Synthesis and Chemical and Biological Evaluation of a Glycine Tripeptide Chelate of Magnesium

Abstract

Magnesium (Mg2+) plays a crucial role in over 80% of all metabolic functions. It is becoming increasingly apparent that magnesium deficiency (hypomagnesemia) may play an important role in chronic disease. To counteract magnesium deficiency, there is an unmet clinical need to develop new fully characterized, highly bioavailable, and substantially water-soluble magnesium supplements. To this end, triglycine (HG3), a tripeptide of the amino acid glycine, was chosen as a chelating ligand for magnesium, given its natural occurrence and water solubility, and entropically-driven metal binding. Herein, we discuss the synthesis, chemical and physical characterization, and cellular uptake of a magnesium triglycine chelate (MgG3), an octahedral complex with extraordinary water solubility and improved cellular uptake in CaCo-2 cells than select commonly used magnesium supplements.

Synthesis, Characterization, and Cellular Uptake of a Glycylglycine Chelate of Magnesium

“…As previously reported by Case et al when analyzing a triglycine chelate of magnesium, the more substantial upfield shift of the proton nearest the terminal amine (H 1 ) implicates the participation of this moiety in coordination . Additionally, coalescing of the H 2 proton signal for 1 relative to HG 2 suggests coordination to the carboxylic acid that results in an even distribution of electron density and subsequent lack of observed splitting.…”

“…These data indicate that 1 acts as a 1:1 electrolyte with only partial dissociation, which is consistent with the previously reported MgG 3 . 20 Conductivity values for both KCl and 1 trend linearly at the given concentration range with R 2 KCl = 1.0000 and R 2 1 = 0.9995.…”

“…Furthermore, observed uptake of 1 was only about half that of the previously reported MgG 3 complex. 20 Uptake increases with increased peptide length from MgBG, 1 , and MgG 3 . This is consistent with the uptake observed in humans for the free mono-, di- and tripeptide glycine ligands observed by Craft et al 18 Craft explains that the rate of cellular uptake of the free ligands is directly related to the available mole quantity of the ligand and the corresponding rate of uptake as it pertains to the amount of ligand available.…”

“…As previously reported by Case et al when analyzing a triglycine chelate of magnesium, the more substantial upfield shift of the proton nearest the terminal amine (H 1 ) implicates the participation of this moiety in coordination. 20 Additionally, coalescing of the H 2 proton signal for 1 relative to HG 2 suggests coordination to the carboxylic acid that results in an even distribution of electron density and subsequent lack of observed splitting. Furthermore, the observation of upfield proton shifting coincides with generalized magnesium coordination and may be observed for the α-proton adjacent to the point of coordination and as far-reaching as the γ-proton.…”

“…While more soluble than MgO, 1 is less soluble than MgCl 2 and about one fifth as soluble as MgG 3 , which is previously reported by Case et al ( Table 2 ). 20 The water solubility of 1 is attributed in part to the inherent change to a more polar complex given the substantial electropositive character of the divalent magnesium and the dipole alteration generated upon ligand coordination. Additionally, as was the case with MgG 3 , 20 it is likely that the extensive hydrogen bond network of the HG 2 ligand is efficacious in generating increased water solubility.…”