Structure and synthesis of amatyemides A and B, cyclic octadepsipeptides from South African stromatolites

Abstract

In the course of investigating living phosphatic stromatolites from Schoenmakerskop barrage pool near Gqeberha (Port Elizabeth), South Africa, we discovered new cyclic octadepsipeptides, amatyemides A (1) and B (2), named using the Xhosa word ‘amatye’ for ‘rock’. The amatyemides were isolated from methanol extractions of a targeted stromatolite sample collection, following an initial metabolomic survey of the Schoenmakerskop pool. Planar structure elucidation of 1 and 2 relied on NMR and LCMS2 data, which delineated the same six amino acids and one 2-hydroxy-3-methylpentanoic acid (Hmpa) residues in each compound. The only difference between the two octadepsipeptides was the presence of a 2-hydroxydodecanoic acid (Hdda) residue in 1 and a 2-hydroxydecanoic acid (Hda) residue in 2. The absolute configuration of each amino acid residue was determined using an enhanced Marfey’s reagent. The configurations of the 2-hydroxy acids were assigned, and the absolute structures of amatyemides A (1) and B (2) confirmed, by total solid phase peptide synthesis of two possible diastereomers for each natural product. Biological testing of natural and synthetic amatyemides against human U87-MG glioblastoma, HCT116 colon and SH-SY5Y neuroblastoma cells, revealed weak, cell-type specific, cytotoxic potential where 2 > 1, and was attributed to the ability of both compounds to induce oxidative stress.