Synthetic analogues of cyanobacterial alkaloid cylindrospermopsin and their toxicological activity

• Published in: Toxicology in vitro 2017-10, Vol.44, p.172-181
• Main Authors: Cartmell, Christopher, Evans, Daniel M., Elwood, Jessica M.L., Fituri, Hisham S., Murphy, Patrick J., Caspari, Thomas, Poniedziałek, Barbara, Rzymski, Piotr
• Format: Article
• Language: English
• Subjects: Adult; Analogs; Bacterial Toxins - chemistry; Bacterial Toxins - toxicity; Biological activity; Biosynthesis; Cell death; Cell Survival - drug effects; Cells, Cultured; Chemical synthesis; Cyanobacteria; Cylindrospermopsin; Guanidine; Guanidine - chemistry; Guanidine synthesis; Humans; Hydroxyl groups; Leukocytes (neutrophilic); Lipid peroxidation; Lipid Peroxidation - drug effects; Male; Neutrophils; Neutrophils - drug effects; Neutrophils - metabolism; Oxidative stress; Peroxidation; Reactive oxygen species; Reactive oxygen species (ROS); Reactive Oxygen Species - metabolism; Substrates; Toxicity; Toxicology; Uracil; Uracil - analogs & derivatives; Uracil - chemistry; Uracil - toxicity; Young Adult
• ISSN: 0887-2333; 1879-3177
• DOI: 10.1016/j.tiv.2017.07.007

Cylindrospermopsin (CYN) is a naturally occurring alkaloid produced by a variety of cyanobacteria and known to induce oxidative stress-mediated toxicity in eukaryotic cells. Despite extensive research on the mechanism of CYN toxicity, an understanding of the structural features responsible for this toxicity and the mechanism by which it can enter the cell are still not clear. It was established that the presence of both the uracil and guanidine groups is essential in biological activity of CYN whilst not much is known in this regard on the role of tether that separates them and the attached hydroxyl group. Therefore, in the present study we have prepared three synthetic analogues possessing uracil and guanidine groups separated by a variable length tether (4–6 carbons) and containing a hydroxyl function in a position orientation to CYN, together with a tetracyclic analogue of CYN lacking the hydroxyl group at C-7. The toxicity of these compounds was then compared with CYN and guanidinoacetate (GAA; the primary substrate in CYN biosynthesis) in an in vitro model using human neutrophils isolated from healthy subjects. The lowest activity measured by means of reactive oxygen species generation, lipid peroxidation and cell death was observed for GAA and the tetracyclic analogue. The greatest toxicity was found in an analogue with a 6-carbon tether, but all three analogues and CYN caused rapid onset of redox imbalance. These results add to the general understanding of CYN toxicity and preliminary findings suggest that the –OH group at C-7 may be significant for the cellular transport of CYN and/or be involved in its toxic activity inside the cell, a hypothesis which requires further testing. Analogues 11a–c of the alkaloid cylindrospermopsin 1, containing the key guanidine, hydroxyl and uracil motifs, have shown comparable cytotoxic activity to the natural material. [Display omitted] •The role of the C7-OH group in the activity of cylindrospermopsin 1 is unknown.•Synthetic analogues (11a–c) of cylindrospermopsin 1 were prepared.•Toxicity of these analogues was compared with 1 using human neutrophils in vitro.•The greatest toxicity was found in 11c with a 6-carbon tether and an –OH group.•An analogue closely resembling 1 but lacking the C7-OH group had low toxicity.