State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, 510632, P. R. China.
Center for Bioactive Natural Molecules and Innovative Drugs, and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, P. R. China.
Nat Commun. 2024 Jul 13;15(1):5879. doi: 10.1038/s41467-024-49629-8.
The development of new antibiotics continues to pose challenges, particularly considering the growing threat of multidrug-resistant Staphylococcus aureus. Structurally diverse natural products provide a promising source of antibiotics. Herein, we outline a concise approach for the collective asymmetric total synthesis of polycyclic xanthene myrtucommulone D and five related congeners. The strategy involves rapid assembly of the challenging benzopyrano[2,3-a]xanthene core, highly diastereoselective establishment of three contiguous stereocenters through a retro-hemiketalization/double Michael cascade reaction, and a Mitsunobu-mediated chiral resolution approach with high optical purity and broad substrate scope. Quantum mechanical calculations provide insight into stereoselective construction mechanism of the three contiguous stereocenters. Additionally, this work leads to the discovery of an antibacterial agent against both drug-sensitive and drug-resistant S. aureus. This compound operates through a unique mechanism that promotes bacterial autolysis by activating the two-component sensory histidine kinase WalK. Our research holds potential for future antibacterial drug development.
新抗生素的开发仍然面临挑战，特别是考虑到耐多药金黄色葡萄球菌的威胁日益增加。结构多样的天然产物为抗生素提供了有希望的来源。在此，我们概述了一种简洁的方法，用于多环蒽酮 myrtucommulone D 和五个相关同系物的集体不对称全合成。该策略涉及通过反-半缩醛/双迈克尔级联反应快速组装具有挑战性的苯并[2,3-a]蒽酮核心，高度非对映选择性地建立三个连续的立体中心，以及通过 Mitsunobu 介导的手性拆分方法获得高光学纯度和广泛的底物范围。量子力学计算提供了对三个连续立体中心立体选择性构建机制的深入了解。此外，这项工作导致发现了一种对抗敏感和耐药金黄色葡萄球菌的抗菌剂。该化合物通过激活双组分感应组氨酸激酶 WalK 来促进细菌自溶，从而发挥独特的作用。我们的研究为未来的抗菌药物开发提供了潜力。
