Cryptophycin – a potent cytotoxic agent

Cyanobacterial algal blooms are expanding temporally and spatially, which is promoted by eutrophication and likely climate change. Those intensified cyanobacterial bloom events across the globe are of increasing concern because of the adverse effects associated with the release of bioactive compounds with different modes of action, including a variety of toxic cyanopeptides. Up to date more than 600 cyanopeptides were identified.¹ Based on their chemical structure they can be classified in classes. Here we present the class of cryptophycin.

The name cryptophycin was given because of the cytotoxicity of these compounds against yeast of the genus Cryptococcus. Cryptophycin is a class of cyclic depsipeptides that was originally isolated from the cyanobacteria Nostoc sp. (Figure 1, right) in 1990 by researchers at Merck as a potent fungicide, however, the compound was found to be highly toxic to be developed as antifungal. Some years later, crypthophycins were discovered to be potent cytotoxins. They deplete microtubules through interaction with tubulin, thereby preventing cell division. Due to this mode of action, cryptophycins are considered potential chemotherapeutic agents.^2,3 Cryptophycin-52 (Figure 1, left), a synthetic analog of natural product cryptophycin, reached phase II clinical trials but was withdraw due to lack of efficacy in vivo combined with toxicity effects, such as arthralgia, constipation, myalgia and neuropathy. In particular, neurotoxicity is a major side effect of cytotoxic agents since they target cellular structures like microtubules that are essential for cells of the nervous system.²

Up to date, around 28 naturally occurring analogues have been identified and they all have been isolated exclusively from Nostoc. Cryptophycins are composed of two hydroxy units, a valeric acid derivative and a phenyl-octanoic acid derivative, and two amino acid units, a tyrosine derivative and a β-amino acid. Structural variability raises mainly from the chlorination of the tyrosine unit and an optional epoxy group at the phenyl-octanoic acid (Figure 1, left).¹

Figure 1: Left: Chemical structure of Cryptophycin-52 (source: PubChem). Right: Microscopic image of  Nostoc.sp ⁴.

Although some cryptophycin analogues failed in clinical studies, there is still an interest on the application of cryptophycin derivatives as bioconjugates in tumor-targeting approaches. On top of that, there is still a lot to be discovered about this cyanopeptide class, not only regarding their toxic effects, but also about their occurrence and fate on the environment.

Smiles Code:  Cryptophycin-52
CC(C)CC1C(=O)OC(CC=CC(=O)NC(C(=O)NCC(C(=O)O1)(C)C)CC2=CC(=C(C=C2)OC)Cl)C(C)C3C(O3)C4=CC=CC=C4

References:

1. Welker, M. & Von Döhren, H. (2006) Cyanobactcerial peptides – Nature’s own combinatorial biosynthesis. FEMS Microbiol Rev, 30:530-563.
2. Weiss, C. et al. (2017) Cryptophycins: cytotoxic cyclodepsipeptides with potential for tumor targeting. Jounal of peptide science, 23:514-531.
3. Kerksiek, K. et al. (1995) Interaction of cryptophycin 1 with tubulin and microtubules. FEBS Letters, 377:59-61.
4. Characterization of Alkane-Producing Nostoc sp. Isolated from a Summer Bloom for Biofuel Potential - Scientific Figure on ResearchGate. Available from: https://www.researchgate.net/figure/Light-microscopy-of-Nostoc-sp-KNUA003_fig1_325927734 [accessed 31 Jan, 2020].