齐墩果酸衍生物的合成及其促进类成骨细胞增殖活性研究

发布时间：2018-03-29 08:17

本文选题：骨质疏松　切入点：齐墩果酸　出处：《南京大学》2014年硕士论文

【摘要】：骨质疏松是一种系统性骨病,以骨密度减少,骨微结构萎缩为特征,导致骨折风险增加。骨质疏松是一种全球性骨病,患者约有数百万。尤其危害绝经期妇女及中老年人。治疗骨质疏松的药物按其对骨组织的作用阶段可分为抑制骨吸收药物、促进骨形成药物。二膦酸盐是一种广泛应用的药物,可以阻止破骨细胞对骨组织的过度吸收。但其对人体胃肠道有副作用。甲状旁腺素是目前应用于骨质疏松症治疗的合成代谢类药物中唯一能够促进骨形成的药物。但因为甲状旁腺素是注射类药物且会增加患骨肉瘤的风险,故临床上用药限制在2年以内。因此,研究新型的抗骨质疏松症药物具有重要意义。齐墩果酸及其糖苷具有包括抗骨质疏松活性在内的广泛的生物活性。在我们的前期研究中,已经合成了一系列在齐墩果酸A环并有杂环及C-28连有胺基的衍生物,并对其抗骨质疏松活性进行了评价。其中大多数化合物能够抑制破骨细胞的形成。本文我们设计合成了一系列A环修饰有杂环及C-28修饰的衍生物,利用1HNMR,13C NMR, ESI-MS表征了结构。同时利用小鼠的头骨类成骨细胞,以MTT法评价了其对成骨细胞增值活性。一、齐墩果酸衍生物的合成我们以齐墩果酸母核为原料合成衍生物。通过钨酸钠-双氧水体系氧化齐墩果酸得到中间体1。1溶于甲苯中在甲醇钠存在下与甲酸乙酯进行Claisen缩合制得中间体2。化合物2与胺缩合得到烯胺类衍生物；化合物2在乙醇中与盐酸肼或盐酸羟胺回流可得到吡唑或异恶唑杂环结构。杂环化合物与亚硫酰氯或草酰氯室温搅拌,抽干溶剂后在三乙胺存在下与胺类化合物反应,得到相应的酰胺衍生物。异恶唑杂环在乙醚／甲醇中与甲醇钠反应开环,除去溶剂和碱后在乙醇中与水合肼回流得到氨基吡唑杂环。二、活性评估成骨细胞是骨形成的主要承担者,合成了大量的细胞外基质蛋白,并控制着这些蛋白的矿化过程。通过MTT法,采用小鼠头骨的类成骨细胞对合成化合物的促进成骨细胞增殖活性进行评估。大多数化合物显示了促进成骨细胞增殖活性,其中化合物C5活性最好。进一步的生物活性测试还在进行中。
[Abstract]:Osteoporosis is a systemic bone disease characterized by reduced bone density and atrophy of bone structure, which increases the risk of fracture. Osteoporosis is a global bone disease. There are about millions of patients, especially menopausal women and middle-aged and elderly people. Drugs for treating osteoporosis can be divided into drugs for inhibiting bone resorption and promoting bone formation according to their stage of action on bone tissue. Diphosphonates are a widely used drug. Parathyroid hormone (PTH) is the only synthetic metabolite currently used in the treatment of osteoporosis, which can promote bone formation. But because parathyroid hormone is an injectable drug and increases the risk of osteosarcoma, Therefore, it is of great significance to study new anti-osteoporosis drugs. Oleanolic acid and its glycosides have a wide range of biological activities, including anti-osteoporosis activities. A series of derivatives with heterocyclic and C-28 amino groups in A ring of oleanolic acid have been synthesized. The antiosteoporosis activity of these compounds was evaluated. Most of them can inhibit the formation of osteoclasts. In this paper, we designed and synthesized a series of A-ring modified heterocyclic and C-28 modified derivatives. The structure was characterized by 1H-NMR-13C-NMR.At the same time, the osteoblasts of mouse skulls were used to evaluate the proliferation activity of osteoblasts by MTT. Synthesis of Oleanolic Acid Derivatives Derivatives from Oleanolic Acid Mother Nucleus Derivatives were synthesized by oxidation of oleanolic acid in sodium tungstate-hydrogen peroxide system to obtain intermediate 1.1 soluble in toluene with ethyl formate in the presence of sodium methoxide. Intermediate 2 was synthesized by Claisen condensation. Compound 2 was condensed with amine to obtain enamine derivatives. Compound 2 was refluxed in ethanol with hydrazine hydrochloride or hydroxylamine hydrochloride to obtain pyrazole or isoxazole heterocyclic structure. The heterocyclic compounds were stirred with thioyl chloride or oxaloyl chloride at room temperature, dried solvent and reacted with amines in the presence of triethylamine. The corresponding amide derivatives were obtained. Isoxazole heterocyclic reaction with sodium methoxide in ether / methanol, removing solvent and alkali, refluxing with hydrazine hydrate in ethanol to obtain aminopyrazole heterocyclic. Activity assessment osteoblasts are the primary carriers of bone formation, synthesizing a large number of extracellular matrix proteins and controlling the mineralization process of these proteins. Osteoblast like cells from mouse skulls were used to evaluate the proliferative activity of synthetic compounds. The activity of compound C _ 5 is the best, and further bioactivity tests are still in progress.
【学位授予单位】：南京大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：O621.13;R914.5;R96

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