本文選題：喜樹堿 + 哌嗪��； 參考：《蘭州大學(xué)》2017年碩士論文

【摘要】：喜樹堿(CPT)是1958年由Monroe E.Wall和Mansukh C.Wani從喜樹中提取分離出的一類有較強(qiáng)抗腫瘤活性的喹啉類生物堿,具有廣譜的抗腫瘤活性,主要用于結(jié)腸癌、卵巢癌、肝癌、骨癌及白血病的治療。喜樹堿是獨(dú)特的拓?fù)洚悩?gòu)酶I(Topo I)抑制劑,由于其獨(dú)特的抗腫瘤作用機(jī)制,截止目前有大量的喜樹堿類衍生物被合成,已經(jīng)被應(yīng)用于臨床的有以下三個:拓?fù)涮婵�、伊立替康和貝洛替�?而且有十四個候選化合物已進(jìn)入臨床前期研究。然而喜樹堿水溶性較差以及在人體生理環(huán)境下不穩(wěn)定的缺陷依然存在,影響喜樹堿類化合物在臨床中的應(yīng)用,為此我們在總結(jié)前期工作的基礎(chǔ)上以喜樹堿A環(huán)和20(S)-位為修飾位點進(jìn)一步進(jìn)行修飾。本論文由以下四部分組成:1.對喜樹堿的研究進(jìn)展、作用機(jī)制、構(gòu)效關(guān)系、喜樹堿類化合物的合成以及生物活性進(jìn)行概述2.喜樹堿A環(huán)衍生物的設(shè)計、合成與構(gòu)效關(guān)系研究喜樹堿9,10-位是A環(huán)的主要修飾位點且有部分9,10位修飾衍生物已被應(yīng)用于臨床或已進(jìn)入臨床前期研究,因此本論文以喜樹堿的A環(huán)的9,10-位為修飾位點,經(jīng)濟(jì)高效地得到了一系列與A環(huán)駢合的六元環(huán)剛性分子和9,10-位單或雙取代的喜樹堿類似物,并進(jìn)行活性測定進(jìn)一步驗證了喜樹堿A環(huán)9,10-位修飾的可行性。3.基于Mannich反應(yīng)的新型9-位哌嗪喜樹堿衍生物的設(shè)計、合成與抗腫瘤活性研究哌嗪是一種值得注意的含氮六元雜環(huán),在藥物化學(xué)領(lǐng)域中扮演著重要的角色,很多已經(jīng)用于臨床的藥物中含有哌嗪或磺酰哌嗪片段,具有廣譜的藥理活性。而且在喜樹堿的9-位運(yùn)用Mannich反應(yīng)引入哌嗪片段的思路與拓?fù)涮婵涤挟惽ぶ?同時我們課題組在前期的工作中也發(fā)現(xiàn)在喜樹堿7-位引入磺酰哌嗪片段后活性十分突出。因此本章設(shè)計得到一類喜樹堿9-甲基哌嗪衍生物和喜樹堿9-甲基磺酰哌嗪衍生物,旨在縱橫向同時進(jìn)行生物活性比較,為后續(xù)的工作奠定基礎(chǔ)。4.喜樹堿20-位肉桂酸衍生物的設(shè)計、合成與抗腫瘤活性研究肉桂酸在生命科學(xué)與藥物化學(xué)領(lǐng)域有廣闊的應(yīng)用前景,引起了大量的科研工作者的關(guān)注,在抗腫瘤藥物的設(shè)計合成中也屢見不鮮。本論文將肉桂酸引入到前期所得的抗腫瘤活性較好的喜樹堿A環(huán)衍生物中,以期得到抗腫瘤活性好且內(nèi)酯環(huán)穩(wěn)定的有發(fā)展前景的喜樹堿類衍生物。
[Abstract]:Camptothecin (CPT) is a class of quinoline alkaloids which were isolated from Camptotheca acuminata by Monroe E.Wall and Mansukh C.Wani in 1958. It has broad spectrum antitumor activity and is mainly used in the treatment of colon cancer, ovarian cancer, liver cancer, bone cancer and leukemia. Camptothecin is a unique inhibitor of topoisomerase I(Topo I. Because of its unique antitumor mechanism, a large number of camptothecin derivatives have been synthesized and have been applied in clinic as follows: topotecan, topotecan, Iritecan and Belo tetecan, and fourteen candidate compounds have entered pre-clinical studies. However, the poor water solubility of camptothecin and the unstability of camptothecin in human physiological environment still exist, which affects the clinical application of camptothecin compounds. Therefore, on the basis of summarizing the previous work, we further modified the camptothecin A ring and the 20 ~ (th) S ~ (+) ~-site as the modification sites. This thesis consists of four parts: 1. The research progress, action mechanism, structure-activity relationship, synthesis and biological activity of camptothecin were reviewed. Design, Synthesis and Structure-Activity relationship of camptothecin A Ring Derivatives; camptothecin 9 ~ (10) is the main modification site of A ring, and some of the 9 ~ (10) modified derivatives have been used in clinical or early clinical studies. Therefore, in this paper, a series of six-member ring rigid molecules and mono- or disubstituted camptothecin analogues with A-ring were obtained by using the 9o ~ 10- site of camptothecin A ring as the modification site. The feasibility of the modification of camptothecin A ring was further verified by the activity determination. Design, Synthesis and Antitumor activity of novel 9-position Piperazine camptothecin Derivatives based on Mannich reaction piperazine is an important nitrogen-containing six-member heterocycle, which plays an important role in the field of pharmaceutical chemistry. Many drugs that have been used clinically contain piperazine or sulfonyl piperazine fragments with broad spectrum pharmacological activities. Moreover, the idea of introducing piperazine fragments into camptothecin by Mannich reaction is similar to that of topotecan. At the same time, our research group also found that the activity of sulfonyl piperazine at the 7-site of camptothecin was very prominent. In this chapter, a class of camptothecin 9-methyl piperazine derivatives and camptothecin 9-methylsulfonyl piperazine derivatives are designed to compare the biological activities of camptothecin 9- methyl-piperazine and camptothecin at the same time in order to lay a foundation for further work. Design, Synthesis and Antitumor activity of Camptothecin 20-site Cinnamic Acid Derivatives; Cinnamic Acid has a wide application prospect in life sciences and pharmaceutical chemistry, and has attracted a lot of researchers' attention. It is also common in the design and synthesis of anti-tumor drugs. In this paper, cinnamic acid was introduced into camptothecin A ring derivatives with good antitumor activity, in order to obtain promising camptothecin derivatives with good antitumor activity and stable lactone ring.
【學(xué)位授予單位】：蘭州大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R914

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本文編號：1921869