喜树碱类抗肿瘤药物的设计、合成与构效关系研究

发布时间：2018-05-22 11:26

本文选题：喜树碱 + 哌嗪　；参考：《兰州大学》2017年硕士论文

【摘要】：喜树碱(CPT)是1958年由Monroe E.Wall和Mansukh C.Wani从喜树中提取分离出的一类有较强抗肿瘤活性的喹啉类生物碱,具有广谱的抗肿瘤活性,主要用于结肠癌、卵巢癌、肝癌、骨癌及白血病的治疗。喜树碱是独特的拓扑异构酶I(Topo I)抑制剂,由于其独特的抗肿瘤作用机制,截止目前有大量的喜树碱类衍生物被合成,已经被应用于临床的有以下三个:拓扑替康、伊立替康和贝洛替康,而且有十四个候选化合物已进入临床前期研究。然而喜树碱水溶性较差以及在人体生理环境下不稳定的缺陷依然存在,影响喜树碱类化合物在临床中的应用,为此我们在总结前期工作的基础上以喜树碱A环和20(S)-位为修饰位点进一步进行修饰。本论文由以下四部分组成:1.对喜树碱的研究进展、作用机制、构效关系、喜树碱类化合物的合成以及生物活性进行概述2.喜树碱A环衍生物的设计、合成与构效关系研究喜树碱9,10-位是A环的主要修饰位点且有部分9,10位修饰衍生物已被应用于临床或已进入临床前期研究,因此本论文以喜树碱的A环的9,10-位为修饰位点,经济高效地得到了一系列与A环骈合的六元环刚性分子和9,10-位单或双取代的喜树碱类似物,并进行活性测定进一步验证了喜树碱A环9,10-位修饰的可行性。3.基于Mannich反应的新型9-位哌嗪喜树碱衍生物的设计、合成与抗肿瘤活性研究哌嗪是一种值得注意的含氮六元杂环,在药物化学领域中扮演着重要的角色,很多已经用于临床的药物中含有哌嗪或磺酰哌嗪片段,具有广谱的药理活性。而且在喜树碱的9-位运用Mannich反应引入哌嗪片段的思路与拓扑替康有异曲同工之妙,同时我们课题组在前期的工作中也发现在喜树碱7-位引入磺酰哌嗪片段后活性十分突出。因此本章设计得到一类喜树碱9-甲基哌嗪衍生物和喜树碱9-甲基磺酰哌嗪衍生物,旨在纵横向同时进行生物活性比较,为后续的工作奠定基础。4.喜树碱20-位肉桂酸衍生物的设计、合成与抗肿瘤活性研究肉桂酸在生命科学与药物化学领域有广阔的应用前景,引起了大量的科研工作者的关注,在抗肿瘤药物的设计合成中也屡见不鲜。本论文将肉桂酸引入到前期所得的抗肿瘤活性较好的喜树碱A环衍生物中,以期得到抗肿瘤活性好且内酯环稳定的有发展前景的喜树碱类衍生物。
[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.
【学位授予单位】：兰州大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R914

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