一种新型芳香烷胺类抗肿瘤化合物的设计、合成及活性研究
发布时间：2018-10-13 10:26
【摘要】：癌症是严重影响人类健康的因素,是目前国内外最常见也是最难治愈的病症之一。近些年来全球范围内癌症患病率呈持续增长态势。对比IARC发布的2012年全球癌症数据库中的中国癌症数据,形势已更为严峻。癌症已成为当前影响人类健康的重要因素。目前,癌症的治疗以化疗为主,但是市面上主流的抗癌药普遍毒副作用较大且价格昂贵,开发出新型抗肿瘤药已是当下亟待解决的问题。钠离子通道(Voltage-Gated Sodium Channels,VGSCs)作为一种通道蛋白受体,通常在可兴奋的细胞中表达(如神经,肌肉细胞等)。近年来许多研究表明,VGSCs在转移的肿瘤细胞中均可表达(如宫颈癌、前列腺癌、乳腺癌、肺癌等),对侵袭和转移起到重要的生理作用,是兴奋组织动作电位的关键离子通道。VGSCs现已成为近几年来新型抗肿瘤药物的研究热点。从第一个VGSCs阻断剂河豚毒素(TTX)被分离出后,数以百计的VGSCs阻断剂化合物已被陆续报道。本研究基于最新报道的增效基团的基础上,以钠离子通道类抗惊厥药苯妥英钠为基础结构,打开乙内酰脲环,保留二苯基结构,对另一边疏水端和中间含NH的富电区进行改造。结合最新报道的增效基团,系统性地设计合成了11个化合物。以4,4,-二(4-氟苯)氯丁烷为原料,经Gabriel反应,肼解,偶联,还原得到(T1 T2)。T3~T11的合成方法类似,用DMSO作溶剂,经一系列偶联反应得到。该方法合成简便,反应条件温和,合成步骤少。本研究所有的化合物经过1H-NMR、13C-NMR、MS确证。11种化合物均用人类前列腺癌细胞(DU145、PC3)和乳腺癌细胞(MCF-7、MDB-MB-231、MDB-MB-453)和926正常上皮细胞利用MTT法测试体外活性。筛选出T5和T7具有良好抗肿瘤活性和低毒性的化合物,具有一定的创新性,为新型抗肿瘤药物设计奠定了一定基础。
[Abstract]:Cancer is one of the most common and difficult diseases at home and abroad. In recent years, the incidence of cancer in the world continues to increase. Compared with China's cancer data from the 2012 global cancer database released by IARC, the situation has become even more severe. Cancer has become an important factor affecting human health. At present, chemotherapy is the main treatment of cancer, but the main anti-cancer drugs in the market are common toxic side effects and expensive, so it is an urgent problem to develop new anti-tumor drugs. Sodium channel (Voltage-Gated Sodium Channels,VGSCs), as a channel protein receptor, is usually expressed in excitable cells (such as nerve, muscle cells, etc.). In recent years, many studies have shown that VGSCs can be expressed in metastatic tumor cells (such as cervical cancer, prostate cancer, breast cancer, lung cancer, etc.), which plays an important physiological role in invasion and metastasis. VGSCs is a key ion channel for excitatory tissue action potential. VGSCs has become a hot research topic of new antitumor drugs in recent years. Hundreds of VGSCs blockers have been reported since the first VGSCs blocker, tetrodotoxin (TTX), was isolated. Based on the newly reported synergistic groups, the sodium channel anticonvulsant sodium phenytoin was used as the base structure to open the glycolylurea ring and retain the diphenylurea structure to reconstruct the electrically rich region containing NH at the hydrophobic end and in the middle of the other side. Eleven compounds were systematically designed and synthesized with the newly reported synergistic groups. (T1T2) was synthesized by Gabriel reaction, hydrazine hydrolysis, coupling and reduction from 4H 4N-bis (4-fluorobenzene) chlorobutane. The synthesis method of T3~T11 was similar. DMSO was used as solvent and obtained by a series of coupling reactions. The method is simple and convenient, the reaction conditions are mild and the steps of synthesis are few. Some compounds were confirmed by 1H-NMR-13C-NMRMS. The activity of 11 compounds was determined by MTT assay in human prostate cancer cells (DU145,PC3), breast cancer cells (MCF-7,MDB-MB-231,MDB-MB-453) and 926 normal epithelial cells. The compounds of T5 and T7 with good antitumor activity and low toxicity were screened, which were innovative and laid a foundation for the design of new antitumor drugs.
【学位授予单位】：重庆医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R914;R96
[Abstract]:Cancer is one of the most common and difficult diseases at home and abroad. In recent years, the incidence of cancer in the world continues to increase. Compared with China's cancer data from the 2012 global cancer database released by IARC, the situation has become even more severe. Cancer has become an important factor affecting human health. At present, chemotherapy is the main treatment of cancer, but the main anti-cancer drugs in the market are common toxic side effects and expensive, so it is an urgent problem to develop new anti-tumor drugs. Sodium channel (Voltage-Gated Sodium Channels,VGSCs), as a channel protein receptor, is usually expressed in excitable cells (such as nerve, muscle cells, etc.). In recent years, many studies have shown that VGSCs can be expressed in metastatic tumor cells (such as cervical cancer, prostate cancer, breast cancer, lung cancer, etc.), which plays an important physiological role in invasion and metastasis. VGSCs is a key ion channel for excitatory tissue action potential. VGSCs has become a hot research topic of new antitumor drugs in recent years. Hundreds of VGSCs blockers have been reported since the first VGSCs blocker, tetrodotoxin (TTX), was isolated. Based on the newly reported synergistic groups, the sodium channel anticonvulsant sodium phenytoin was used as the base structure to open the glycolylurea ring and retain the diphenylurea structure to reconstruct the electrically rich region containing NH at the hydrophobic end and in the middle of the other side. Eleven compounds were systematically designed and synthesized with the newly reported synergistic groups. (T1T2) was synthesized by Gabriel reaction, hydrazine hydrolysis, coupling and reduction from 4H 4N-bis (4-fluorobenzene) chlorobutane. The synthesis method of T3~T11 was similar. DMSO was used as solvent and obtained by a series of coupling reactions. The method is simple and convenient, the reaction conditions are mild and the steps of synthesis are few. Some compounds were confirmed by 1H-NMR-13C-NMRMS. The activity of 11 compounds was determined by MTT assay in human prostate cancer cells (DU145,PC3), breast cancer cells (MCF-7,MDB-MB-231,MDB-MB-453) and 926 normal epithelial cells. The compounds of T5 and T7 with good antitumor activity and low toxicity were screened, which were innovative and laid a foundation for the design of new antitumor drugs.
【学位授予单位】：重庆医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R914;R96
【参考文献】
相关期刊论文 前10条
1 Hong Chen;Fang Xu;Bing-Bing Xu;Jing-Yi Xu;Bin-Hao Shao;Bi-Yun Huang;Mu Yuan;;Design, synthesis and biological evaluation of novel arylpiperazine derivatives on human prostate cancer cell lines[J];Chinese Chemical Letters;2016年02期
2 王q，
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