29 October 2018

Cyclamide – a wealth of different bioactivities

Natural toxin

Cyanobacteria have been extensively studied since the 1970s since their toxins have imposed a threat to the life of humans, domestic and wild animals. Freshwater cyanobacteria produce a variety of bioactive peptides, with microcystins being the most famous toxic metabolite.

To date, more than 600 cyanobacterial peptides have been described. From the 7 classes described by Welker & Von Döhren (2006), the classes cyanopeptolin, anabaenopeptin and aeruginosin were already presented at the “toxin of the week”. Here, we present the class of  cyclamides. This class has currently over 20 members of cyclic peptides that have been obtained either from marine (e.g. Oscillatoria sp. and Lyngbya sp.) and freshwater cyanobacteria (e.g.  Microcystis aeruginosa and Nostoc) or from animal sources (sea-hares and ascidians)2,3. However, the cyclamides isolated from animal sources are thought to be of cyanobacterial origin as well and are suggested to be either produced by symbionts or obtained through dietary uptake. The naming of this peptide class is very incoherent being linked either to the producing organism (e.g. nostocyclamide) or to the origin of the sample or strain (e.g. banyascyclamide)1. Contrary to the other cyanopeptide classes, this group of metabolites is ribosomally synthesized.

This compound class encompasses hexa and octameric cyclopeptides characterized by thiazole and oxazole moieties thought to be cysteine and threonine derivatives, respectively.  In typical peptides of this class, thiazole/oxazole units occur in alternation with unmodified amino acids (see Figure 1).

Figure 1: Left: Chemical structure of aerucyclamide A representative of the general chemical structure of aerucyclamide type peptides with the oxazole and thiazole moieties. Variation in the other three moieties are listed as the three-letter code of canonical amino acid (modified from Welker et al., 2006). Center: Microscopic image of Nostoc (Source: gettyimages.ch). Right: Microscopic image of Microcystis aeruginosa (Source: pinterest).

Cyclamides display a wealth of different bioactivities. Venturamide A and B, isolated from the cyanobacteria Oscillatoria sp., showed in vitro antimalarial activity against Plasmodium falciparum (IC50 of 8.2 and 5.6 µM respectively)2. While, Microcyclamide A was reported to have moderate cytotoxicity against P388 murine leukemia cells. The interest in exploring cyclamides as potential pharmaceuticals is based on the fact that other compounds containing thiazole/oxazole moieties show promising anti-tumor, antibacterial, anti-viral, and antimalarial activities2.

The association of cyclamides with cyanobacterial water blooms suggests that they likely have a particular biological role. Speculation of the ecological function range from metal ion binding based on their cyclic hexapeptide structure to protection of intracellular and oxygen sensitive nitrogenase with thiazoline/oxazoline moieties being the oxygen scavengers5. In addition, cyclamides also exhibit toxicity against grazing organisms and allelopathy against related cyanobacteria. However, comparison of toxicity against the freshwater crustacean Thamnocephalus platyurus suggests that Aerucyclamides A and B from the cyanobacteria Microcystis aeruginosa are approximately 1 order of magnitude less toxic than microcystins4.

Advancing the research of cyclamides is important in order to define their potential ecological and human toxicity, to understand their role in harmful cyanobacterial bloom events, and to further explore their potential use as a natural drug.

SMILES: O=C(N[C@]1([H])[C@H](C)CC)C2=CSC(CNC([C@@]3([H])N=C([C@]([C@@H](C)CC)([H])NC([C@@]4([H])CSC1=N4)=O)O[C@@H]3C)=O)=N2

References:

  1. Welker, M. & Von Döhren, H. (2006) Cyanobactcerial peptides – Nature’s own combinatorial biosynthesis. FEMS Microbiol Rev, 30:530-563.
  2. Davyt,D. & Serra, G. (2010) Thiazole and Oxazole Alkaloids: Isolation and Synthesis. Mar. Drugs, 8:2755-2780.
  3. Jüttner, F. et al. (2001) Nostocyclamide M: a cyanobacterial cyclic peptide with allelopathic activity from Nostoc 31. Phytochemistry, 57:613-619.
  4. Portmann, C. et al. (2008) Aerucyclammides A and B: Isolation and synthesis of toxic ribosomal heterocyclic peptides from the cyanobacterium Microcystis aeruginosa PCC7806. J. Nat. Prod, 71:1193-1196.
  5. Zafrir-Ilan, E. (2010) Two new microcyclamides from a water bloom of the cyanobacterium Microcystis sp. Tetrahedron Letters, 51:6602-6604.