基呋喃-2-基)乙烯]-4-羟基喹啉
此化合物是自5,6,7-三甲氧基-2-甲基4-羟基喹啉及(5-硝基呋喃-2-基)二乙酸亚甲酯由化合物21所述的方法制得,并自乙醇中再结晶,产率40%。
熔点:237-238℃;1H-NMR(400MHz,DMSO-d6):3.74(s,3H,OMe),3.76(s, 3H,OMe),3.90(s,3H,OMe),6.23(s,1H),6.88(s,1H),7.12-7.17(m,2H),7.55(d, 1H,J=16.0Hz),7.80(d,1H,J=3.6Hz,furanyl-H),11.30(s,1H,OH);13C-NMR (100MHz,DMSO-d6):55.79,60.98,61.76,95.37,109.78,114.23,114.55,115.21, 119.75,126.47,138.59,139.26,142.91,151.50,152.06,154.03,156.36,176.12;分析计算值:C18H16N2O7·1.5H2O:C54.12,H 4.80,N 7.01;实际值:C 54.44,H 4.92,N 7.26。
化合物32:(E)-5,6,7-三甲氧基-2-[2-(5-硝基噻吩-2-基)乙烯]-4-羟基喹啉
此化合物是自5,6,7-三甲氧基-2-甲基4-羟基喹啉及5-硝基噻吩-2-甲醛由化合物22所述的方法制得,并自乙醇中再结晶,产率45%。
熔点:>320℃;1H-NMR(400MHz,DMSO-d6+TFA):3.88(s,3H,OMe),3.93 (s,3H,OMe),4.02(s,3H,OMe),7.20(s,1H),7.32(s,1H),7.43(d,1H,J=16.4 Hz),7.60(d,1H,J=4.4Hz,thiophenyl-H),8.08(d,1H,J=16.4Hz),8.17(d,1H,J =4.4Hz,thiophenyl-H),11.22(s,1H,OH);13C-NMR(100MHz,DMSO-d6+ TFA):56.60,61.22,62.33,96.34,103.97,110.34,123.57,129.88,130.80,130.89, 138.92,142.06,146.57,148.32,149.85,151.31,159.17,169.46;分析计算值: C18H16N2O6S:C 55.66,H 4.15,N 4.21;实际值:C55.45,H 4.21N 4.15。
B.本发明式(IB)化合物是以如下流程所示的方法制备,下文将详细说明化合物的制备方法:
化合物3X=O;化合物8X=S
化合物3:(E)-2-[2-(5-硝基呋喃-2-基)乙烯]苯并[d]恶唑
将0.4克(3毫摩尔)的2-甲基苯并[d]恶唑、2.92克(12毫摩尔)的5-硝基 -2-糠醛二乙酯及100毫升乙酸酐的混合物于150℃加热18小时(以薄层色层分析监控)。待混合物冷却后,于真空中浓缩以移除溶剂而获得一粗产物,接续以骤沸管柱色层分析(FC,硅胶,甲醇:二氯甲烷=1:15)进行纯化,制得(E)-2-[2-(5-硝基呋喃-2-基)乙烯]苯并[d]恶唑(化合物3,0.33公克,产率 43%)。
熔点:165-166℃;1H-NMR(400MHz,CDCl3):6.76(d,1H,J=3.6Hz, furanyl-H),7.26(d,1H,J=3.6Hz),7.33-7.40(m,3H),7.53(d,1H,J=16.0Hz), 7.52-7.55(m,1H),7.75(d,1H,J=8.4Hz);13C-NMR(100MHz,CDCl3):110.22, 114.21,117.62,120.13,123.76,124.33,128.64,133.58,142.76,149.82,152.36, 154.39,162.48;分析计算值:C13H8N2O4·0.1H2O:C 60.52,H 3.20,N 10.86;实际值:C 60.44,H 3.29,N 10.92。
化合物8:(E)-2-[2-(5-硝基噻吩-2-基)乙烯]-苯并[d]恶唑
此化合物是自2-甲基苯并[d]恶唑(3毫摩尔)及5-硝基噻吩-2-甲醛(12 毫摩尔)由化合物3所述的方法制得,并以骤沸管柱色层分析(FC,硅胶,甲醇:二氯甲烷=1:20)进行纯化,制得(E)-2-[2-(5-硝基噻吩-2-基)乙烯]- 苯并[d]恶唑。
整理上述化合物制备实施例如下表1:
3.活性测试
3.1本发明的化合物可有效抑制大肠癌及乳癌细胞生长
此处利用MTT(3-[4,5-二甲基噻唑-2-基]-2,5-二苯基四唑溴盐)分析法分析上述制备的化合物抑制癌症细胞生长的活性。其作用原理为MTT经由线粒体中琥珀酸脱氢酶(SDH)和细胞色素C的作用还原为不溶于水的甲臜产物 (3-[4,5-二甲基噻唑-2-基]-2,5-二苯基甲臜)沉积于细胞中,接续以二甲亚砜溶解沉淀产物并测量吸光值,由于仅有活细胞具有琥珀酸脱氢酶的酵素活性,故可经此评估细胞的存活率。
首先于37℃含有5%二氧化碳的培养箱中,以DMEM培养基培养大肠癌细胞DLD-1(BCRC:60132)、SW620(BCRC:60343)及乳癌细胞MCF-7(BCRC: 60436)约2-3天,待细胞占满培养盘面空间时即进行细胞毒性测试。
将各细胞以105的细胞密度种植于24孔培养盘中培养12-16小时,接着于培养皿中分别加入本发明的化合物(1μM)、二甲亚砜(DMSO,1μM)及正控制组雷帕霉素(Rapamycin,1μM),24小时后于显微镜下观察细胞型态,并以MTT计算细胞存活率。
雷帕霉素已证实可抑制多种癌细胞的生长与增生,故于此作为癌细胞毒性的正控制组。如图1所示,经本发明的化合物处理细胞后,发现可显著降低癌细胞的存活率,其中化合物14可显著降低DLD-1及SW620的细胞存活率,而化合物8的癌细胞毒性效果最佳,对于三种癌细胞均可显著降低存活率达20%至40%。
经由上述实例证明,本发明的化合物8及化合物14对于大肠癌及乳癌细胞具有显著的细胞毒性,其效果类似或更优于正控制组-雷帕霉素,因此可用于抑制癌症细胞生长及治疗癌症。
3.2化合物浓度对于癌症细胞存活率的影响
以MTT分析法测试不同浓度的化合物对于癌症细胞存活率的影响。将大肠癌细胞SW620以105的细胞密度种植于24孔培养盘中培养12-16小时。接着于培养皿中分别加入本发明的化合物8及化合物14、伯舒替尼(Bosutinib)、达沙替尼(Dasatinib)或塞卡替尼(Saracatinib),于处理后24小时于显微镜下观察细胞型态,以MTT计算细胞存活率。
MTT的分析结果如图2所示,显示本发明的化合物可有效抑制大肠癌细胞SW620的生长,化合物8及化合物14具降低癌症细胞存活率的功效。
3.3本发明的化合物可显著降低大肠癌细胞的存活率
以MTT分析法测试化合物14(对于癌症细胞存活率的影响。将大肠癌细胞DLD-1以105的细胞密度种植于24孔培养盘中培养12-16小时。接着于培养皿中分别加入本发明的化合物(1μM)、二甲亚砜(DMSO,1μM)及正控制组雷帕霉素(Rapamycin,1μM),于24小时后于显微镜下观察细胞型态,并以MTT计算细胞存活率。
如图3所示,本发明的化合物14可有效抑制DLD-1细胞的生长,于药物处理后6小时,雷帕霉素尚未影响DLD-1细胞的存活率,而化合物14已降低细胞存活率至80%,且随着时间增加效果更为显著,于药物处理后24小时后,雷帕霉素可降低DLD-1存活率至80%,而化合物14可降低DLD-1存活率至60%左右,效果优于雷帕霉素,证明本发明的化合物可显著降低大肠癌细胞的存活率。
以上结果证实本发明的化合物可显著降低癌细胞的存活率、抑制癌细胞生长,其效果近似于甚或优于抗癌药物雷帕霉素,且分子量较小有助于生物体的吸收,故可用于制备抗癌药物并有效治疗癌症。
4.抑癌机制分析
4.1西方墨点分析(western blot)
于实施例3.3中已证实化合物14可有效抑制DLD-1细胞的生长,接续以西方墨点分析探讨其抑癌机制。
首先以雷帕霉素(IC50=5.3μM)或化合物14(IC50=5.6μM)处理DLD-1 细胞12小时,的后吸除培养液以PBS清洗,将培养盘置于冰上并添加细胞裂解溶液(lysis buffer)溶解细胞,以刮勺刮取细胞并收集于微量离心管,接着离心以收取上清液并进行蛋白质定量。将萃取获得的蛋白质以6-8%的 SDS-PAGE进行分离,接着转渍至PVDF膜进行西方墨点分析,以抗mTOR抗体(Sigma,No.T2949)侦测蛋白质表现(二级抗体:链结辣根过氧化酶的山羊抗兔子IgG;化学冷光法呈色)。
西方墨点分析的结果如图4A和图4B所示,以雷帕霉素处理DLD-1细胞 12小时后可发现其目标mTOR蛋白质的表现量显著降低,约为控制组的60%,而以化合物14处理DLD-1细胞12小时后,mTOR蛋白质的表现量亦显著降低,效果于雷帕霉素相当。已知mTOR于细胞的讯息传递扮演中心枢纽角色,细胞可透过控制mTOR路径来统整能量、养分、压力、刺激及生长讯号,而雷帕霉素可藉由抑制mTOR的表现来达到阻止细胞生长、增生、分化、分裂及合成细胞蛋白质,进一步抑制肿瘤的生长或促使癌症细胞自体凋亡,由此证实本发明化合物的抑癌机制的一涉及mTOR讯息传递路径,因此可用于治疗涉及mTOR讯息传递路径的疾病,例如癌症。
4.2DNA微数组分析(DNA microarray)
于实施例3.1中已证实化合物8可有效抑制乳癌细胞及大肠癌细胞的生长,接续以DNA微数组及生物信息工具分析其抑癌机制,首先将大肠癌细胞SW620以化合物8处理6小时,随后抽取总RNA,进行反转錄成并标记荧光染剂(Cyanine 3,Cy3),从实验组和对照组取等量的cRNA,并与微数组生物芯片(Agilent Human G3Whole Genome Oligo 8×60K生物芯片)进行杂交反应。随后将雷射扫描影像分析与资料进行标准化,数据以倍数改变值(Foldchange)值为2为标准,筛选出表现量显著上调和下调的基因,再利用生物信息网站DAVID(Functional Annotation Bioinformatics Microarray Analysis)与 KEGG(KyotoEncyclopedia of Genes and Genomes)分析显著上调和下调的基因途径,结果如表2所示。
表2
类别 | 计数 | % | p值 |
细胞激素-细胞激素受体交互作用 | 16 | 3.5 | 0.00022 |
p53讯息途径 | 7 | 1.5 | 0.0024 |
细胞色素P450的异生物质代谢 | 6 | 1.3 | 0.007 |
类固醇荷尔蒙生合成 | 5 | 1.1 | 0.014 |
JAK-STAT讯息途径 | 8 | 1.7 | 0.037 |
MAPK讯息途径 | 11 | 2.4 | 0.043 |
膀胱癌 | 4 | 0.9 | 0.052 |
经化合物8处理后的样本中,具有显著差异化表现的基因涉及有丝分裂原活化蛋白激酶(MAPK)途径及杰纳斯激酶-转录讯息转换子及活化子 (JAK-STAT)途径,说明本发明化合物的抑制作用涉及上述途径。
由上述癌细胞存活率分析、西方墨点分析及DNA微数组分析,显示本发明的化合物可显著降低癌细胞的存活率,且涉及mTOR讯息传递路径、有丝分裂原活化蛋白激酶(MAPK)途径及杰纳斯激酶-转录讯息转换子及活化子(JAK-STAT)途径,因此可用于制备抗癌药物并有效治疗癌症。
咸信本发明所属技艺中具一般知识者基于本文的叙述,无须进一步的例示即可将本发明应用至其最广泛的范围。因此,应了解此处所提供的叙述及申请专利范围是供例示目的而非以任何方式限制本发明的范畴。
Claims (7)
2.一种化合物,其是选自以下群组:
(E)-2-[2-(5-硝基噻吩-2-基)乙烯]苯并[d]噻唑;以及
(E)-2-[2-(5-硝基噻吩-2-基)乙烯]-苯并[d]恶唑。
3.一种医药组合物,其包含如权利要求1至2任一项所述的化合物及医药上可接受的载剂。
4.一种如权利要求1至2任一项所述的化合物用于治疗癌症制剂的用途。
5.一种治疗癌症的医药组合物,其包含治疗有效量的如权利要求1至2任一项所述的化合物或其医药上可接受的盐。
6.如权利要求5所述的医药组合物,其中该化合物是:
(E)-2-[2-(5-硝基噻吩-2-基)乙烯]-苯并[d]恶唑,或
其医药上可接受的盐。
7.如权利要求5或6所述的医药组合物,其用于治疗大肠癌与乳癌。
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NL108227C (zh) * | 1955-11-28 | |||
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GB1039111A (en) * | 1962-05-04 | 1966-08-17 | Dainippon Pharmaceutical Co | 2-[2-(5-nitrofuryl)-vinyl]-azoles and process for their production |
JPS4840736B1 (zh) * | 1970-12-22 | 1973-12-03 | ||
WO2009140215A2 (en) * | 2008-05-11 | 2009-11-19 | Geraghty, Erin | Method for treating drug-resistant bacterial and other infections with clioquinol, phanquinone, and related compounds |
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Structure-activity relationships of novel heteroaryl-acrylonitriles as cytotoxic and antibacterial agents;Saczewski, Franciszek,et al.;《European Journal of Medicinal Chemistry》;20071205;第43卷(第9期);第1847-1857页 * |
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TW201639833A (zh) | 2016-11-16 |
CN106117188A (zh) | 2016-11-16 |
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