Structure and biological evaluation of new cyclic and acyclic laxaphycin-A type peptides

Five new laxaphycins were isolated and fully characterised from the bloom forming cyanobacteria Anabaena torulosa sampled from Moorea, French Polynesia: three acyclic laxaphycin A-type peptides, acyclolaxaphycin A (1), [des-Gly(11)]acyclolaxaphycin A (2) and [des-(Leu(10)-Gly(11))]acyclolaxaphycin A (3), as well as two cyclic ones, [L-Val(8)]laxaphycin A (4) and [D-Val(9)]laxaphycin A (5). The absolute configuration of the amino acids, established using advanced Marfey's analysis for compounds 2-5, highlights a conserved stereochemistry at the C alpha carbons of the peptide ring that is characteristic of this family. To the best of our knowledge, this is the first report of acyclic analogues within the laxaphycin A-type peptides. Whether these linear laxaphycins with the aliphatic beta-amino acid on the N-terminal are biosynthetic precursors or compounds obtained after enzymatic hydrolysis of the macrocycle is discussed. Biological evaluation of the new compounds together with the already known laxaphycin A shows that [L-Val(8)]laxaphycin A, [D-Val(9)]laxaphycin A and [des-Gly(11)]acyclolaxaphycin induce cellular toxicity whereas laxaphycin A and des-[(Leu(10)-Gly(11))]acyclolaxaphycin A do not affect the cellular viability. An analysis of cellular death shows that the active peptides do not induce apoptosis or necrosis but instead, involve the autophagy pathway.