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，通常指向合成生物学上有趣的分子，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和它们在特定目标结构上的应用。谷胱甘肽过氧化物酶（GPx）是一种硒酶，通过催化破坏有害过氧化物来保护高等生物免受氧化应激，有害过氧化物是有氧代谢的副产物，与炎症、心血管和神经疾病、诱变和其他有害疾病有关。GPx与三肽硫醇谷胱甘肽协同作用，在此过程中充当牺牲还原剂。我们正在设计和合成具有不同寻常结构基序的新型小分子硒化合物，以模仿酶的活性，我们正在研究它们起作用的机制。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性再灌注期间发生的心血管和神经损伤（例如使用溶栓药物）。未来的工作将是开发具有更好的催化活性、更大的水溶性和更慢的清除速度的化合物，而不是我们早期的几种化合物。在任何氧化还原过程中，每一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氧化有机底物，过氧化氢是一种廉价且对环境无害的氧化剂。我们最近证明了我们的一种GPx模拟物（环硒酸酯）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，尽可能广泛地扩展这些反应的范围，并开发这些过程的对映选择性变化。在另一个项目中，基于不饱和砜的新型环化方案正在开发中，为各种含生物碱和合成药物化合物中常见结构基序的氮杂环提供了有效的新途径。例如，我们最近发现了一种铜催化的交叉偶联反应，为苯胺和乙基砜合成吲哚提供了一种新的合成途径，吲哚是自然界和医学上最优越的化合物之一。这个过程可以忍受空气和水的存在，不需要配体，并且使用稳定的Cu（II）盐代替更习惯的，但不太稳定的Cu(I)物种。目前正在研究这些环化在合成结构复杂的圆柱碱海洋生物碱和毒蛙生物碱中的应用，其中许多生物碱具有强心、镇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，是发达国家的主要死亡原因和经济负担。我们以硒为基础的抗氧化剂可以减少对这类患者的神经和心血管损害。(2)新型硒基氧化还原催化剂的开发在实验室和工业中都具有重要意义，可以提供更便宜和更有效的替代方案。(3)在高效、环保的条件下，发现简洁的新合成方法来制备多种氮杂环，这些氮杂环是许多药用化合物的核心结构，对制药、生物技术和精细化工行业都是有利的。