Matthijs
MatthijsPhD Student
09/2011 – present
Room: WN-N357
Lab: WN-KA395
Phone: +31 (0)20 59 87481
E-mail: m.j.van.lint@vu.nl

Acetogenins:

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).[1] 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.[2] Therefore, Complex I is an interesting target for differential drug design.[3]

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.[4] 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).

1

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.[5]

[1] Lenaz et al., Biochim Biophys Acta 2009, 1787, 384–392
[2] Manda et al., Curr. Chem. Biol. 2009, 3, 342-366
[3] Westerhoff, Systems Biology: New Paradigms for Cell Biology and Drug Design, Springer Berlin Heidelberg, 2007, 45-67. Print
[4] McLaughlin, J. Nat. Prod. 1999, 62, 504-540
[5] Faber et al. Eur. J. Org. Chem. 2001, 4537-4542