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-2019-04373
• 负责人: Back, Thomas
• 金额: $ 3.5万
• 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: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=713907
• 关键词: Organic; Synthesis; Biologically; Interesting; Compounds

Our program is in the area of synthetic organic chemistry, generally directed toward biologically interesting molecules, with special emphasis on organosulfur/selenium compounds. More specifically, we are studying selenium redox chemistry, total synthesis of alkaloids and novel antiprotozoan agents. We discovered several highly effective compounds that mimic the antioxidant enzyme glutathione peroxidase (GPx) and are now working on improving their catalytic activity and elucidating their mechanisms. Such compounds complement GPx in catalytically reducing harmful peroxides and decreasing the high levels of oxidative stress that occur during reperfusion treatment of heart attacks/strokes, and in many other diseases and degenerative conditions. The “flip side” of redox chemistry of GPx mimetics is the catalysis of oxidations of organic substrates with hydrogen peroxide, a cheap, environmentally benign oxidant. Some of our novel GPx mimetics effectively catalyze several synthetically useful oxidations, such as epoxidations. Our objective is to improve our mechanistic understanding of these reactions, to expand their scope and to develop enantioselective variations. We engage in the total synthesis of alkaloids, partly because of their bioactivities but mainly for the wealth of new chemistry that is typically discovered during such endeavours. Our principal target is currently cylindricine C, a scarce marine alkaloid with an unusual tricyclic structure, and its congeners. A new approach to the design and synthesis of antiprotozoan drugs is based on the purine salvage pathway found in protozoa, but not in mammals. We have prepared a series of nucleoside-based antimetabolites that were tested against four pathogens by the Swiss Tropical Disease & Public Health Institute. We currently have lead compounds against malaria and leishmaniasis with nanomolar IC50 activities and remarkable therapeutic selectivities of 1010 and 2720, respectively, with respect to their relative toxicities to the pathogen and a mammalian cell line. The synthesis of new analogues, based on structure-activity relationships of those prepared to date, is continuing. These products will be tested for antiprotozoan activity by our collaborators in Switzerland. Potential benefits to Canada: 1) Heart attacks and strokes are a leading cause of death and an economic liability. Reducing neurological and cardiovascular damage from such events has obvious benefits. 2) Novel catalysts for oxidation processes are of importance in both the laboratory and industry in the preparation of e.g. pharmaceuticals and industrial chemicals. 3) New methods for the synthesis of alkaloids are often applicable to other nitrogen heterocycles, including core structures of many current drugs. 4) Internationally, protozoan diseases affect millions and cause hundreds of thousands of fatalities each year. Existing drugs are encountering resistant pathogens and there is an urgent need for new therapies.

我们的程序位于合成有机化学领域，通常针对生物学上有趣的分子，特别强调有机硫酸/硒化合物。更具体地说，我们正在研究硒氧化还原化学，生物碱的总合成和新型的抗壮气剂。 我们发现了几种模仿抗氧化剂谷胱甘肽过氧化物酶（GPX）的高效化合物，现在正在努力改善其催化活性并阐明其机制。这种化合物在催化降低有害的过氧化物中完全GPX，并降低了在心脏病/中风的再灌注治疗过程中发生的高水平氧化应激，以及许多其他疾病和退行性疾病。 GPX Mimetics的氧化还原化学的“另一面”是用过氧化氢（一种便宜的，环境良性的氧化物催化有机底物的氧化）。我们一些新颖的GPX Mimetics有效地催化了几种合成有用的氧化，例如环氧化。我们的目标是提高我们对这些反应的机械理解，扩大它们的范围并发展对映选择性变化。 我们从事生物碱的完全合成，部分原因是它们的生物活性，但主要是出于通常在此类努力中发现的新化学财富。我们的主要目标是目前的圆柱c，这是一种稀缺的海洋生物碱，具有不寻常的三根结构及其同类物。 一种新的抗植物药物设计和合成的方法是基于原生动物中发现的嘌呤挽救途径，但在哺乳动物中却没有。我们已经准备了一系列核基抗代谢物，这些反替代物由瑞士热带疾病与公共卫生研究所对四种病原体进行了测试。目前，对于纳摩尔IC50活性，针对疟疾和利什曼病的铅化合物分别具有1010和2720的显着治疗性选择性，其相对的毒性与病原体和哺乳动物细胞系有关。基于迄今为止准备的人的结构活性关系的新类比的综合正在继续。我们在瑞士的合作者将对这些产品进行抗逆转录活动的测试。 加拿大的潜在好处：1）心脏病发作和中风是死亡和经济责任的主要原因。减少此类事件的神经系统损害和心血管损伤具有明显的好处。 2）在制备例如药品和工业化学品。 3）生物碱合成的新方法通常适用于其他氮杂环，包括许多当前药物的核心结构。 4）在国际上，原生动物疾病会影响数百万，每年造成数十万死亡。现有药物正在遇到抗性病原体，迫切需要新疗法。