Synthesis And Biochemistry Of Ascorbic Acid Analogues

抗坏血酸类似物的合成与生物化学

• 批准号: 6983851
• 负责人: KENNETH L KIRK
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6983851
• 关键词: ascorbate; biochemistry; biological transport; carbopolycyclic compound; chemical kinetics; chemical structure function; chemical synthesis; flavonoids; glucose transport; intermolecular interaction; nutrition related tag; radiotracer; transport inhibitor; vitamin analog; vitamin metabolism

Ascorbic acid (vitamin C), a dietary requirement for human health, is an electron donor for several enzymatic actions, functions as an antioxidant, and is implicated in host defense mechanisms, endocrine function and the visual process (lens). Recent renewed interest in the biochemistry of ascorbic acid has been prompted by the realization that relatively little is known concerning the concentrations of the vitamin required for optimum functioning of these several roles. In the case of enzymatic reactions, optimal rate of a process is defined as that concentration that allows the reaction to reach Vmax without toxicity. As part of a program to determine these concentrations, in situ kinetic measurements have been carried out for certain vitamin C-linked reactions. In addition to examination of functional roles of vitamin C, recent characterization of efficient transport mechanisms that translocate vitamin C across cellular membranes has emphasized the importance of the vitamin to biological processes. In previous work, we synthesized radiolabelled 6-deoxy-6-iodoascorbic acid as a tool for studying additional details of the ascorbic acid transport system. Transport studies indicate this will be a useful tool in attempts to isolate the ascorbic acid transport protein. To investigate the importance of the 2-hydroxyl group on ascorbic acid activity, we also previously prepared 2-deoxy-ascorbic acid, and 2-deoxy-2-halo ascorbic acids, including 2-deoxy-2-fluoroascorbic acid, an isosteric and isopolar, non-oxidizable, analogue. In addition, the cyclic hemiketal form of 2,2-difluoro-2-deoxyascorbic acid also was prepared, a structure that corresponds to the cyclic hemiketal form of dehydroascrobic acid. Experiments with 6-bromo-6-deoxyascorbic acid have revealed that the oxidized form (6-bromo-deoxyascorbic acid) is not transported by the glucose trasporter that translocates deoxyascorbic acid itself. On the other hand, we had shown previously that 6-bromo-6-ascorbic acid is transported by the ascorbic acid transport protein. A working hypothesis is that it is the cyclic ketal form of dehydroascorbic acid that is recognized by the trasmprot protein. It is impossible for oxidized 6-bromo-6-deoxyascorbic acid to form such a cyclic ketal. In a new approach to the study of ascorbic acid glucose transport, we are preparing new flavonoid analogues to study sturtural parameters of these inhibitors of ascorbate and glucose transport. Inculded will be potential affinity labels for the transport protein(s). Effects of fluorine substitution biolgical begavior of the flavonoids also will be examined. A series of fluorinated chalcones have been prepared and will be cyclized under conditions that produce the flavonoid structures.

抗坏血酸(维生素C)是人类健康所必需的饮食，是几种酶作用的电子供体，具有抗氧化剂的功能，并与宿主防御机制、内分泌功能和视觉过程(晶状体)有关。最近，人们对抗坏血酸的生物化学重新产生了兴趣，因为人们意识到，人们对这几个角色发挥最佳作用所需的维生素浓度知之甚少。在酶反应的情况下，过程的最佳速率被定义为允许反应达到Vmax而没有毒性的浓度。作为确定这些浓度的计划的一部分，已经对某些与维生素C相关的反应进行了原位动力学测量。除了研究维生素C的功能作用外，最近对通过细胞膜转运维生素C的有效运输机制的表征强调了维生素在生物过程中的重要性。在以前的工作中，我们合成了放射性标记的6-脱氧-6-碘抗坏血酸，作为研究抗坏血酸运输系统的额外细节的工具。运输研究表明，这将是分离抗坏血酸运输蛋白的有用工具。为了研究2-羟基对抗坏血酸活性的重要性，我们还制备了2-脱氧-抗坏血酸和2-脱氧-2-卤代抗坏血酸，包括2-脱氧-2-氟抗坏血酸，一种等位、等极、不可氧化的类似物。此外，还制备了2，2-二氟-2-脱氧抗坏血酸的环半酮式抗坏血酸，其结构与脱氢抗坏血酸的环半酮式相对应。 6-溴-6-脱氧抗坏血酸的实验表明，氧化形式(6-溴-脱氧抗坏血酸)不是由转运脱氧抗坏血酸的葡萄糖转运蛋白运输的。另一方面，我们之前已经证明了6-溴-6-抗坏血酸是由抗坏血酸运输蛋白运输的。一种工作假说是脱氢抗坏血酸的环缩酮形式被trasmprot蛋白识别。氧化的6-溴-6-脱氧抗坏血酸不可能形成这样的环缩酮。 在研究抗坏血酸葡萄糖转运的新方法中，我们正在制备新的类黄酮类类似物来研究这些抗坏血酸和葡萄糖转运抑制剂的结构参数。被包含的将是运输蛋白的潜在亲和标记(S)。此外，还将考察类黄酮类化合物的氟代换生物效应。一系列氟化查尔酮已经被制备出来，并将在产生类黄酮结构的条件下进行环化。