本文選題：胸苷酸合成酶抑制劑　切入點(diǎn)：喹唑啉　出處：《青島科技大學(xué)》2014年碩士論文　論文類型：學(xué)位論文

【摘要】：胸苷酸合成酶（Thymidylate synthase，TS）是一種葉酸依賴性酶，其參與胸苷嘧啶核苷酸的起始合成過程，胸苷嘧啶核苷酸是脫氧核糖核酸（DNA）生物合成的所必需物質(zhì)，抑制胸苷酸合成酶的活性將引起胞內(nèi)胸苷嘧啶的缺失，這樣會(huì)使腫瘤細(xì)胞內(nèi)的DNA合成不能正常進(jìn)行，隨后會(huì)產(chǎn)生缺陷的DNA合成、裂解以及細(xì)胞凋亡。因此，胸苷酸合成酶已經(jīng)成為化療藥物一個(gè)非常重要的作用靶點(diǎn)，，其抑制劑是抗腫瘤藥物研究的重要方向。 本研究的目的是合成新型的胸苷酸合成酶抑制劑喹唑啉酮類抗腫瘤先導(dǎo)藥物，通過對(duì)其中間體及其衍生物中間體的合成篩選獲得具有一定活性和自主知識(shí)產(chǎn)權(quán)的化合物，用于進(jìn)一步的活性研究。本文主要進(jìn)行了以下方面的工作： 1對(duì)新型喹唑啉-嘧啶酮類衍生物A2-氨基-5-[2-（二氫嘧啶-2,4（1H,3H）-二酮-5-基）乙基]喹唑啉-4-酮進(jìn)行合成探索，通過逆向合成分析，設(shè)計(jì)了其合成路線。以苯為原料，經(jīng)付克�；�、硝化、酯化、硝基還原、羰基還原、縮合成肟、閉環(huán)成靛紅開環(huán)等8步反應(yīng)，全合成抑制劑A的重要中間體4-（3-氨基-2-羧基苯基）丁酸。對(duì)每一步的反應(yīng)條件進(jìn)行了優(yōu)化，提高了各步反應(yīng)的收率。所有合成的化合物都通過1HNMR確認(rèn)。 2對(duì)新型喹唑啉-嘧啶酮類衍生物B5-[3-(2-氨基-4-氧代-3,4-二氫喹唑啉-5-基)丙基]-二氫嘧啶-2,4（1H,3H）-二酮進(jìn)行合成探索，其主要合成路線和A相似，以苯和戊二酸酐為原料，經(jīng)過對(duì)付克�；磻�(yīng)、硝化反應(yīng)、硝基還原、酯化、羰基還原等反應(yīng)的實(shí)驗(yàn)條件探索，掌握了化合物B的中間體5-（3-氨基苯基）戊酸乙酯的合成方法。 3對(duì)3,4-二氨基苯甲酸乙酯進(jìn)行了合成探索。我們以對(duì)氨基苯甲酸為原料，經(jīng)酰基化、硝化、水解、硝基還原、酯化合成了3,4-二氨基苯甲酸乙酯。對(duì)每一步的反應(yīng)條件進(jìn)行了優(yōu)化，提高了各步反應(yīng)的收率。所有合成的化合物都通過1HNMR確認(rèn)。 4對(duì)6-(3-氨基苯基)-4,5-二氫-3(2H)-噠嗪-2-酮進(jìn)行了合成探索。以3-(3-硝基苯甲�；�)-丙酸為原料，與水合肼在雷尼鎳的催化下合成了目標(biāo)化合物。此反應(yīng)一步完成了硝基還原和成環(huán)，減少了反應(yīng)步驟，提高了產(chǎn)率。目標(biāo)產(chǎn)物經(jīng)過通過1HNMR和紅外確認(rèn)。
[Abstract]:Thymidylate synthase (Thymidylate synthase) is a folic acid-dependent enzyme involved in the initiation of thymidine nucleotide synthesis, and thymidine nucleotides are essential for the biosynthesis of deoxyribonucleic acid (DNA). Inhibition of the activity of thymidine synthase will lead to the deletion of thymidine, which will lead to abnormal DNA synthesis in tumor cells, followed by defective DNA synthesis, cleavage and apoptosis. Thymidine synthase has become a very important target of chemotherapeutic drugs, and its inhibitor is an important research direction of antitumor drugs. The aim of this study was to synthesize novel antitumor drugs of thymidine synthase inhibitor quinazolinone, and to obtain some active and independent intellectual property rights compounds through the synthesis and screening of intermediates and their derivatives. The main work of this paper is as follows:. 1 A _ 2-amino-5- [2-( dihydropyrimidine-2-dihydropyrimidine) -4H (dihydropyrimidine) -3H _ (3H) -diketone] -ethyl] quinazoline-4-one derivative of quinazoline-pyrimidone was synthesized and explored. The synthetic route of quinazoline-pyrimidinone derivatives was designed by reverse synthetic analysis. Nitration, esterification, nitro reduction, carbonyl reduction, synthesis of oxime, closed-loop ring opening reaction of indirubin, etc. The main intermediate of the total synthesis inhibitor A, 4-Amino-2-carboxyphenyl) butyric acid. The reaction conditions of each step were optimized. All the synthesized compounds were confirmed by 1H NMR. 2 A new quinazoline pyrimidinone derivative B5- [3-butadiene-2-amino-4-oxo-4-oxo-4-dihydroquinazoline -5-yl] -dihydropyrimidine -4H _ 2H _ 3H _ 3-diketone was synthesized by using benzene and glutaric anhydride as raw materials. The synthetic method of ethyl valerate, the intermediate of compound B, was obtained by exploring the experimental conditions for the reaction of ketoacylation, nitration, nitro reduction, esterification, carbonyl reduction and so on. 3. The synthesis of ethyl 3o 4-diaminobenzoate was studied. We used p-aminobenzoic acid as raw material through acylation, nitration, hydrolysis and nitro reduction. The reaction conditions of each step were optimized and the yield of each reaction was improved. All the synthesized compounds were confirmed by 1H NMR. (4) the synthesis and exploration of 6-O3-Aminophenyl-4-Aminophenyl-5-dihydro-3H-Pa-pyridazine-2-one was carried out. The target compound was synthesized with hydrazine hydrate and hydrazine hydrate as raw materials, and the nitro reduction and ring formation were completed in one step. The reaction steps were reduced and the yield was increased. The target product was confirmed by 1H NMR and IR.
【學(xué)位授予單位】：青島科技大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R914.5

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