para-Aminosalicylic acid in the treatment of manganese toxicity. Complexation of Mn²⁺ with 4-amino-2-hydroxybenzoic acid and its N-acetylated metabolite

Abstract

Manganese excess can induce in humans neurological disorders known as manganism. A possible remedy should be chelation therapy, even if a chelation schedule for manganism is not currently established. Para aminosalicylic acid (PAS) has demonstrated effectiveness in reducing manganism symptoms. In this work, a study of protonation equilibria of para aminosalicylic acid and of its Nacetylated metabolite (Ac-PAS) and of their complexation reactions with Mn 2+ is presented, also extended to the main essential metal ions Cu 2+ and Fe 3+ . A number of complementary techniques (potentiometry, spectrophotometry, fluorimetry, EPR) have been used for a thorough comprehension of protonation and complex formation equilibria, with the addition of DFT calculations, which provide 2 insights on the relative stabilities and electronic properties of the formed species. Both PAS and Ac-PAS form 1:1 and 1:2 metal:ligand complexes with the target Mn 2+ ion; surprisingly the N-acetylated metabolite forms stronger complexes, whose implications in chelation therapy have been pointed out by a speciation study. It is presumed that the relatively small metabolite can penetrate across the bloodbrain-barrier and exert its Mn-mobilizing action intracellularly in vulnerable neurons.

Exploring the Specificity of Rationally Designed Peptides Reconstituted from the Cell-Free Extract of Deinococcus radiodurans toward Mn(II) and Cu(II)

“…A pMn of 6.53 calculated under CMT physiological conditions for the strongest Mn(II)−Mid-DEH complex is higher than values of 90% of the ligands normally used, or proposed, in metal chelation therapy, 61,63 and also higher than those of the Mn(II)−peptide complexes, derived from Ypk9, a vacuolar Mn(II)-transporting ATPase protein encoded from a Parkinson's disease gene whose role is in manganese efflux and detoxification (pMn = 6.01). 33 ■ CONCLUSION D. radiodurans is a source of several biotechnological potential applications: environmental bioremediation of contaminated sites and nuclear wastes, human bioprotection (prophylactic measure before radiation exposure or for preventing radiation toxicity after nuclear accidents or military activity), biomedical applications (radiotherapy and nuclear medicine), and the formulation of personal care products (antiaging cosmetics and sunscreens).…”

“…A pMn of 6.53 calculated under CMT physiological conditions for the strongest Mn­(II)–Mid-DEH complex is higher than values of 90% of the ligands normally used, or proposed, in metal chelation therapy, , and also higher than those of the Mn­(II)–peptide complexes, derived from Ypk9, a vacuolar Mn­(II)-transporting ATPase protein encoded from a Parkinson’s disease gene whose role is in manganese efflux and detoxification (pMn = 6.01) …”

Chelation Combination—A Strategy to Mitigate the Neurotoxicity of Manganese, Iron, and Copper?

“…Recent experiences have reported that chelation treatment may improve the clinical features in overexposed welders when administered in the early phases of the clinical course [ 52 ]. Sodium p-aminosalicylic acid (PAS), which is presumed to act also intracellularly, has been observed to be effective in treating manganese-induced clinical manifestations in severe cases [ 52 , 53 ]. It is tempting to propose a combination therapy using the water-soluble agent CaEDTA together with PAS in addition to L-dopa in cases of severe manganism ( Table 3 ).…”

Metals and Metal-Nanoparticles in Human Pathologies: From Exposure to Therapy

“…Manganese constitutes the enzymatic center of various metalloproteins, such as phosphoenolpyruvate decarboxylase, glutamine synthetase, arginase, pyruvate carboxylase, and manganese-SOD enzymes, which regulates the cellular redox status, mitochondrial function, and neurotransmitter synthesis [63,64]. Human manganese brain concentration increases with age and was correlated with PD [65].…”