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Chemoenzymatic Synthesis And Molecular Probing Of Respiratory NADH Dehydrogenases
Complex I (NADH dehydrogenase) plays a central role in cellular energetics and is a major source of reactive oxygen species (ROS). It appears that tumour cells are closer to excessive ROS generation than healthy cells due to a more negative redox potential of the NAD(H) couple. Therefore, Complex I is an interesting target for differential drug design.
The most potent among the many structurally diverse inhibitors of Complex I are the annonaceous acetogenins, a large class of polyketide natural products isolated from the Annonaceae family of flowering plants. The typical structure of these compounds comprises of a (S)-5-methylbutenolide ring substituted at the 3-position with a long linear aliphatic chain incorporating often two tetrahydrofuran (THF) fragments (e.g. compounds 1, 2 and 3).
We envision that the bis-THF-bis-epoxides 4 can be synthesized stereo¬selectively from meso-epoxides 5 by biocatalytic hydrolysis, using a broad range of epoxide hydrolases from the collection hosted at the University of Graz.
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