Breiner Logan M, Slowinski Roman P, Lowell Andrew N
Department of Chemistry, Virginia Polytechnic Institute and State University (Virginia Tech), Blacksburg, Virginia 24061, United States.
Center for Emerging, Zoonotic, and Arthropod-borne Pathogens, Virginia Polytechnic Institute and State University (Virginia Tech), Blacksburg, Virginia 24061, United States.
J Org Chem. 2025 Jan 10;90(1):919-924. doi: 10.1021/acs.joc.4c02683. Epub 2024 Dec 18.
The semisynthetic derivatization of natural products is crucial for their continued development as antibiotics. While commercial pleuromutilin derivatives depend on amines for solubility, we demonstrate the high activity and solubility of oligoethylene glycol-substituted pleuromutilins achieved via a one-pot deprotection/attachment approach using thiolates protected as thioesters. The bifunctional linker synthesis is versatile and can be broadly applied to other chemistries. Antibacterial assays revealed this simple glycolate modification enhanced inhibition 4-8-fold relative to that of pleuromutilin. A new microscale solubility method is also introduced.
天然产物的半合成衍生化对于其作为抗生素的持续发展至关重要。虽然市售截短侧耳素衍生物依靠胺类来提高溶解度，但我们证明了通过使用被保护为硫酯的硫醇盐的一锅法脱保护/连接方法所获得的低聚乙二醇取代截短侧耳素具有高活性和溶解性。双功能连接子的合成具有通用性，可广泛应用于其他化学领域。抗菌试验表明，这种简单的乙醇酸修饰使抑制作用相对于截短侧耳素增强了4至8倍。还引入了一种新的微量溶解度方法。
