Synthesis and biology of cyclic imine toxins, an emerging class of potent, globally distributed marine toxins

Abstract

From a small group of exotic compounds isolated only two decades ago, Cyclic Imine (CI) toxins have become a major class of marine toxins with global distribution. Their distinct chemical structure, biological mechanism of action, and intricate chemistry ensures that CI toxins will continue to be the subject of fascinating fundamental studies in the broad fields of chemistry, chemical biology, and toxicology. The worldwide occurrence of potent CI toxins in marine environments, their accumulation in shellfish, and chemical stability are important considerations in assessing risk factors for human health. This review article aims to provide an account of chemistry, biology, and toxicology of CI toxins from their discovery to the present day.

Spirolides and Cyclic Imines: Toxicological Profile

“…The pinnatoxins and pteriatoxins are differentiated by the substituent at C33, which might be carboxyl (pinnatoxin A), vinyl (pinnatoxins G and H), glycinyl (pinnatoxins B and C), butyrolactone (pinnatoxin F), or hydroxy/keto-butyric acid (pinnatoxins D and E), as well as S-cysteinyl derivatives (pteriatoxins A-C). Other positions with substituent variability are 21, 22, and 28, for which are observed two substitution patterns: H, H and OH (pinnatoxins A, B, C, G and pteriatoxins A, B, C), and CH 3 , OH and H (pinnatoxins D, E, F, H), respectively (O'Connor and Brimble 2007; Stivala et al 2015).…”

“…Although many dinoflagellate species can produce various natural toxins that impact humans, those involved in the production of cyclic imine toxins are limited to mainly Alexandrium, Karenia (formerly Gymnodinium), Vulcanodinium, and Prorocentrum species (for reviews, see Molgó et al 2014;Stivala et al 2015). All known spirolides have been so far linked to Alexandrium species, and differences in spirolides content and profiles have been reported for dinoflagellate strains from different coastal regions.…”

“…Hence, to date, most if not all studies regarding the It is worth noting that cyclic imine oral administration, with feeding taking priority over gavage, is a more relevant method since, first, it closely reproduces the situation in humans, and second, it avoids the use of high concentrations of solvent (i.e., ethanol) to dissolve the toxins (for reviews, see Molgó et al 2014;Stivala et al 2015). Spirolides, as the other cyclic imines, are classified as "fast-acting" toxins because they induced rapid onset of neurological symptoms -including hyperactivity, jumping, piloerection, hyperextension of the back, stiffening and arching of the tail toward the head, tremors progressing to spasms, as well as skeletal muscle paralysis and extension of the hind limbs, respiratory distress with marked abdominal breathing, tremors of the whole body, and severe dyspnea -followed by death due to respiratory arrest within 3-50 min, whatever the route of administration is.…”

“…Dinoflagellate toxins known to interact with nAChRs include the spirolides, gymnodimines, and pinnatoxins (for a recent review, see Stivala et al 2015).…”

“…Since then, the spirolides have been found to have a worldwide distribution, with a remarkable diversity in their chemical profiles. Spirolides belong to the so-called cyclic imine group of neurotoxins that also include the gymnodimines, pinnatoxins, pteriatoxins, portimine, spiro-prorocentrimine, and prorocentrolides (for a recent review, see Stivala et al 2015). The generic chemical structure of the cyclic imine toxins is represented by a macrocycle, with the ring size between 14 and 27, and two conserved features that include two subunits: the cyclic imine group (which in most cases is found as a spiroimine) and the spiroketal ring system.…”