Department of Chemistry , Vanderbilt University , Nashville , Tennessee 37235 , United States.
J Med Chem. 2019 Sep 26;62(18):8412-8428. doi: 10.1021/acs.jmedchem.9b00246. Epub 2019 Apr 26.
Molecules isolated from natural sources including bacteria, fungi, and plants are a long-standing source of therapeutics that continue to add to our medicinal arsenal today. Despite their potency and prominence in the clinic, complex natural products often exhibit a number of liabilities that hinder their development as therapeutics, which may be partially responsible for the current trend away from natural product discovery, research, and development. However, advances in synthetic biology and organic synthesis have inspired a new generation of natural product chemists to tackle powerful undeveloped scaffolds. In this Perspective, we will present case studies demonstrating the historical and current focus on making targeted, but significant, changes to natural product scaffolds via biosynthetic gene cluster manipulation, total synthesis, semisynthesis, or a combination of these methods, with a focus on increasing activity, decreasing toxicity, or improving chemical and pharmacological properties.
从细菌、真菌和植物等天然来源中分离出的分子是治疗药物的长期来源，这些药物至今仍在不断丰富我们的药物库。尽管这些复杂的天然产物在临床上具有强大的功效和重要地位，但它们往往存在多种缺陷，这阻碍了它们作为治疗药物的发展，这可能是导致目前人们对天然产物的发现、研究和开发的兴趣减弱的部分原因。然而，合成生物学和有机合成的进步激发了新一代天然产物化学家去攻克那些具有强大但尚未开发的骨架的天然产物。在本观点中，我们将展示一些案例研究，这些研究通过生物合成基因簇操作、全合成、半合成或这些方法的组合，有针对性地但显著地改变天然产物骨架，重点是提高活性、降低毒性或改善化学和药理学性质，展示了历史和当前的研究重点。
