摘要
糖类是自然界极为重要的一类天然化合物,糖生物学的研究表明,糖几乎参与所有真核生物的每一个过程,它们的功能是复杂而多样的。糖生物学的发展不断的揭示出糖在生命过程的重要作用。糖类化合物被认为在抗癌、抗炎、抗病毒、糖尿病治疗、免疫调节、免疫疫苗、器官移植等领域都有良好的应用前景。这些前沿的发现极大的激发了学术界和制药业的兴趣。
糖酯类化合物在医药、食品、日用化妆品、化工及其他行业均有广泛的应用。其中,某些糖酯类化合物具有抗肿瘤、杀菌、抗高血压等生物活性,可作为血管紧张素转换酶(ACE)抑制剂、肿瘤转移抑制剂等。一些活性较高的化合物由于本身存在的毒性和对环境的负面影响以及生物组织难以吸收的特点使其使用受到了限制,而对这种活性功能化合物进行糖基化,将糖分子引入到活性小分子结构中,通过活性测试已证明糖基化后的化合物作为前体药物具有较好的药效。因此,有关糖酯类化合物的合成及其性质的研究已成为人们关注的课题。
肽在生物体内有重要的作用,其在体内参与多种代谢及调节活动。由于许多肽基蛋白质在生命过程中的突出重要性,有关的科技领域如药物化学、分子免疫学、动物学、农业及食品工业的发展均需要大量各种结构的肽类似物,以便进行结构和活性关系的研究。在世界范围内迄今共有17个ACE抑制剂上市,其中属于N-羧烷基二肽结构类型的有13种。
本论文采用相转移催化法立体专一性合成了出了13个新型的含有肽键结构的糖酯类化合物,其中包括7种新的N-(N-乙酰基-N-芳氨基乙酰基)-N-芳氨基乙酸β-葡萄糖酯和6种新的N-(N-乙酰基-N-芳氨基乙酰基)-N-芳氨基乙酸β-半乳糖酯。为合成目标分子还合成了21个中间体化合物,并通过IR、~1H NMR、MS及元素分析对中间体及目标分子进行了结构表征,利用谱学技术确证了目标分子的结构均为β-型异构体,并给出了相应的反应机理。对所合成的新型糖酯类化合物进行了抗肿瘤及抗高血压体外生物活性试验,初步生物活性实验结果表明,目标化合物对蛋白酪氨酸磷酸酶α(PTPα)有较弱的抑制活性,部分化合物化合物对α1A肾上腺素受体有极弱的激动活性。这一研究结果为进一步研究此类化合物的合成、生物活性的研究奠定了基础。
Carbohydrates are a kind of very important natural products. Glycobiology studies have shown that sugar participates in every process in all eukaryote, and their roles are complex and diverse. The development of the glycobiology has been revealed its important function in the process of the life. Carbohydrates are considered to have good application prospects in the anti-cancer, anti-inflammatory, anti-virus, diabetes treatment, immune regulation, immune vaccines, organ transplantation and other fields. These discoveries have been stimulated the interest of the academia and the pharmaceutical industry.
Sugar esters have wide applications in the pharmaceutical, food, daily cosmetics, chemical industry and other field. Among them, some sugar esters have many biological activities such as anti-tumor, sterilization, anti-high blood pressure, and can be used as angiotensin-converting enzyme (ACE) inhibitors, tumor metastasis inhibitors, and so on. Because a great amount of active compounds exist toxicity, negative impact on the environment and the characteristics of difficult absorption to biological tissue, it makes its use to have been limited. But if sugar structure is introduced into this molecular, this glycosylation molecular has good efficacy as precursor drug, which has been proved by the activity test. Therefore, the studies of the synthesis and properties on sugar esters have been a concerned topic. Peptide plays an important role in the biological body. It participates in a variety of metabolisms and regulations in the body. Since many peptide-based proteins have the outstanding importance in the process of the life, relative science and technology fields such as medicinal chemistry, molecular immunology, zoology, agriculture and food industry, require a large number of various structures of peptide analogues in order to study the relationship of the structure and activity. So far, seventeen ACE inhibitors have been commercialized, among them there are thirteen N-carboxyalkyl dipeptides
In this paper, thirteen novel sugar esters containing the peptide bond have been synthesized by the phase transfer catalysis, including seven new per-acetylatedβ-glucosyl N-(N-acetyl-N-arylglycyl)-N-aryglycines esters and six new per-acetylatedβ-galactosyl N-(N-acetyl-N-arylglycyl)-N-aryglycines esters. In order to synthesize the target compounds, twenty-one relative intermediate compounds were also synthesized. Their structures were characterized by IR, ~1H NMR, MS and elemental analysis. The configuration of the target molecules which areβ-type isomer have been confirmed by the spectroscopic techniques. The mechanism of the esterification reaction is given according to the result.
The results of the anti-tumor and anti-hypertensive tests in vitro show that the synthesized new sugar esters have weak inhibitory activity to the protein tyrosine phosphataseα(PTPα), partial sugar esters have weak exciting activity to theα1A adrenergic receptor. These results will be the foundation of the further study of the synthesis and biological activity for sugar ester compounds.
引文
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