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，通常是针对生物感兴趣的分子的合成，并且经常基于有机硫和硒化学的新方面。我们的计划既包括发现新的合成有用的反应，也包括将它们应用于特定的目标结构。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酶来保护高等生物免受氧化应激的伤害。有氧代谢的副产物与炎症、心血管和神经疾病、突变和其他有害条件有关。GPX与三肽硫醇谷胱甘肽协同工作，后者在这一过程中起到牺牲还原剂的作用。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，以模拟酶的活性，我们正在研究它们的作用机制。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心血管和神经损伤，这种损伤发生在缺血再灌注期间(例如，使用溶栓药物)。未来的工作将致力于开发比我们以前的几种化合物更好的催化活性、更大的水溶性和更慢的清除速度的化合物。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来催化过氧化氢氧化有机底物，过氧化氢是一种廉价且对环境友好的氧化剂。我们最近证明，我们的一种GPX模拟物(一种环硒酸酯)可以有效地催化几个合成有用的过程，通常用于制药和精细化工制造部门。我们的目标是提高我们对机理的理解，尽可能广泛地扩大这些反应的范围，并开发这些过程的对映选择性变体。在另一个项目中，正在开发基于不饱和磺酸的新型环化方案，这些方案提供了各种氮杂环的有效新路线，这些氮杂环包含生物碱和合成药物中常见的结构基元。例如，我们最近发现了一种铜催化的交叉偶联反应，它提供了一条从苯胺和乙酰砜合成吲哚的新路线，吲哚是自然界和医药中最有特权的化合物之一。这个过程可以容忍空气和水的存在，不需要配体，并且使用稳定的铜(II)盐来代替更常见的、但空气不太稳定的铜(I)物种。这些环化反应在合成结构复杂的圆柱状海洋生物碱和毒蛙生物碱方面的应用正在被研究中，其中许多生物碱具有强心、止痛和其他有用的活性。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，在发达国家既是主要的死亡原因，也是一种经济负担。我们的基于硒的抗氧化剂可以减少对这类患者的神经和心血管损害。(2)为实验室和工业上重要的氧化过程开发新型的硒基氧化还原催化剂可以提供更便宜和更有效的替代方案。(3)发现简明的新的合成方法，在高效、环境友好的条件下制备作为许多药物核心结构的各种氮杂环，可能对制药、生物技术和精细化学工业有利。