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Issue 17, 1997
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Design and preparation of serine–threonine protein phosphatase inhibitors based upon the nodularin and microcystin toxin structures: Part 1. Evaluation of key inhibitory features and synthesis of a rationally stripped-down nodularin macrocycle

Abstract

The natural nodularin and microcystin toxins are powerful but non-selective inhibitors of the ubiquitous and structurally related eukaryotic Ser-Thr protein phosphatases, PP1 and PP2A, enzymes that are intimately involved in controlling cellular metabolism. Both families of toxin are cyclic tri-isopeptides typified by the presence of two free carboxylic acid groups, a dehydroamino acid moiety, and a large, rigid exocyclic lipophilic side-chain. To learn how to design specific inhibitors for each enzyme, the nature of specific interactions with potential inhibitor-conferring moieties in the toxin was considered. Borohydride reduction of the dehydroalanine residue present in microcystin-LR, a potential Michael acceptor, gave two diastereoisomeric dihydromicrocystin products. Each of these displayed subnanomolar activities as inhibitors for PP2A, as for the parent compound, indicating that the dehydroamino acid residue in microcystin and, probably, in nodularin, is not essential for activity. Other conserved features appeared to be required to confer activity, hence strategies towards the synthesis of simplified non-dehydroamino acid- containing analogues of each macrocycle type were considered. In each case it was planned to elaborate the lipophilic side-chain functionality after the formation of the macrocyclic ring. In order to synthesize the precursor nodularin-type macrolactam, two peptide-bond disconnections of the ring were investigated using a model system, cyclo-[β-Ala-(R)-Glu-α- OMe-γ-Sar-(R)-Asp-α-OMe- β-(S)-Phe-], one bond disconnecting between the sarcosine carboxy group and the (2R)-Asp N-atom and the other disconnecting between the (2R)-Asp β-carboxy group and the (2S)-Phe N-atom. Preparation of the linear precursors was achieved using solution-phase chemistry without incident. Macrolactamisation via the displacement of the β-pentafluorophenyl ester of the (2R)-Asp α-methyl ester residue by the free amino group of the (2S)-phenylalanine residue proceeded in excellent yield (89%), but the alternative strategy failed. Application of the successful macrolactamisation strategy to other nodularin macrocycles and to the construction of the microcystin-type macrocycle is described in the following article.

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Article information


J. Chem. Soc., Perkin Trans. 1, 1997, 2495-2512
Article type
Paper

Design and preparation of serine–threonine protein phosphatase inhibitors based upon the nodularin and microcystin toxin structures: Part 1. Evaluation of key inhibitory features and synthesis of a rationally stripped-down nodularin macrocycle

A. P. Mehrotra, K. L. Webster and D. Gani, J. Chem. Soc., Perkin Trans. 1, 1997, 2495
DOI: 10.1039/A702407J

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