Design and preparation of serine–threonine protein phosphatase inhibitors based upon the nodularin and microcystin toxin structures: Part 2.1 Synthesis of a functionalised nodularin macrocycle and a stripped-down microcystin macrocycle

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Antony B. Maude, Amit P. Mehrotra and David Gani


Abstract

Nodularins and microcystins are complex natural isopeptidic hepatotoxins that serve as subnanomolar inhibitors of the eukaryotic serine–threonine protein phosphatases, PP1 and PP2A. In Part 1 (A. P. Mehrotra, K. L. Webster and D. Gani, J. Chem. Soc., Perkin Trans. 1, 1997, preceding paper) each of the key structural or potentially reactive motifs within each macrocycle type was assessed as a contributor towards phosphatase inhibitory efficacy and a stripped-down nodularin-type macrocycle was identified as a suitable precursor to potentially active synthetic inhibitors. Subsequently, synthetic routes to the 19-membered nodularin macrocyclic system were developed, using solution-phase chemistry, which demonstrated that only certain cyclisation protocols were viable. Here we describe an extension of this chemistry to provide a 19-membered nodularin macrocycle, cyclo-[(3R)-3-hydroxymethyl-β-Ala-( R)-Glu-α-OMe-γ-Sar-(R)-Asp- α-OMe-β-(S[hair space])-Phe-], appropriately functionalised with a hydroxymethyl group for the incorporation of lipophilic side-chains. We also demonstrate that the 25-membered microcystin macrocycle, cyclo-[β-Ala-(R)-Glu-α- OMe-γ-Sar-(R)-Ala-(S[hair space])-Leu-( R)-Asp-α-OMe-β-(S[hair space])- Phe-], can be prepared in good yield using similar protocols in which macrocyclisation is effected through the reaction of the amino group of the (2S[hair space])-phenylalanine residue with the β-pentafluorophenyl ester of the (2R)-aspartic acid residue.


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