Towards new antibiotics targeting bacterial transglycosylase: Synthesis of a Lipid II analog as stable transition-state mimic inhibitor |
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Authors: | Xiaolei Wang Larissa Krasnova Kevin Binchia Wu Wei-Shen Wu Ting-Jen Cheng Chi-Huey Wong |
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Affiliation: | 1. The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92122, USA;2. Genomics Research Center, Academia Sinica, 128 Sec 2 Academia Road, Taipei, Nankang 115, Taiwan |
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Abstract: | Described here is the asymmetric synthesis of iminosugar 2b, a Lipid II analog, designed to mimic the transition state of transglycosylation catalyzed by the bacterial transglycosylase. The high density of functional groups, together with a rich stereochemistry, represents an extraordinary challenge for chemical synthesis. The key 2,6-anti- stereochemistry of the iminosugar ring was established through an iridium-catalyzed asymmetric allylic amination. The developed synthetic route is suitable for the synthesis of focused libraries to enable the structure–activity relationship study and late-stage modification of iminosugar scaffold with variable lipid, peptide and sugar substituents. Compound 2b showed 70% inhibition of transglycosylase from Acinetobacter baumannii, providing a basis for further improvement. |
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Keywords: | Iminosugar Inhibitor Lipid II Transglycosylase Synthesis |
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