【作者】 刘娜；

【导师】 田红旗；

【作者基本信息】 天津科技大学 ， 药物化学（医）， 2017， 硕士

【摘要】 肿瘤成为人类健康的十大杀手之一,随着生活环境的恶化,使其所占比例逐年攀升。随着分子生物学和肿瘤病理学研究的发展,分子靶向治疗逐渐成为人们研究的焦点。其中,癌症驱动基因ALK和c-Met在包括肺癌、胃癌、乳腺癌、卵巢癌、结肠癌、肝癌、直肠癌、肾癌、神经胶质瘤、黑素瘤、前列腺癌等多种肿瘤的发生和发展中扮演了重要作用。本文以OSI Pharmaceuticals,Inc.研发的专利化合物3-(1-(2,6-二氯-3-氟苯基)乙基)-5-(1-(哌啶-4-基)-1H-吡唑-4-基)-1H-吡咯[2,3-b]吡啶(OSI-1)为先导化合物,采用生物电子等排体原理,以7-氮杂吲哚和7-氮杂吲唑结构构建母核,改变母核与2,6-二氯-3-氟苯基之间的连接臂,并以硫原子取代次甲基中的碳原子,其中7-氮杂吲哚母核与2,6-二氯-3-氟苯基之间的硫原子进一步氧化成亚砜结构来模拟甲基,据此来设计合成了两个新型具有生理活性的化合物:3-((2,6-二氯-3-氟苯基)亚硫酰基)-5-(1-(哌啶-4-基)-1H-吡唑-4-基)-1H-吡咯并[2,3-b]吡啶(A)和化合物3-((2,6-二氯-3-氟苯基)硫)-5-(1-哌啶-4-基)-1H-吡唑并-4-基)-1H-吡唑并[3,4-b]哌啶(B),以廉价易得的2,4-二氯氟苯为起始原料,经氧化反应、Ullmann芳醚反应、Suzuki偶联、脱保护基等一系列反应得到目标分子,各步收率良好。所合成的两个新化合物及重要中间体均通过核磁共振氢谱、核磁共振碳谱、质谱进行了结构表征以及高效液相色谱进行纯度检测。对这两个新化合物进行了初步的体外抗肿瘤活性测试。生物活性结果表明,化合物(A)、(B)对c-Met/ALKWT/ALKL1196M/ALKC1156Y激酶均显示出一定的抑制活性,其中化合物(B)对c-Met激酶抑制的IC50达到22.8 nM;对Ba/F3 EML4-ALK,Ba/F3 EML4-ALK L1 196M,Ba/F3 EML4-ALK C1 156Y细胞生长均有一定的抑制作用,其中化合物(B)对Ba/F3 EML4-ALK L1 196M细胞生长抑制的IC50达到376.8 nM。更多还原

【Abstract】 Tumor has become one of the ten largest killers toward human health,as the deterioration of living environment,the proportion of tumor morbidity and death rate rising year by year.With the development of molecular biology and tumor pathology,molecular targeted therapy gradually becomes the focus of people’s study.Among them,the driving cancer genes of ALK and c-Met play important roles in the occurrence and development of cancers happens on following different organs,such as lung,stomach,breast,ovarian,colon,liver,rectum,kidney,prostate,and glioma cancer,melanoma cancer and other tumors.Based on the bioisostere principle,with 3-(1-(2,6-dichloro-3-fluorophenyl)ethyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine(OSI-1 in Fig.1-17,invented by OSI Pharma,Inc.)as lead compound,following the replacement of the 7-azaindole in OSI-1 with the closely related 7-azaindazole and the replacement of the methylene between the 7-azaindazole and the 2,6-dichloro-3-fluorophenyl with S or sulfoxide,novel 7-azaindole and 7-azaindazole derivatives,3-((2,6-dichloro-3-fluorophenyl)sulfinyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine and 3-((2,6-dichloro-3-fluorophenyl)thio)-5-(1-(piperidin-4-yl)-1 H-pyrazol-4-yl)-1 H-pyrazolo[3,4-b]pyridine,with a monatomic as a linker,were designed,synthesized,characterized and biologically evaluated.The target compound was synthesized from cheap and commercially available 2,4-dichloro-fluorobenzene.which through the substitution reaction,Ullmann aromatic ether reaction,Suzuki coupling and off-protecting group and a series of reactions,the compound was synthesized,and every step is in good yield.The target compound and new intermediates were characterized by nuclear magnetic resonance spectrum and mass spectrum,and the purity of target compound was detected by High Performance Liquid Chromatography.The biologically study showed that compound(A)and(B)act inhibition on c-Met/ALKWT/ALKL1196M/ALKC1156Y.Particularly compound(B)has inhibition on c-Met whose IC50 reaches 22.8 nM.It also has inhibition on Ba/F3 EML4-ALK,Ba/F3 EML4-ALKL1196M and Ba/F3 EML4-ALKC1156Y cells,and compound(B)has inhibition on Ba/F3 EML4-ALK L1196M cell lines whose IC50 reaches 376.8 nM.更多还原