Structure and Synthesis of Amatyemides A and B, Cyclic Octadepsipeptides from South African Stromatolites.

An investigation of living phosphatic stromatolites from Schoenmakerskop barrage pool near Gqeberha (Port Elizabeth), South Africa, yielded new cyclic octadepsipeptides, amatyemides A (1) and B (2), named using the Xhosa word 'amatye' for 'rock'. The amatyemides were isolated from methanol extracts 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 two octadepsipeptides differed only in the presence of a 2-hydroxydodecanoic acid (Hdda) residue in 1 and a 2-hydroxydecanoic acid (Hda) residue in 2. The absolute configurations of most amino acid residues in 1 were determined using an enhanced Marfey's reagent. The configurations of the 2-hydroxy acids and O-methylthreonine were assigned, and the absolute structures of amatyemides A (1) and B (2) were 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 this was attributed to induction of oxidative stress by 2.