新型甾体杂环衍生物的设计、合成及其抗肿瘤活性研究

发布时间：2018-05-28 19:50

  本文选题：甾体杂环 + 甾体螺吲哚　； 参考：《郑州大学》2017年硕士论文

【摘要】：作为药物研发的热门领域,甾体因其独特的结构和多取代位点从而被更多的药物学家所关注,扩大甾体化合物的结构多样性以及探究其丰富的生物学活性越来越成为重中之重。结构改造后的甾体化合物也不局限于原有的激素类活性,抗菌、抗肿瘤等更多潜在的药效正在被发现利用。其中,甾体杂环化是甾体化学修饰的热点,利用化学方法在甾体骨架结构中引入杂环结构可丰富甾体类化合物的种类,增加其结构新颖性、复杂性和多样性,同时亦赋予其新的生物学活性,为甾体新药研发打下了基础。故本论文设计合成基于甾体的杂环化衍生物,并对合成的系列衍生物进行抗肿瘤、抗菌活性评价,主要包括以下几个方面:(1)利用廉价易得的的DHEA二腈基烯、靛红、丙二腈、乙酸铵一锅四组分法经关键的索普-齐格勒反应,自身环合异构化高效制备了DHEA螺吲哚环己二烯衍生物Ⅱ-8a-m。化合物Ⅱ-8a和Ⅱ-8b对G+金黄色葡萄球菌和耐药的MRSA菌均有良好的抑菌活性,最优可达到MIC50=2μM;化合物对PC-3、Hela和EC-109细胞都具有良好的抑制作用,尤其是Ⅱ-8a、Ⅱ-8b表现出相当强的抑制效果,对PC-3活性是5-FU的4倍,Hela更是达到了8倍,且合成的所有化合物对GES-1的IC50128μM,显示出极好的选择性;此外,化合物Ⅱ-8a可呈浓度依赖性的方式促进PC-3细胞的线粒体膜电位降低和诱导PC-3细胞凋亡,尤其是早期凋亡细胞且具有浓度依赖性特征。(2)以DHEA为原料,与乙酰乙酸乙酯通过酯交换得到化合物Ⅱ-11,然后化合物Ⅱ-11与芳香醛和脲(或硫脲)在甲磺酸催化下以一锅多组分的Biginelli反应构建去氢表雄酮嘧啶类衍生物Ⅱ-14a-r。化合物Ⅱ-14a-r对肺癌A549的抑制活性是最好的,其中Ⅱ-14k的抑制程度可达到阳性对照5-FU的活性3倍(IC50=4.0μM,5-FU的IC50=12.0μM),Ⅱ-14l也是5-FU的两倍强度,甲基、异丙基、异丁基烷基取代苯基的嘧啶衍生物也表现出强于5-FU的优秀抑制活性。(3)以DHEA与芳香醛发生Claisen-Schmidt缩合而成的α,β 不饱和酮结构,碱性条件下与活泼1,4-二硫-2,5-二醇发生分子内Sulfa-Michael反应和Aldol反应,一步高效地构建了一系列具有一个C-C键、一个C-S键和一个全碳季碳手性中心的去氢表雄酮D环螺噻吩类衍生物Ⅱ-19a-f。此系列化合物对EC-109、PC-3、Hela和F10B16都有较强的抑制活性,尤其PC-3和Hela的抑制效果都优于5-FU,其中化合物Ⅱ-19a的IC50=1.8μM,是阳性对照5-FU的8.5倍(IC50=15.4μM);化合物Ⅱ-19a可以显著地浓度性依赖诱导PC-3细胞凋亡,尤其是晚期凋亡;进一步的线粒体研究结果表明其随浓度递增促进PC-3细胞的线粒体膜电位下降。
[Abstract]:As a hot field of drug research and development, steroids have attracted more and more attention from pharmacologists because of their unique structure and polysubstitution sites. It has become more and more important to expand the structural diversity of steroids and explore their rich biological activities. The steroids after structural modification are not limited to the original hormone activity, antibacterial, anti-tumor and more potential drug effects are being found. Among them, heterocyclization of steroids is a hot spot in chemical modification of steroids. The introduction of heterocyclic structures into steroid skeleton structures can enrich the species of steroids and increase their structural novelty, complexity and diversity. At the same time, it is endowed with new biological activity, which lays the foundation for the research and development of new steroidal drugs. In this paper, the heterocyclic derivatives based on steroids were designed and synthesized, and the antitumor and antibacterial activities of the synthesized derivatives were evaluated, including the following aspects: 1) using cheap and easily available DHEA dinitrile, indigo red, malonitrile, DHEA spiroindole cyclohexadiene derivatives 鈪，

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