Total Structure and Inhibition of Tumor Cell Proliferation of Laxaphycins

Abstract

From a mixed assemblage of Lyngbya majuscula rich marine cyanobacteria, we isolated a series of cell growth inhibitory cyclic peptides. The structures of the two major components, laxaphycins A (1) and B (2), and of two minor peptides, laxaphycins B2 (3) and B3 (4), were determined by spectroscopic methods and degradative analysis. Absolute configurations of natural and nonproteinogenic amino acids were determined by a combination of hydrolysis, synthesis of noncommercial residues, chemical derivatization, and HPLC analysis. The organism producing the laxaphycins was identified as the cyanobacterium Anabaena torulosa. The antiproliferative activity of laxaphycins was investigated on a panel of solid and lymphoblastic cancer cells. Our results demonstrate that in contrast to laxaphycin A, laxaphycin B inhibits the proliferation of sensitive and resistant human cancer cell lines and that this activity is strongly increased in the presence of laxaphycin A. This effect appears to be due to an unusual biological synergism.

Antifungal activity improved by coproduction of cyclodextrins and anabaenolysins in Cyanobacteria

“…Discussion Synergistic Antifungal Activity. Cyanobacteria are known to produce lipopeptides with antifungal activity, such as nostofungicidine (18), laxaphycins (19)(20)(21), lobocyclamides (22), and hassallidins (14,23,24). In this study, we show that anabaenolysins have a weak antifungal activity (Fig.…”

“…1D). Previously, lipopeptides, such as laxaphycins (19)(20)(21) and lobocyclamides (22), showed synergistic antifungal activity. Portoamides A and B have also shown synergistic allelophatic activity inhibiting the green microalgae Chlorella vulgaris (25).…”

Genetic Variation of Adenylation Domains of the Anabaenopeptin Synthesis Operon and Evolution of Substrate Promiscuity

“…In addition, a number of tailoring enzymes, such as methyltransferases, epimerases, and thioesterases (TEs), lead to the modification of the synthesized product (11). It is a characteristic feature of cyanobacterial NRPS pathways that they often produce entire families of structurally related compounds co-occurring in one specific isolate, e.g., the cryptophycins (15), laxaphycins (2,13), and nostopeptolides (16). In such NRPS peptide families, structurally related amino acids, such as Val, Ile, and Leu, are found in equivalent positions of the peptides, suggesting that the A domains of these NRPS enzymes may possess a relaxed substrate specificity (19).…”

Marine Peptide Secondary Metabolites

“…Later, the structure of laxaphycins A and B were fully elucidated. Two other congeners, B2 and B3, having different degrees of hydroxylation, were also isolated from Anabaena torulosa harvested in French Polynesia (Bonnard et al, 1997;Bonnard et al, 2007). This peptide family broadened over the years with the successive isolation and structure elucidation of lobocyclamide A from Lyngbya confervoides containing serine (Ser 2 ), tyrosine (Tyr 6 ) in place of the homoserine (Hse 2 ) and phenylalanine (Phe 6 ) found in laxaphycin A, while conserving the same E geometry of Dhb 3 .…”

“…A comparable typing error is also noted for lobocyclamide B, in which all of the natural amino acids are described to be of the natural L configuration in the text , whereas Leu and Glu are represented in the figure in the D configuration. An error is also suspected in the proposed structure of laxaphycin B (Bonnard et al, 2007). The two Hleu residues are described as (2S,3S)-Hleu 3 and (2R,3S)-Hleu 5 , whereas they are both of (2R,3S) configuration in lobocyclamide B .…”