Program in the chemoenzymatic synthesis of alkaloids and medicinal agents and the development of new chiral building blocks, asymmetric protocols, and reagents

生物碱和药剂的化学酶合成以及新的手性构件、不对称方案和试剂的开发项目

• 批准号: RGPIN-2018-03723
• 负责人: Hudlicky, Tomas
• 金额: $ 5.76万
• 依托单位: Brock University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=692069
• 关键词: Program; chemoenzymatic; synthesis; alkaloids; medicinal

Our research program is focused on developing efficient manufacturing protocols for important medicinal compounds by environmentally friendly methods (green chemistry). The key component of the program is biocatalysis (or biotransformations) where we use special organisms (or isolated enzymes) to perform some chemical reactions in aqueous medium. We use these tools to make useful substances in fewer steps by a safer process that produces less hazardous waste.***Over the next five years our program will focus on the following:*** By means of biocatalysis, we will make new building blocks useful for other chemical reactions. We will also develop a new method for converting alkaloid components of the poppy plant to medicinally useful substances. Enzymes will be used to remove a methyl group from the nitrogen in the natural compounds, a process that is difficult to achieve by chemical methods. *** We will develop two new synthetic methods. (1) We will make carbasugars (structurally related to sugars, with a number of pharmaceutical applications) from some of the building blocks made by biocatalysis. (2) We will develop a short process for converting an ester to a methyl group.*** In the area of target-oriented synthesis, we will design and synthesize new derivatives of compounds naturally occurring in various plants in the amaryllis family and study their mode of action. Some that we have already made have anti-cancer properties. We will also embark on a new generation of syntheses of morphine-related substances, an area in which we have a lot of experience. *** Among other projects in our program, we will study the structureactivity relationship of pleiogenone, a substance with biological activity isolated from the bark of Burdekin plum trees and recently prepared. We will complete a formal total synthesis of tetrodotoxin, the potent neurotoxin from puffer fish, where we will make more efficiently a key intermediate used in another synthesis. We will use building blocks from our biocatalytic processes to make chiral polymers to use in materials and templates for catalysis. Another long-term goal is to design a catalyst as a chemical equivalent of the enzyme that is employed in our biocatalysis projects. ******Our research will contribute to the development of new replacement technology for traditional manufacturing of specialty chemicals and pharmaceutical agents through biological methods and the use of enzymes from bacteria, fungi, and plants. The research will provide excellent training for future chemistry professionals both in the pharmaceutical industry and in academia. The best means of training chemists is offered by projects in total synthesis where they are exposed to a full set of situations and challenges encountered in pharmaceutical industry. Collaborations that emerge during our research require team effort and meeting of timelines. Together, such training produces outstanding professionals.

我们的研究计划专注于通过环境友好的方法（绿色化学）为重要的药用化合物开发高效的生产方案。该计划的关键组成部分是生物催化（或生物转化），我们使用特殊的生物体（或分离的酶）在水介质中进行一些化学反应。我们使用这些工具，通过更安全的工艺，以更少的步骤生产有用的物质，从而产生更少的危险废物。*在接下来的五年里，我们的计划将集中在以下方面：* 通过生物催化，我们将为其他化学反应提供新的构建模块。我们还将开发一种新的方法，将罂粟植物的生物碱成分转化为药用物质。酶将被用来去除天然化合物中氮的甲基，这是一个难以通过化学方法实现的过程。* 我们将开发两种新的合成方法。(1)我们将从生物催化产生的一些积木中制造卡巴糖（结构上与糖相关，具有许多制药应用）。(2)我们将开发一种将酯转化为甲基的短过程。***在目标导向合成领域，我们将设计和合成天然存在于孤挺花科各种植物中的化合物的新衍生物，并研究其作用方式。我们已经制造的一些具有抗癌特性。我们还将着手进行新一代的吗啡相关物质的合成，我们在这一领域有着丰富的经验。* 在我们计划的其他项目中，我们将研究pleiogenone的结构反应关系，这是一种从Burdekin李子树的树皮中分离出来的具有生物活性的物质，最近制备出来。我们将完成河豚毒素的正式全合成，河豚毒素是一种来自河豚的强效神经毒素，在那里我们将更有效地制造另一种合成中使用的关键中间体。我们将使用生物催化过程中的构建模块来制造手性聚合物，用于催化材料和模板。另一个长期目标是设计一种催化剂，作为我们生物催化项目中使用的酶的化学等价物。** 我们的研究将有助于开发新的替代技术，通过生物方法和使用来自细菌，真菌和植物的酶来替代传统的特种化学品和药剂制造。该研究将为制药行业和学术界未来的化学专业人员提供良好的培训。培训化学家的最佳方式是通过全合成项目提供的，在那里他们接触到制药行业遇到的全套情况和挑战。在我们的研究过程中出现的合作需要团队的努力和时间表的会议。这样的培训共同造就了杰出的专业人才。