Natural products: biosynthesis, biomimetic synthesis and mechanism of action

天然产物：生物合成、仿生合成及作用机制

• 批准号: 92423-2007
• 负责人: Harrison, Paul
• 金额: $ 3.13万
• 依托单位: McMaster University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2011
• 资助国家: 加拿大
• 起止时间: 2011-01-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=475214
• 关键词: Natural; products; biosynthesis; biomimetic; synthesis

Natural products have an enormous impact on all of our lives: they include, or form the basis of, many of the antibiotics, cholesterol-lowering statins, immunosuppressants, and other therapeutic agents in use today. Our research program aims to understand how these small organic compounds are made by the producing organisms, be they bacteria, fungi, or plants. Knowledge of the assembly of these metabolites in vivo aids not only in the control of pharmaceutical production, but also holds promise for creating new structures not found before in nature: these have potential as the drugs of tomorrow. Another important aspect of generating novel chemical entities as potential drugs is to explore their chemical synthesis. Our program aims to learn from the natural assembly process how to perform more effective chemistry. Thus, we have developed a novel method that allows the fatty acid and polyketide classes of natural products to be assembled in the test tube by following the same sequence of events that occurs in nature. We are developing this method for the general synthesis of polyketide structures. In another area, we are mimicking the natural formation of beta-lactone natural products; these are relatives of the penicillin antibiotics. A third aspect of natural products that is also being explored in our lab is the mode of action of these compounds. We are exploring how two classes of compound work; understanding this mechanism of action will allow the development of better drugs. One class of compound induces apoptosis, i.e. programmed cell death, an area of enormous interest in cancer chemotherapy. The other class, the beta-lactones, is being investigated as novel anti-fungal agents; there is a great need for improved anti-fungal drugs due to the development of drug-resistant fungal strains. Our collaborator at McMaster has identified a novel cellular target for attack, a promising result since resistance is rare when new cellular pathways are targeted. We are providing the natural products and analogues to inactivate this target.

天然产品对我们所有人的生活产生了巨大的影响：它们包括或构成了许多抗生素，降胆固醇他汀类药物，免疫抑制剂和今天使用的其他治疗药物的基础。 我们的研究项目旨在了解这些小的有机化合物是如何由生产生物体，无论是细菌，真菌还是植物。 这些代谢物在体内组装的知识不仅有助于控制药物生产，而且还有望创造出以前在自然界中未发现的新结构：这些结构具有作为未来药物的潜力。 产生作为潜在药物的新化学实体的另一个重要方面是探索它们的化学合成。 我们的计划旨在从自然组装过程中学习如何进行更有效的化学。 因此，我们开发了一种新的方法，该方法允许天然产物的脂肪酸和聚酮化合物类通过遵循自然界中发生的相同事件序列在试管中组装。 我们正在开发这种方法的聚酮化合物结构的一般合成。 在另一个领域，我们正在模仿β-内酯天然产物的自然形成;这些是青霉素抗生素的亲戚。我们实验室也在探索天然产物的第三个方面是这些化合物的作用方式。 我们正在探索两类化合物的工作原理;了解这种作用机制将有助于开发更好的药物。 一类化合物诱导细胞凋亡，即程序性细胞死亡，这是癌症化疗中非常感兴趣的领域。 另一类，β-内酯，正在研究作为新的抗真菌剂;由于耐药真菌菌株的发展，非常需要改进的抗真菌药物。 我们在麦克马斯特的合作者已经确定了一种新的细胞攻击目标，这是一个有希望的结果，因为当新的细胞通路被靶向时，抗性是罕见的。 我们正在提供天然产品和类似物来实现这一目标。