Daniela De Freitas Câmara

Direct synthesis of 4-organylsulfenyl-7-chloro quinolines and their toxicological and pharmacological activities in Caenorhabditis elegans

We describe herein our results on the synthesis and biological properties in Caenorhabditis elegans of a range of 4-organylsulfenyl-7-chloroquinolines. This class of compounds have been easily synthesized in high yields by direct reaction of 4,7-dichloroquinoline with organylthiols using DMSO as solvent at room temperature under air atmosphere and tolerates a range of substituents in the organylsulfenyl moiety. We have performed a toxicological and pharmacological screening of the synthesized 4-organylsulfenyl-7-chloroquinolines in vivo in C. elegans acutely exposed to these compounds, under per se and stress conditions. Hence, we determined the lethal dose 50% (LD50), in order to choose a nonlethal concentration (10 μM) and verified that at that concentration some of the compounds depicted protective action against the induced damage inflicted by paraquat, a superoxide generator. Two compounds (3c and 3h) reduced the toxicity inflicted by paraquat above survival, reproduction and longevity of the worms, at least in part, by reducing the reactive oxygen species (ROS) generated by the toxicant exposure. Besides, these compounds increased the quantities of superoxide dismutase (SOD-3::GFP) and catalase (CTL-1,2,3::GFP), antioxidant enzymes. We concluded that the protective effects of the compounds observed in this study might have been a hormetic response dependent of the transcriptional factor DAF-16/FOXO, causing a non-lethal oxidative stress that protects against the subsequently damage induced by paraquat.

Behavioral and dopaminergic damage induced by acute iron toxicity in Caenorhabditis elegans

Iron (Fe) is an important metal to organism homeostasis and exists abundantly in the environment. Moderate levels of Fe obtained from food are necessary for normal cell physiology; however, abnormally high levels of Fe may have toxic effects by reducing H2O2 to the highly cytotoxic hydroxyl radical (OH˙) (Fenton catalysis). Fe is a ubiquitous toxicant to the environment and also widely used in food products; however, its effects on the nervous system are not well understood. Herein, we evaluated the toxic effects of Fe using C. elegans and investigated various parameters in order to contribute to the understanding of Fe-induced toxicity and to validate this model. The Fe LD50 of acute exposure (30 min) was 1.2 mM, and we verified that worms readily take up this metal. Furthermore, sublethal Fe concentrations significantly decreased the worms’ lifespan and brood size compared to non-exposed worms. We also observed that animals exposed to Fe had decreased locomotor activity and decreased mechanical sensitivity, suggesting the possible dysfunction of the nervous system. In agreement, we found cholinergic and dopaminergic alterations in the worms. In summary, we suggest that Fe leads to selective neuronal damage, which might be the underlying cause of altered behavior and reproductive defects.