本文選題：炔基　切入點：銨基葉立德　出處：《華東師范大學(xué)》2017年碩士論文　論文類型：學(xué)位論文

【摘要】：炔基廣泛存在于天然產(chǎn)物和一些藥物中,尤其是抗癌藥中,主要是由于炔基能和一些靶蛋白的半胱氨酸殘基上的巰基會發(fā)生加成反應(yīng)而形成共價作用,進(jìn)而增強了藥物與一些靶點蛋白的結(jié)合而更好地發(fā)揮藥物作用。炔基是一個高能量、不飽和的活潑官能團,很容易與其他基團如氨基、羥基、亞胺、重氮等發(fā)生反應(yīng),所以在含有多官能團的復(fù)雜分子中快速引入炔基是不易的�；趤啺凡蹲戒@基葉立德的多組分反應(yīng)(MCRs),我們使用一些簡單原料通過"一鍋"法成功的構(gòu)建含多官能團、結(jié)構(gòu)多樣性的炔酰胺取代的α,β-二氨基酸酯衍生物4,并研究了其生物活性,并初步對其進(jìn)行構(gòu)效關(guān)系研究。論文第一章,介紹了炔基在抗癌藥物中的重要作用及其構(gòu)建方法,并在課題組現(xiàn)有研究基礎(chǔ)上提出了本論文的研究構(gòu)思和課題目標(biāo)。論文第二章,我們首先創(chuàng)建了一種以芳基重氮甲酸酯1、丙炔酰胺2和亞胺3為底物,醋酸銠為催化劑的"一鍋"法以較好的收率和高非對映選擇性成功地實現(xiàn)了構(gòu)建炔酰胺取代的α,β-二氨基酸酯衍生物4。論文第三章,我們對這類新型α,β-二氨基酸酯衍生物4進(jìn)行生物學(xué)抗腫瘤或抗癌活性研究,發(fā)現(xiàn)這類化合物在結(jié)腸癌和人肝癌細(xì)胞中初步顯示了良好的生物學(xué)抗癌活性,IC50值在幾微摩爾水平。而后,進(jìn)行構(gòu)效關(guān)系研究發(fā)現(xiàn),不帶羥基的炔酰胺取代的產(chǎn)物4抗癌活性可達(dá)到納摩爾級別,尤其是在人骨肉瘤SJSA-1細(xì)胞中IC50值可達(dá)9.56 nM,表明羥基為非必須官能團;當(dāng)炔基被烯基或烷基取代或關(guān)環(huán)所得苯并VA唑哌嗪酮類衍生物7,直接無抗癌作用,說明炔基是該類化合物表現(xiàn)抗癌作用的關(guān)鍵因素。總之,我們設(shè)計合成的炔酰胺取代的α,β-二氨基酸酯衍生物4是一類非常有效的潛在抗癌藥物,這為我們后續(xù)的藥理學(xué)研究提供了物質(zhì)基礎(chǔ),為成藥性研究提供了可能性。
[Abstract]:Alkynyl widely exists in some natural products and drugs, especially anticancer drugs, mainly because of alkynyl thiol and some target protein cysteine residues on the addition reaction and the formation of covalent interactions, thereby enhancing the combination of drugs and some target proteins and better use of drugs. Alkynyl is a high energy, unsaturated active functional groups, easily with other groups such as hydroxyl, amino, imino, diazotization reaction, so the complex molecules containing multiple functional groups in the rapid introduction of alkynyl is not easy. Multicomponent reaction of imines capture ammonium ylide (based on MCRs), we use some simple construction materials with multi functional success through a "one pot" method, structural diversity of alkyne substituted alpha, beta two amino acid ester derivative 4, and study its biological activity, and carries on the preliminary study on structure-activity relationship theory. The first chapter introduces the important role of alkyne in anti-cancer medicament and its construction method, and put forward the research ideas and research goals of this thesis in the research group. Based on the existing research in the second chapter, we first create a aryl diazonium acid ester amide 1, propargyl imine 3 and 2 as the substrate, rhodium acetate as catalyst of the "one pot" method with good yield and high diastereoselectivity were successfully constructed alkyne substituted alpha, beta two amino acid ester derivatives of 4. in the third chapter, we for this type of alpha, beta two amino acid ester derivatives in biological anti-tumor or 4 study on the anticancer activity of these compounds found in primary colon cancer and hepatocellular carcinoma showed good biological anticancer activity, IC50 value in a few Moore level. Then, structure-activity relationship study found that the product of alkyne without hydroxyl substituted 4 anticancer activity Can reach the level especially in the nanomolar, human osteosarcoma SJSA-1 cells in IC50 value can reach 9.56 nM, which indicated that hydroxyl for non essential functional groups; when alkynyl or alkenyl or alkyl substituted by the cyclization of benzo VA oxazole ketone piperazine derivative 7, no direct antitumor effect, that is the key factor of acetylenic compounds expression of anti-cancer effects. In short, we design the synthesis of alkyne substituted alpha, beta two amino acid ester derivative 4 is a kind of potential anticancer drugs are very effective, which provides the material basis for our further research into the pharmacology, drug research provides a possibility.

【學(xué)位授予單位】：華東師范大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R914;R96
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本文編號：1583375