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.

我们的工作位于合成有机化学领域，通常针对生物学上有趣的分子的合成，并且经常基于Organosulfur和-selenium Chemistry的新方面。我们的程序既包括发现新型合成有用的反应，又包括它们在特定目标结构中的应用。谷胱甘肽过氧化物酶（GPX）是一种硒酶，通过催化破坏有害的过氧化物，有氧代谢的副产物，可保护较高的生物体免受氧化应激，与炎症，心血管疾病和神经学疾病，诱变和其他有害条件有关。 GPX与三肽硫醇谷胱甘肽合作，在此过程中起牺牲性还原剂。我们正在设计和合成新型的小分子硒化合物，具有非同寻常的结构基序，这些基序模仿了酶的活性，我们正在研究它们起作用的机制。我们的主要目标是开发可保护心脏病发作和中风受害者免受心血管和神经系统损害的新颖化合物，这在缺血性再灌注期间发生（例如，用凝块破坏药物）。未来的工作将用于开发具有改进的催化活性，更大的水溶性和较慢的清除率的化合物的发展，这比我们早期的几种化合物所证明的。在任何氧化还原过程中，每次还原都会伴随着氧化。因此，在不同的情况下，我们的GPX Mimetics原则上可以用来用过氧化氢催化有机底物的氧化，这是一种廉价且环境良性的氧化剂。我们最近证明，我们的GPX Mimetics之一（循环硒酸酯）可以有效地催化几种合成有用的过程，通常在药品和细化的化学制造扇区中使用。我们的目标是提高我们的机械理解，以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化。在另一个项目中，正在开发基于不饱和硫酮的新型环化方案，该方案为各种构成生物碱和合成药用化合物中常见的结构基序提供了有效的新途径。例如，我们最近发现了一种Cu催化的交叉偶联反应，该反应提供了一种新的合成途径，这是来自苯胺和乙酰基硫酮的自然和医学中最有特权的化合物之一。这个过程可忍受空气和水的存在，不需要配体，并且使用稳定的Cu（II）盐，而不是惯常但更较少的空气稳定Cu（I）种。这些环化的应用在结构复杂的圆柱源生物碱的合成中，以及在许多具有心脏，镇痛和其他有用活动的生物碱（毒药）生物碱中的应用。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了巨大的痛苦，既是发达国家的死亡原因，又是经济责任。我们基于硒的抗氧化剂可以减少对此类患者的神经系统和心血管损伤。 （2）开发基于硒的新型氧化还原催化剂，用于实验室和工业中的重要性氧化过程，可以提供更便宜，更有效的替代方法。 （3）发现简洁的新合成方法论，用于制备各种氮杂环，这些方法是在有效，环境良性条件下许多药用化合物中的核心结构，这可能对药物，生物技术和精细的化学工业有利。