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香豆素类衍生物合成及其抗白癜风活性和抗菌活性研究
庞广宪
学位类型博士
导师阿吉艾克拜尔·艾萨
2018-06-02
学位授予单位中国科学院大学
学位授予地点北京
学位专业有机化学
关键词香豆素衍生物 补骨脂素 抗白癜风 黑色素生成 抗菌活性
摘要

香豆素(Coumarin)类化合物是邻羟基桂皮酸内酯类成分的总称,具有苯并α-吡喃酮母核的基本骨架,广泛存在于自然界伞形科等高等植物中,香豆素类化合物在抗白癜风、抗菌和抗肿瘤等方面具有较强的生物活性,成为近年来新药开发领域的热点。补骨脂素属呋喃香豆素类,可配合日光浴治疗白癜风,即PUVA疗法,是目前治疗白癜风最重要和有效的一线药物。为找到具有抗白癜风活性的新型香豆素类衍生物,进一步探究黑素生成诱导机制,本文第二章分别通过酯化反应和亚胺化反应在补骨脂素分子骨架的C-5引入取代苯基,共合成2个系列28个补骨脂素类衍生物,在50 μM浓度下,14个化合物表现出比8-MOP (136%)更优的促黑素生成活性,其中:化合物8n(200%)、8o(197%)和9K(237%)的活性最为突出。所有化合物对白色念珠菌(CA)均表现出较强的抑菌活性,在苯环对位存在取代基的化合物9b-9c、9e-9h和9k普遍能够抑制金黄色葡萄球菌(SA),且化合物5对大肠杆菌(EC)和金黄色葡萄球菌(SA)也表现出广谱的抑菌活性。此外,选取并研究了化合物BSP-1(9a)对B16细胞黑色素合成影响及其信号通路,结果显示BSP-1能够促进B16细胞内黑色素生成及TYR活性,上调 TYR、TRP-1、TRP-2和MITF的蛋白表达,并呈浓度依赖性。机制研究发现,BSP-1通过提高Akt和GSK-3β磷酸化水平,上调细胞核中β-catenin含量,最终使得微小眼球转录因子(MITF)蛋白表达增加。第三章,通过多步反应合成了15个含有异噁唑片段的香豆素类衍生物6a-6o,经筛查发现,在50 μM浓度下,化合物6d(242%)和6f(390%)促黑素生成活性优于阳性对照8-MOP(149%),另有7个衍生物(6d-6f,6i 和 6l-6n)表现出抗白色念珠菌(CA)活性。本文共合成了43个化合物,均为新化合物。经过初步的抗白癜风活性实验筛选,其中38个化合物在B16细胞中表现出促黑素生成活性,且24个化合物在相同剂量下活性优于阳性对照8-MOP。本论文的研究结果将为新型抗白癜风先导候选化合物筛选提供新的选择,并为部分化合物在抑菌方面的开发和应用提供科学依据。

其他摘要

Coumarin compounds, are the generic terms of o-hydroxycinnamic acid lactones, which have the basic skeleton of benzo alphapyrone, and are widely distributed in the higher plants such as leguminous plants in nature. Coumarin compounds exhibited strong anti-vitiligo, anti-bacterial and anti-tumor biological activity and become a hot spot in the field of new drug development in recent years. Psoralen, which belongs to coumarin, are often used for treatment of vitiligo supplemented with UV radiation, called the PUVA method. And it is the most important and effective first-line drugs for the skin depigmentation nowadays.In the second chapter of the paper, two novel series of twenty-eight psoralen derivatives were synthesized through introduction of different substituted phenyl groups to the C-5 of the molecular to explore the candidate for vitiligo treatment and its melanogenesis-stimulating mechanism. After biological evaluation, it was found that half of the compounds showed better melanogenic activity than 8-MOP(136%), especially for compound 8n(200%), 8o(197%) and 9k(237%), which were most potent at the concentration of 50 μM. All the compounds exhibited strong antibacterial activity against Candida albicans(CA) in vitro. Psoralen Schiff base derivatives(9b-9c, 9e-9h, and 9k) with p-substitution in the phenyl ring, generally inhibited growth of Staphylococcus aureus(SA). In addition, compound 5 also demonstrated extensive antibacterial activity against Escherichia coli (EC) and SA in vitro. After that, the effect of compound BSP-1(9a) on the melanogenesis in B16 cells and its signaling pathway were further studied. The results showed that BSP-1 could promote melanin production and TYR activity in B16 cells, and up-regulate the protein expression of TYR, TRP-1, TRP-2, and MITF in a concentration dependent manner. Further study revealed that BSP-1 increased the phosphorylation levels of Akt and GSK-3β, up-regulated the content of β-catenin in the nucleus, and finally increased the expression of the MITF protein.In the third Chapter, fifteen coumarin derivatives(6a-6o) bearing isoxazole were synthesized by the multistep reaction. Compounds 6d(242%)and 6f(390%) were more potent than the positive control 8-MOP(149%)at the concentration of 50 μM. Moreover, seven derivatives(6d-6f, 6i and 6l-6n) exhibited antibacterial activity against CA in vitro.In this paper, three novel serious of fourty-three compounds were synthesized. After activity screening, thirty-eight derivatives could promoted melanogenesis in B16 cells, and twenty-four of them were found to be more efficient than the 8-MOP at the same concentration. The results will provide several compounds for the screening of new leading candidates for vitiligo, as well as the scientific basis for the further development and utilization of some antibacterial compounds in the paper

页数128
文献类型学位论文
条目标识符http://ir.xjipc.cas.cn/handle/365002/5469
专题资源化学研究室
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庞广宪. 香豆素类衍生物合成及其抗白癜风活性和抗菌活性研究[D]. 北京. 中国科学院大学,2018.
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