Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
Department of Biochemistry, University of Cambridge, Downing Site, Cambridge, CB2 1QW, UK.
ChemMedChem. 2020 Jul 20;15(14):1289-1293. doi: 10.1002/cmdc.202000179. Epub 2020 Jun 12.
The cylindrocyclophanes are a family of macrocyclic natural products reported to exhibit antibacterial activity. Little is known about the structural basis of this activity due to the challenges associated with their synthesis or isolation. We hypothesised that structural modification of the cylindrocyclophane scaffold could streamline their synthesis without significant loss of activity. Herein, we report a divergent synthesis of the cylindrocyclophane core enabling access to symmetrical macrocycles by means of a catalytic, domino cross-metathesis-ring-closing metathesis cascade, followed by late-stage diversification. Phenotypic screening identified several novel inhibitors of methicillin-resistant Staphylococcus aureus. The most potent inhibitor has a unique tetrabrominated [7,7]paracyclophane core with no known counterpart in nature. Together these illustrate the potential of divergent synthesis using catalysis and unbiased screening methods in modern antibacterial discovery.
筒环芳烃是一类具有报道抗菌活性的大环天然产物。由于其合成或分离的挑战性，对其活性的结构基础知之甚少。我们假设对筒环芳烃支架的结构修饰可以简化其合成，而不会显著降低其活性。在此，我们报告了一种筒环芳烃核心的发散合成方法，通过催化的、串联的交叉复分解-关环复分解级联反应，以获得对称的大环，然后进行后期的多样化。表型筛选鉴定出几种新型耐甲氧西林金黄色葡萄球菌抑制剂。最有效的抑制剂具有独特的四溴化[7,7]并环芳烃核心，在自然界中没有已知的对应物。这些共同说明了在现代抗菌药物发现中使用催化和无偏筛选方法进行发散合成的潜力。
