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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
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
)-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)-Leu-(
R)-Asp-α-OMe-β-(S)-
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)-phenylalanine residue with the
β-pentafluorophenyl ester of the (2R)-aspartic
acid residue.
)-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)-Leu-(
R)-Asp-α-OMe-β-(S)-
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)-phenylalanine residue with the
β-pentafluorophenyl ester of the (2R)-aspartic
acid residue.
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