【摘要】：癌癥是嚴(yán)重影響人類(lèi)健康的因素,是目前國(guó)內(nèi)外最常見(jiàn)也是最難治愈的病癥之一。近些年來(lái)全球范圍內(nèi)癌癥患病率呈持續(xù)增長(zhǎng)態(tài)勢(shì)。對(duì)比IARC發(fā)布的2012年全球癌癥數(shù)據(jù)庫(kù)中的中國(guó)癌癥數(shù)據(jù),形勢(shì)已更為嚴(yán)峻。癌癥已成為當(dāng)前影響人類(lèi)健康的重要因素。目前,癌癥的治療以化療為主,但是市面上主流的抗癌藥普遍毒副作用較大且價(jià)格昂貴,開(kāi)發(fā)出新型抗腫瘤藥已是當(dāng)下亟待解決的問(wèn)題。鈉離子通道(Voltage-Gated Sodium Channels,VGSCs)作為一種通道蛋白受體,通常在可興奮的細(xì)胞中表達(dá)(如神經(jīng),肌肉細(xì)胞等)。近年來(lái)許多研究表明,VGSCs在轉(zhuǎn)移的腫瘤細(xì)胞中均可表達(dá)(如宮頸癌、前列腺癌、乳腺癌、肺癌等),對(duì)侵襲和轉(zhuǎn)移起到重要的生理作用,是興奮組織動(dòng)作電位的關(guān)鍵離子通道。VGSCs現(xiàn)已成為近幾年來(lái)新型抗腫瘤藥物的研究熱點(diǎn)。從第一個(gè)VGSCs阻斷劑河豚毒素(TTX)被分離出后,數(shù)以百計(jì)的VGSCs阻斷劑化合物已被陸續(xù)報(bào)道。本研究基于最新報(bào)道的增效基團(tuán)的基礎(chǔ)上,以鈉離子通道類(lèi)抗驚厥藥苯妥英鈉為基礎(chǔ)結(jié)構(gòu),打開(kāi)乙內(nèi)酰脲環(huán),保留二苯基結(jié)構(gòu),對(duì)另一邊疏水端和中間含NH的富電區(qū)進(jìn)行改造。結(jié)合最新報(bào)道的增效基團(tuán),系統(tǒng)性地設(shè)計(jì)合成了11個(gè)化合物。以4,4,-二(4-氟苯)氯丁烷為原料,經(jīng)Gabriel反應(yīng),肼解,偶聯(lián),還原得到(T1 T2)。T3~T11的合成方法類(lèi)似,用DMSO作溶劑,經(jīng)一系列偶聯(lián)反應(yīng)得到。該方法合成簡(jiǎn)便,反應(yīng)條件溫和,合成步驟少。本研究所有的化合物經(jīng)過(guò)1H-NMR、13C-NMR、MS確證。11種化合物均用人類(lèi)前列腺癌細(xì)胞(DU145、PC3)和乳腺癌細(xì)胞(MCF-7、MDB-MB-231、MDB-MB-453)和926正常上皮細(xì)胞利用MTT法測(cè)試體外活性。篩選出T5和T7具有良好抗腫瘤活性和低毒性的化合物,具有一定的創(chuàng)新性,為新型抗腫瘤藥物設(shè)計(jì)奠定了一定基礎(chǔ)。
[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.
【學(xué)位授予單位】：重慶醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R914;R96

【參考文獻(xiàn)】

相關(guān)期刊論文 前10條

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，

本文編號(hào)：2268274