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: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=747768
• 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.

我们的计划是在合成有机化学领域，一般针对生物有趣的分子，特别强调有机硫/硒化合物。更具体地说，我们正在研究硒氧化还原化学，生物碱和新的抗原动物剂的全合成。 我们发现了几种模仿抗氧化酶谷胱甘肽过氧化物酶（GPx）的高效化合物，现在正在努力提高其催化活性并阐明其机制。这些化合物在催化还原有害过氧化物和降低在心脏病发作/中风的再灌注治疗期间以及在许多其他疾病和退行性病症中发生的高水平氧化应激方面补充GPx。 GPx模拟物的氧化还原化学的“另一面”是用过氧化氢（一种廉价的环境友好的氧化剂）催化有机底物的氧化。我们的一些新的GPx模拟物有效地催化几种合成有用的氧化，如环氧化。我们的目标是提高我们对这些反应的机械理解，扩大其范围，并开发对映选择性的变化。 我们从事生物碱的全合成，部分原因是它们的生物活性，但主要是因为在这种努力中通常会发现丰富的新化学。我们目前的主要目标是柱孢菌素C，一种稀有的海洋生物碱，具有不寻常的三环结构，及其同系物。 抗原生动物药物设计和合成的一种新方法是基于原生动物中发现的嘌呤补救途径，但不是哺乳动物中的。我们已经准备了一系列基于核苷的抗代谢物，并由瑞士热带疾病和公共卫生研究所对四种病原体进行了测试。我们目前有针对疟疾和利什曼病的先导化合物，其纳摩尔IC 50活性和显着的治疗选择性分别为1010和2720，就其对病原体和哺乳动物细胞系的相对毒性而言。根据迄今为止所制备的类似物的结构-活性关系，合成新的类似物的工作仍在继续。这些产品将由我们在瑞士的合作者进行抗原动物活性测试。 对加拿大的潜在好处：1）心脏病发作和中风是死亡的主要原因和经济负担。减少此类事件对神经和心血管的损害有明显的好处。2)用于氧化过程的新型催化剂在实验室和工业中例如在药物和工业化学品的制备中都是重要的。3)合成生物碱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，原生动物疾病每年影响数百万人并导致数十万人死亡。现有的药物正在遭遇耐药病原体，迫切需要新的治疗方法。