(Aminomethylene)phosphonate Analogues as Zn<sup>II</sup> Chelators: Synthesis and Characterization

Hevroni, Bosmat Levi; Jantz, Thomas; Gottlieb, Hugo E.; Fischer, Bilha

doi:10.1002/ejic.201700210

Cited by 2 publications

(12 citation statements)

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“…Heterocyclic moieties such as the imidazolyl group mimic histidine, which is known as the best amino acid ligand for Cu(II) and Zn(II) ions in proteins and peptides . Indeed, we recently reported that AMP-(Im) 2 forms a most stable complex with Zn(II) (log β = 22) . AMP-(Im) 2 was synthesized by formation of an intermediate Schiff base from imidazolyl aldehyde and AMPA followed by Schiff base reduction by 2-picoline-borane.…”

Section: Results and Discussionmentioning

confidence: 99%

“…Moreover, ligands with soft binding sites (e.g., N-heterocycles, thiols, or those with π-bonds) usually form stronger complexes with Cu(II) than with Zn(II) . Although AMPA analogues 3–9 formed strong complexes with Zn(II) with log K values from 6.69 to 12.68, AMP-Th formed the least stable Zn(II) complex, with the lowest log K value, 6.69 . In this study, we determined the stability constants for Cu(II)-AMP-Th and Cu(II)-AMP-(Im) 2 complexes by potentiometric pH titration.…”

Section: Results and Discussionmentioning

confidence: 99%

“…AMP-(Im) 2 , 4 , was synthesized as described previously . Purification of compound 4 was performed by subjecting the reaction’s residue to ion-exchange chromatography (on DEAE-Sephadex A-25 chloride form, swollen overnight in a 1 M NaHCO 3 solution at 4 °C).…”

Section: Experimental Sectionmentioning

confidence: 99%

“…Aminomethylenephosphonic acid (AMPA), 1 , is similar to glycine, 2 , the simplest amino acid, where the carboxylic acid group is replaced by phosphonic acid, yet AMPA is dibasic compared to the monobasic glycine, thus allowing better binding for metal ions and increased water solubility. Therefore, for the synthesis of the new Zn(II)/Cu(II) chelators targeted for medicinal applications, we previously selected the aminomethylene-phosphonate scaffold …”

Section: Introductionmentioning

confidence: 99%

“…Therefore, for the synthesis of the new Zn(II)/Cu(II) chelators targeted for medicinal applications, we previously selected the aminomethylene-phosphonate scaffold. 1 Recently, we reported on a series of aminomethylenephosphonate (AMP) analogues, 3−9, bearing one or two heterocyclic moieties (imidazolyl, pyridyl, and thiazolyl) on the aminomethylene group, as potential Zn(II) chelators (Figure 1). 1 Analogues 3−9 formed stable water-soluble 2:1 L:Zn(II) complexes.…”

Section: ■ Introductionmentioning

confidence: 99%

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Aminomethylene-Phosphonate Analogue as a Cu(II) Chelator: Characterization and Application as an Inhibitor of Oxidation Induced by the Cu(II)–Prion Peptide Complex

et al. 2019

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Recently, we reported on a series of aminomethylene-phosphonate (AMP) analogues, bearing one or two heterocyclic groups on the aminomethylene moiety, as promising Zn(II) chelators. Given the strong Zn(II) binding properties of these compounds, they may find useful applications in metal chelation therapy. With a goal of inhibiting the devastating oxidative damage caused by prion protein in prion diseases, we explored the most promising ligand, {bis[(1H-imidazol-4yl)methyl]amino}methylphosphonic acid, AMP-(Im) 2 , 4, as an inhibitor of the oxidative reactivity associated with the Cu(II) complex of prion peptide fragment 84−114. Specifically, we first characterized the Cu(II) complex with AMP-(Im) 2 by ultraviolet−visible spectroscopy and electrochemical measurements that indicated the high chemical and electrochemical stability of the complex. Potentiometric pH titration provided evidence of the formation of a stable 1:1 [Cu(II)-AMP-(Im) 2 ] + complex (ML), with successive binding of a second AMP-(Im) 2 molecule yielding ML 2 complex [Cu(II)-(AMP-(Im) 2 ) 2 ] + (log K′ = 15.55), and log β′ = 19.84 for ML 2 complex. The CuN3O1 ML complex was demonstrated by X-ray crystallography, indicating the thermodynamically stable square pyramidal complex. Chelation of Cu(II) by 4 significantly reduced the oxidation potential of the former. CuCl 2 and the 1:2 Cu:AMP-(Im) 2 complex showed one-electron redox of Cu(II)/Cu(I) at 0.13 and −0.35 V, respectively. Indeed, 4 was found to be a potent antioxidant that at a 1:1:1 AMP-(Im) 2 :Cu(II)-PrP 84−114 molar ratio almost totally inhibited the oxidation reaction of 4-methylcatechol. Circular dichroism data suggest that this antioxidant activity is due to formation of a ternary, redox inactive Cu(II)-Prp 84−114 -[AMP-(Im) 2 ] complex. Future studies in prion disease animal models are warranted to assess the potential of 4 to inhibit the devastating oxidative damage caused by PrP.

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Section: Results and Discussionmentioning

confidence: 99%

Section: Results and Discussionmentioning

confidence: 99%

Section: Experimental Sectionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

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Aminomethylene-Phosphonate Analogue as a Cu(II) Chelator: Characterization and Application as an Inhibitor of Oxidation Induced by the Cu(II)–Prion Peptide Complex

et al. 2019

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Optimization of 1,2,4-Triazole-3-thiones toward Broad-Spectrum Metallo-β-lactamase Inhibitors Showing Potent Synergistic Activity on VIM- and NDM-1-Producing Clinical Isolates

et al. 2022

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Metallo-β-lactamases (MBLs) contribute to the resistance of Gram-negative bacteria to carbapenems, last-resort antibiotics at hospital, and MBL inhibitors are urgently needed to preserve these important antibacterial drugs. Here, we describe a series of 1,2,4-triazole-3-thione-based inhibitors displaying an αamino acid substituent, which amine was mono-or disubstituted by (hetero)aryl groups. Compounds disubstituted by certain nitrogencontaining heterocycles showed submicromolar activities against VIM-type enzymes and strong NDM-1 inhibition (K i = 10−30 nM). Equilibrium dialysis, native mass spectrometry, isothermal calorimetry (ITC), and X-ray crystallography showed that the compounds inhibited both VIM-2 and NDM-1 at least partially by stripping the catalytic zinc ions. These inhibitors also displayed a very potent synergistic activity with meropenem (16-to 1000-fold minimum inhibitory concentration (MIC) reduction) against VIM-type-and NDM-1-producing ultraresistant clinical isolates, including Enterobacterales and Pseudomonas aeruginosa. Furthermore, selected compounds exhibited no or moderate toxicity toward HeLa cells, favorable absorption, distribution, metabolism, excretion (ADME) properties, and no or modest inhibition of several mammalian metalloenzymes.

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(Aminomethylene)phosphonate Analogues as Zn^II Chelators: Synthesis and Characterization

Abstract: TOC

Cited by 2 publications

References 44 publications

Aminomethylene-Phosphonate Analogue as a Cu(II) Chelator: Characterization and Application as an Inhibitor of Oxidation Induced by the Cu(II)–Prion Peptide Complex

Aminomethylene-Phosphonate Analogue as a Cu(II) Chelator: Characterization and Application as an Inhibitor of Oxidation Induced by the Cu(II)–Prion Peptide Complex

Optimization of 1,2,4-Triazole-3-thiones toward Broad-Spectrum Metallo-β-lactamase Inhibitors Showing Potent Synergistic Activity on VIM- and NDM-1-Producing Clinical Isolates

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(Aminomethylene)phosphonate Analogues as ZnII Chelators: Synthesis and Characterization

Abstract: TOC

Cited by 2 publications

References 44 publications

Aminomethylene-Phosphonate Analogue as a Cu(II) Chelator: Characterization and Application as an Inhibitor of Oxidation Induced by the Cu(II)–Prion Peptide Complex

Aminomethylene-Phosphonate Analogue as a Cu(II) Chelator: Characterization and Application as an Inhibitor of Oxidation Induced by the Cu(II)–Prion Peptide Complex

Optimization of 1,2,4-Triazole-3-thiones toward Broad-Spectrum Metallo-β-lactamase Inhibitors Showing Potent Synergistic Activity on VIM- and NDM-1-Producing Clinical Isolates

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(Aminomethylene)phosphonate Analogues as Zn^II Chelators: Synthesis and Characterization