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: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=654038
• 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 structure–activity 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.

我们的研究计划的重点是通过环保方法（绿色化学）为重要的药用化合物开发有效的制造方案。该程序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（或分离的酶）在水性培养基中进行一些化学反应。我们使用这些工具通过一个安全的过程来制造有用的物质，从​​而使危险浪费较小。***在接下来的五年中，我们的计划将重点介绍以下内容：***•通过生物催化，我们将使我们的新构件对其他化学反应有用。我们还将开发一种将罂粟植物的生物碱成分转换为有用的物质的新方法。酶将用于从天然化合物中的氮中去除甲基，这一过程很难通过化学方法实现。 ***•我们将开发两种新的合成方法。 （1）我们将从生物催化制造的一些构件中制造卡巴斯格（与糖结构相关，并具有许多药物应用）。 （2）我们将开发一个简短的过程，将酯转化为甲基。***•在目标综合的区域中，我们将设计和合成在Amaryllis家族中各种植物中自然发生的化合物的新衍生物，并研究其作用方式。我们已经制作的一些具有抗癌特性。我们还将踏上新一代与吗啡相关物质的合成，这是我们有很多经验的领域。 ***•在我们计划中的其他项目中，我们将研究吡酮酮的结构 - 活性关系，吡酮酮是一种从Burdekin Plum树皮中分离出来的生物活性的物质，并最近准备。我们将完成对四毒素的形式总合成，即河豚鱼的潜在神经毒素，在这里我们将更有效地成为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块使手性聚合物用于催化剂的材料和模板中。另一个长期目标是将催化剂设计为我们生物催化项目中使用的酶的化学品。 *****我们的研究将通过生物学方法以及使用细菌，真菌和植物的酶来开发新的替代技术，以开发新的替代技术，用于传统的特种化学品和药品制造。这项研究将为制药行业和学术界的未来化学专业人员提供出色的培训。培训化学家的最佳手段是由整体综合项目提供的，即他们面临制药行业遇到的全套情况和挑战。在我们的研究期间出现的合作需要团队努力和时间表的会议。这样的培训共同创造出色的专业人士。