[15]aneN4S: Synthesis, Thermodynamic Studies and Potential Applications in Chelation Therapy

Torres, Nuno; Goncalves, S.; Fernandes, Ana Sofia; Machado, João Franco; Brito, Maria J. Villa de; Oliveira, Nuno G.; Castro, Matilde; Costa, Judite; Cabral, M. Fátima

doi:10.3390/molecules19010550

Cited by 3 publications

(1 citation statement)

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“…In fact, macrocyclic compounds may exhibit important properties such as high kinetic and thermodynamic stabilities and low toxicity, making them very promising agents in this context [25]. The macrocyclic chelator, 1-thia-4,7,10,13-tetraazacyclopentadecane ([15]aneN 4 S, Figure 1) was recently shown to have a high affinity for Hg 2+ with a high thermodynamic stability constant (log K ML = 23.74) indicating that this compound may be useful in chelation therapy [26].…”

Section: Introductionmentioning

confidence: 99%

In Vitro Assessment of the Efficacy of a Macrocyclic Chelator in Reversing Methylmercury Toxicity

Nobre

Cabral

Costa

et al. 2019

IJERPH

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Methylmercury (MeHg) is a highly neurotoxic compound to which human populations are exposed via fish consumption. Once in cells, MeHg actively binds thiols and selenols, interfering with the activity of redox enzymes such as thioredoxin (Trx) and the selenoenzyme thioredoxin reductase (TrxR) which integrate the thioredoxin system. In fact, it has been shown that inhibition of this system by MeHg is a critical step in the unfolding of cell death. Current clinical approaches to mitigate the toxicity of MeHg rely on the use of chelators, such as meso-2,3-dimercaptosuccinic acid (DMSA) which largely replaced British anti-Lewisite or 2,3-dimercapto-1-propanol (BAL) as the prime choice. However, therapeutic efficacy is limited and therefore new therapeutic options are necessary. In this work, we evaluated the efficacy of a macrocyclic chelator, 1-thia-4,7,10,13-tetraazacyclopentadecane ([15]aneN4S), in preventing MeHg toxicity, namely by looking at the effects over relevant molecular targets, i.e., the thioredoxin system, using both purified enzyme solutions and cell experiments with human neuroblastoma cells (SH-SY5Y). Results showed that [15]aneN4S had a similar efficacy to DMSA and BAL in reversing the inhibition of MeHg over purified TrxR and Trx by looking at both the 5,5′-dithiobis(2-nitrobenzoic acid) (DTNB) reduction assay and insulin reduction capability. In experiments with cells, none of the chelating agents could reverse the inhibition of TrxR by MeHg, which corroborates the high affinity of MeHg to the selenol in TrxR active site. [15]aneN4S and BAL, unlike DMSA, could prevent inhibition of Trx, which allows the maintenance of downstream functions, although BAL showed higher toxicity to cells. Overall these findings highlight the potential of using [15]aneN4S in the treatment of MeHg poisoning and encourage further studies, namely in vivo.

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Section: Introductionmentioning

confidence: 99%