多取代靛红衍生物的合成与抗肿瘤活性研究

发布时间：2018-04-04 08:51

本文选题：靛红　切入点：抗肿瘤　出处：《天津科技大学》2014年硕士论文

【摘要】：靛红又名吲哚满二酮或2,3-吲哚醌,是存在于哺乳动物组织和体液中的内源性活性物质,它也存在于中药青黛中。靛红及其衍生物具有很好的抗肿瘤、抗菌、抗病毒和抗结核等活性。近年来,以靛红为母核结构的衍生物的有机合成及其药理活性研究受到越来越多人的关注。靛红及其衍生物的吡咯环及苯环上可以发生多种类型的化学反应,为其衍生物的研究提供了广阔的空间。在以往合成的靛红衍生物中,多数是在靛红苯环上进行一个位置取代基衍生合成,其它是在吡咯环上进行反应衍生取代,苯环上多位置取代靛红的合成及生物活性的研究报道较少。本文设计合成了一系列在靛红的4,5,6,7-位进行衍生修饰的多取代靛红衍生物,并对其进行了体外抑制肿瘤细胞生长活性的研究,根据初步构效关系,又对1,3,7-位做了进一步结构修饰与活性研究。本课题以不同位置的不同取代的苯胺为原料,通过四条合成路线,经Sandmeyer法(成肟、傅克反应)、溴化、硝化、氧化、酯化、重氮化还原、烷化等一系列反应共合成了68个目标化合物,其结构经1HNMR、13C NMR和MS进行了确证,其中41个化合物未见文献报道。选用人白血病细胞(K562)、人肝癌细胞(HepG2)人结肠癌细胞(HT-29)对目标化合物进行体外肿瘤细胞生长抑制活性的研究,结果表明：当多取代靛红衍生物5-位是吸电子硝基取代,4-位和6-位是较弱的吸电子卤素取代,7-位是甲酸甲酯或甲酸酰胺,1-位是苄基取代,3-位羰基保持不变时,有助于靛红衍生物抗肿瘤活性的提高。该课题的研究将为具有抗肿瘤活性的靛红类衍生物新药研究奠定基础。
[Abstract]:Indirubin, also known as indomedione or isatin, is an endogenous active substance in mammalian tissues and body fluids.Indirubin and its derivatives have excellent anti-tumor, anti-bacterial, anti-viral and anti-tuberculosis activities.In recent years, more and more attention has been paid to the organic synthesis and pharmacological activity of indirubin derivatives.There are many kinds of chemical reactions on pyrrole ring and benzene ring of indirubin and its derivatives, which provides a wide space for the study of its derivatives.In the past, most of the indirubin derivatives were synthesized on the indirubin ring with one position substituent and the others on the pyrrole ring.There are few studies on the synthesis and bioactivity of indirubin in benzene ring.In this paper, we designed and synthesized a series of polysubstituted indirubin derivatives modified at 4 ~ 5 ~ 6 ~ 6 ~ (-) ~ (-) position of indirubin, and studied their inhibitory activity on tumor cell growth in vitro, according to the preliminary structure-activity relationship.The structure modification and the activity of the 1 ~ 3 ~ 3 ~-~-site were also studied.68 target compounds were synthesized by a series of alkylation reactions. Their structures were confirmed by 1HNMR-13C NMR and MS, among which 41 compounds were not reported in literature.Human leukemia cell line K562and human hepatoma cell line HepG2) were used to study the growth inhibitory activity of the target compounds on tumor cells in vitro.The results show that when the 5-position of the polysubstituted indirubin derivatives is the electron-absorbing nitro-substituted 4-site and the 6-position is the weaker electron-absorbent halogen substitution-7-position is methyl formate or the 1-position of amides formate is benzyl substituted 3-carbonyl, the carbonyl position remains unchangedIt is helpful to enhance the antitumor activity of indirubin derivatives.The research will lay a foundation for the study of new drugs of indirubin derivatives with anti-tumor activity.
【学位授予单位】：天津科技大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914.5;R96

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