Divergent Synthesis of Novel Cylindrocyclophanes that Inhibit Methicillin-Resistant Staphylococcus aureus (MRSA) |
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| Authors: | Dr Julien J Freudenreich Dr Sean Bartlett Dr Naomi S Robertson Dr Sarah L Kidd Dr Suzie Forrest Dr Hannah F Sore Dr Warren R J D Galloway Dr Martin Welch Prof David R Spring |
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| Affiliation: | 1. Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW UK;2. Department of Biochemistry, University of Cambridge, Downing Site, Cambridge, CB2 1QW UK |
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| Abstract: | 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. |
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| Keywords: | cross metathesis cylindrocyclophane macrocycles ring-closing metathesis |
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