Total synthesis of melleumins A and B and their analogs: Determination of stereochemistry and Wnt signal inhibitory activity

Abstract

During our studies in a search for natural products from myxomycetes [1], we have isolated a novel peptide lactone, melleumin A (1), and its seco acid methyl ester, melleumin B (2), from the cultured plasmodium of the myxomycete Physarum melleum [2]. Absolute stereochemistry of these compounds was determined by synthesis of a segment and HPLC analysis [3]. We recently achieved total syntheses of melleumins A (1) and B (2), which further provided evidence for the whole structure of them. We also examined the Wnt signal inhibitory activity of 1, 2, and diastereomers (3–5) prepared by synthesis. The Wnt signaling pathway has important functions in vertebrate development, and its deregulation is believed to occur early in human colorectal cancer. Recently, compounds down-regulating Wnt signaling were therefore expected in new strategy for cancer therapy. A cell-based luciferase assay system showed that compound 3 moderately inhibited Wnt signal transcriptional activity and its diastereomers showed inhibition enhancement, suggesting that melleumin analogues may be useful as Wnt signal inhibitors.