Peptide Hydrolysis by Metal (Oxa)cyclen Complexes: Revisiting the Mechanism and Assessing Ligand Effects

Abstract

The mechanism responsible for peptide bond hydrolysis by Co­(III) and Cu­(II) complexes with (oxa)­cyclen ligands has been revisited by means of computational tools. We propose that the mechanism starts by substrate coordination and an outer-sphere attack on the amide C atom of a solvent water molecule assisted by the metal hydroxo moiety as a general base, which occurs through six-membered ring transition states. This new mechanism represents a more likely scenario than the previously proposed mechanisms that involved an inner-sphere nucleophilic attack through more strained four-membered rings transition states. The corresponding computed overall free-energy barrier of 25.2 kcal mol–1 for hydrolysis of the peptide bond in PheAla by a cobalt­(III) oxacyclen catalyst (1) is consistent with the experimental values obtained from rate constants. Also, we assessed the influence of the nature of the ligand throughout a systematic replacement of N by O atoms in the (oxa)­cyclen ligand. Increasing the number of coordinating O atoms accelerates the reaction by increasing the Lewis acidity of the metal ion. On the other hand, the higher reactivity observed for the copper­(II) oxacyclen catalyst with respect to the analogous Co­(III) complex can be attributed to the larger Brönsted basicity of the copper­(II) hydroxo ligand. Ultimately, the detailed understanding of the ligand and metal nature effects allowed us to identify the double role of the metal hydroxo complexes as Lewis acids and Brönsted bases and to rationalize the observed reactivity trends.

Probing Unexpected Reactivity in Radiometal Chemistry: Indium-111-Mediated Hydrolysis of Hybrid Cyclen-Hydroxypyridinone Ligands

“…Given that these complexes have been isolated, we hypothesize that it is unlikely that In 3+ dissociates from these respective ligand systems during a hydrolysis process. At later time points in the reaction of L 1 with 111 In 3+ at pH 8 and pH 10, minimal or negligible “unchelated” 111 In 3+ remains in solutioninitial 111 In 3+ complexation is rapid. However, there continues to be an increase in the amount of [ 111 In]In- L 1B over time, while simultaneously, there is a decrease in the amount of [ 111 In]In- L 1A . There is no evidence of “free” L 1B or L 2B ligand in studies with either nat In 3+ or 111 In 3+ . DFT calculations indicate that In 3+ coordination of an intramolecular amide carbonyl, as well as coordination of a hydroxide ion are likely, enabling an intramolecular hydrolysis mechanism (Figures and S20), similar to that previously reported for cyclen and oxacyclen complexes. − …”

“…DFT calculations indicate that In 3+ coordination of an intramolecular amide carbonyl, as well as coordination of a hydroxide ion are likely, enabling an intramolecular hydrolysis mechanism (Figures and S20), similar to that previously reported for cyclen and oxacyclen complexes. − …”

“…Metal ions and their complexes are widely known to catalyze or mediate hydrolysis of amide/peptide bonds, through either (i) coordination of an amide carbonyl group, and concurrent activation of the carbonyl toward nucleophilic attack, (ii) activation of a coordinated water or hydroxide ion to enable nucleophilic attack of an amide, or (iii) a combination of both of the above, in which an amide carbonyl and hydroxide are both coordinated to a metal center . Complexes of cyclen and oxacyclen derivatives with metal ions, significantly Cu 2+ and Co 3+ , have demonstrated hydrolytic activity toward peptides. − …”

“… 27 Complexes of cyclen and oxacyclen derivatives with metal ions, significantly Cu 2+ and Co 3+ , have demonstrated hydrolytic activity toward peptides. 28 − 30 …”

Zirconium oxo clusters as discrete molecular catalysts for the direct amide bond formation

“…Such H-bonding interactions facilitating amine attack, and subsequent C-O bond cleavage have been shown instrumental to afford the final product in ours 56 and other's previous studies. 69,75 From intermediate C, product formation releasing a molecule of water, and ligand exchange steps could regenerate species A.…”