Natural products: biosynthesis, biomimetic synthesis and mechanism of action

天然产物对我们所有人的生活都有巨大的影响：它们包括或构成了许多抗生素、降胆固醇的他汀类药物、免疫抑制剂和其他目前使用的治疗药物的基础。我们的研究计划旨在了解这些小的有机化合物是如何由生产生物，无论是细菌，真菌还是植物产生的。了解这些代谢物在体内的组装不仅有助于控制药物生产，而且还有望创造自然界中以前没有发现的新结构：这些有可能成为未来的药物。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。我们的项目旨在从自然组装过程中学习如何进行更有效的化学反应。因此，我们开发了一种新的方法，允许脂肪酸和聚酮类天然产物通过遵循自然界发生的相同事件序列在试管中组装。我们正在发展这种方法用于聚酮结构的一般合成。在另一个领域，我们正在模仿自然形成的-内酯天然产物；这些都是青霉素类抗生素的近亲。我们实验室正在探索的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是如何起作用的；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，这是癌症化疗中一个非常有趣的领域。另一类，β -内酯类，正在研究作为新型抗真菌药物；由于耐药真菌菌株的发展，对改进抗真菌药物的需求很大。我们在麦克马斯特大学的合作者已经确定了一种新的细胞攻击目标，这是一个很有希望的结果，因为当新的细胞途径被靶向时，抵抗是罕见的。我们正在提供天然产品和类似物来灭活这个目标。

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.