Divergent Synthesis of Novel Cylindrocyclophanes that Inhibit Methicillin-ResistantStaphylococcus aureus(MRSA)

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 cylindr...

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Bibliographic Details
Published inChemMedChem Vol. 15; no. 14; pp. 1289 - 1293
Main Authors Freudenreich, Julien J., Bartlett, Sean, Robertson, Naomi S., Kidd, Sarah L., Forrest, Suzie, Sore, Hannah F., Galloway, Warren R. J. D., Welch, Martin, Spring, David R.
Format Journal Article
LanguageEnglish
Published WEINHEIM Wiley 20.07.2020
Subjects
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
cylindrocyclophane
FUNCTIONALIZATION
macrocycles
MEROCYCLOPHANES
BIOSYNTHESIS
cross metathesis
ring-closing metathesis
REVERSIBLE NATURE
DISCOVERY
(-)-CYLINDROCYCLOPHANE
CHALLENGES
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Summary: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-resistantStaphylococcus 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.
Bibliography:UKRI
ISSN:1860-7179
1860-7187
DOI:10.1002/cmdc.202000179