Organic Synthesis of Biologically Interesting Compounds and Organosulfur/Selenium Chemistry

生物感兴趣的化合物的有机合成和有机硫/硒化学

• 批准号: RGPIN-2014-06670
• 负责人: Back, Thomas
• 金额: $ 3.93万
• 依托单位: University of Calgary
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2017
• 资助国家: 加拿大
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=632800
• 关键词: Organic; Synthesis; Biologically; Interesting; Compounds

Our work is in the area of synthetic organic chemistry, generally directed toward the synthesis of biologically interesting molecules, and frequently based on novel aspects of organosulfur and -selenium chemistry. Our program includes both the discovery of novel synthetically useful reactions and their application to specific target structures. Glutathione peroxidase (GPx) is a selenoenzyme that protects higher organisms from oxidative stress by catalytically destroying harmful peroxides, byproducts of aerobic metabolism that are implicated in inflammation, cardiovascular and neurological disease, mutagenesis and other deleterious conditions. GPx works in concert with the tripeptide thiol glutathione, which functions as a sacrificial reductant in this process. We are designing and synthesizing novel small-molecule selenium compounds with unusual structural motifs that mimic the activity of the enzyme and we are investigating the mechanisms by which they function. Our principal objective is to develop novel compounds that could protect heart attack and stroke victims from cardiovascular and neurological damage, which occurs during ischemic reperfusion (e.g. with clot-busting drugs). Future work will be directed toward the development of compounds with improved catalytic activity, greater water-solubility and slower clearance than demonstrated by several of our earlier compounds. In any redox process, for every reduction there is an accompanying oxidation. Thus, in different circumstances, our GPx mimetics could, in principle, be used to catalyze the oxidation of organic substrates with hydrogen peroxide, a cheap and environmentally benign oxidant. We have recently demonstrated that one of our GPx mimetics (a cyclic seleninate ester) can effectively catalyze several synthetically useful processes, often employed in the pharmaceutical and fine chemical manufacturing sectors. Our objective is to improve our mechanistic understanding, to expand the scope of these reactions as broadly as possible and to develop enantioselective variations of these processes. In another project, novel cyclization protocols based on unsaturated sulfones are being developed that provide efficient new routes to a variety of nitrogen heterocycles that comprise structural motifs common in alkaloids and synthetic medicinal compounds. For example, we recently discovered a Cu-catalyzed cross-coupling reaction that provides a new synthetic route to indoles, one of the most privileged classes of compounds in nature and medicine, from anilines and acetylenic sulfones. This process tolerates the presence of air and water, requires no ligands and employs stable Cu(II) salts instead of the more customary, but less air-stable Cu(I) species. Applications of these cyclizations to the synthesis of the structurally complex cylindricine marine alkaloids and to dendrobatid (poison frog) alkaloids, many of which have cardiotonic, analgesic and other useful activities, are being investigated. This work provides potential health and economic benefits to Canada: (1) Heart attacks and strokes create considerable suffering and are both a leading cause of death and an economic liability in developed countries. Our selenium-based antioxidants could reduce neurological and cardiovascular damage to such patients. (2) Development of novel selenium-based redox catalysts for oxidation processes of importance in both the laboratory and in industry could provide cheaper and more efficient alternatives. (3) Discovery of concise new synthetic methodology for preparing diverse nitrogen heterocycles that are core structures in many medicinal compounds under efficient, environmentally benign conditions could be advantageous to the pharmaceutical, biotech and fine chemical industries.

我们的工作是在合成有机化学领域，一般针对生物有趣的分子的合成，并经常基于有机硫和硒化学的新方面。我们的计划包括发现新的合成有用的反应及其应用到特定的目标结构。谷胱甘肽过氧化物酶（GPx）是一种硒酶，通过催化破坏有害的过氧化物，有氧代谢的副产物，涉及炎症，心血管和神经疾病，诱变和其他有害条件，保护高等生物免受氧化应激。GPx与三肽巯基谷胱甘肽协同工作，后者在此过程中充当牺牲还原剂。我们正在设计和合成具有不寻常结构基序的新型小分子硒化合物，这些结构基序模仿酶的活性，我们正在研究它们发挥作用的机制。我们的主要目标是开发新的化合物，可以保护心脏病发作和中风患者免受缺血再灌注期间发生的心血管和神经损伤（例如使用血栓破坏药物）。未来的工作将致力于开发比我们早期的几种化合物具有更高的催化活性、更大的水溶性和更慢的清除率的化合物。在任何氧化还原过程中，每次还原都伴随着氧化。因此，在不同的情况下，我们的GPx模拟物原则上可以用于催化过氧化氢（一种廉价且环境友好的氧化剂）氧化有机底物。我们最近已经证明，我们的GPx模拟物之一（环状硒酸酯）可以有效地催化几种合成有用的过程，通常用于制药和精细化学品制造领域。我们的目标是提高我们的机械理解，扩大这些反应的范围尽可能广泛，并开发这些过程的对映选择性变化。在另一个项目中，正在开发基于不饱和砜的新型环化方案，这些方案为各种氮杂环提供了有效的新途径，这些氮杂环包含生物碱和合成药用化合物中常见的结构基序。例如，我们最近发现了一种铜催化的交叉偶联反应，该反应提供了一种新的合成路线，可以从苯胺和炔砜合成吲哚，吲哚是自然界和医学中最有特权的化合物之一。该方法耐受空气和水的存在，不需要配体，并且使用稳定的Cu（II）盐代替更常规的但空气稳定性较差的Cu（I）物质。这些环化的应用程序的结构复杂的cylindricine海洋生物碱的合成和dendrobatid（毒蛙）生物碱，其中许多具有强心，镇痛和其他有用的活动，正在调查。这项工作为加拿大提供了潜在的健康和经济利益：（1）心脏病发作和中风造成相当大的痛苦，是发达国家的主要死亡原因和经济负担。我们的硒基抗氧化剂可以减少此类患者的神经和心血管损伤。(2)开发新型硒基氧化还原催化剂用于实验室和工业中重要的氧化过程，可以提供更便宜和更有效的替代品。(3)在高效、环境友好的条件下，发现用于制备多种氮杂环的简洁的新合成方法，可以有利于制药、生物技术和精细化工行业。