A three-component Mannich-type condensation leading to phosphinic dipeptides—extended transition state analogue inhibitors of aminopeptidases

Dziełak, Anna; Pawełczak, Małgorzata; Mucha, Artur

doi:10.1016/j.tetlet.2011.04.037

Cited by 12 publications

(8 citation statements)

References 30 publications

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“…The studied group included phosphonic derivative of arginine ( 1 ), an analogue of the fasted cleaved natural amino acid substrate Arg-ACC. All other five are derivatives of homophenyloalanine: α-aminophosphonic acid ( 2 ) [26], α-amino- H -phosphinic acid ( 3 ) [27] and three phosphinic pseudodipeptide analogues ( 4 – 6 ) [27,28]. Previously, this hydrophobic amino acid (hPhe) appeared to bear a P1 substituent privileged for inhibition of metalloaminopeptidases [27].…”

Section: Resultsmentioning

confidence: 99%

“…The solvent composition system was as follows: stream A (water with 0.1 % of trifluoroacetic acid, TFA] and stream B (acetonitrile/water 80%/20% (v/v) with 0.1% of TFA). The appropriate inhibitors were available from previous studies [26–28]. Gene cloning, protein expression in E. coli and purification of Nm APN were performed using the procedure described elsewhere [13].…”

Section: Methodsmentioning

confidence: 99%

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An integrated approach to the ligand binding specificity of Neisseria meningitidis M1 alanine aminopeptidase by fluorogenic substrate profiling, inhibitory studies and molecular modeling

et al. 2013

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Neisseria meningitides is a gram-negative diplococcus bacterium and is the main causative agent of meningitis and other meningococcal diseases. Alanine aminopeptidase from N. meningitides (NmAPN) belongs to the family of metallo-exopeptidase enzymes, which catalyze the removal of amino acids from the N-terminus of peptides and proteins, and are found among all the kingdoms of life. NmAPN is suggested to be mostly responsible for proteolysis and nutrition delivery, similar to the orthologs from other bacteria. To explore the possibility of NmAPN being a potential drug target for inhibition and development of novel therapeutic agents, the specificity of the S1 and S1′ binding sites were explored using an integrated approach. Initially, an extensive library consisting of almost 100 fluorogenic substrates derived from both natural and unnatural amino acids, were used to obtain a detailed substrate fingerprint of the S1 pocket of NmAPN. A broad substrate tolerance of NmAPN was revealed, with bulky basic and hydrophobic ligands being the most favored substrates. Additionally, the potency of a set of organophosphorus inhibitors of neutral aminopeptidases, amino acid and dipeptide analogues was determined. Inhibition constants in the nanomolar range, determined for phosphinic dipeptides, proves the positive increase in inhibition impact of the P1′ ligand elongation. The results were further verified via molecular modeling and docking of canonical aminopeptidase phosphinic dipeptide inhibitors in the NmAPN active site. These studies present comprehensive characterization of interactions responsible for specific ligand binding. This knowledge provides invaluable insight into understanding of the enzyme and development of novel NmAPN inhibitors.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

An integrated approach to the ligand binding specificity of Neisseria meningitidis M1 alanine aminopeptidase by fluorogenic substrate profiling, inhibitory studies and molecular modeling

et al. 2013

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“…38,39 As proven in our previous study, the phospha-Mannich condensation was not efficient for primary amines and produced a complex mixture of the desired product and byproducts. 40 Therefore, obtaining monosubstituted bis-(aminomethyl)phosphinic acid analogues demanded the use of the appropriate N-benzyl-N-alkylamines as secondary precursors. Accordingly, primary amines were subjected to Nbenzylation by a reductive amination and then used in the three-component condensation to give 32−40 in reasonable yields and purity.…”

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confidence: 99%

Bis(aminomethyl)phosphinic Acid, a Highly Promising Scaffold for the Development of Bacterial Urease Inhibitors

Macegoniuk

Dziełak

Mucha

et al. 2014

ACS Med. Chem. Lett.

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Inhibitors of bacterial ureases are considered to be promising compounds in the treatment of infections caused by Helicobacter pylori in the gastric tract and/or by urealytic bacteria (e.g., Proteus species) in the urinary tract. A new, extended transition state scaffold, bis(aminomethyl)phosphinic acid, was successfully explored for the construction of effective enzyme inhibitors. A reliable methodology for the synthesis of phosphinate analogues in a three-component Mannich-type reaction was elaborated. The obtained molecules were assayed against ureases purified from Sporosarcina pasteurii and Proteus mirabilis, and aminomethyl(N-n-hexylaminomethyl)phosphinic acid was found to be the most potent inhibitor, with a K i = 108 nM against the S. pasteurii enzyme.

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“…Aminomethylphosphinates should have also merged advantageous active site interactions of phosphonamidates with the chemical stability of phosphinates. Indeed, such a system appeared effective in the construction of inhibitors for aminopeptidases [ 7 ] and urease [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

N-Benzyl Residues as the P1′ Substituents in Phosphorus-Containing Extended Transition State Analog Inhibitors of Metalloaminopeptidases

et al. 2020

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Peptidyl enzyme inhibitors containing an internal aminomethylphosphinic bond system (P(O)(OH)-CH2-NH) can be termed extended transition state analogs by similarity to the corresponding phosphonamidates (P(O)(OH)-NH). Phosphonamidate pseudopeptides are broadly recognized as competitive mechanism-based inhibitors of metalloenzymes, mainly hydrolases. Their practical use is, however, limited by hydrolytic instability, which is particularly restricting for dipeptide analogs. Extension of phosphonamidates by addition of the methylene group produces a P-C-N system fully resistant in water conditions. In the current work, we present a versatile synthetic approach to such modified dipeptides, based on the three-component phospha-Mannich condensation of phosphinic acids, formaldehyde, and N-benzylglycines. The last-mentioned component allowed for simple and versatile introduction of functionalized P1′ residues located on the tertiary amino group. The products demonstrated moderate inhibitory activity towards porcine and plant metalloaminopeptidases, while selected derivatives appeared very potent with human alanyl aminopeptidase (Ki = 102 nM for 6a). Analysis of ligand-protein complexes obtained by molecular modelling revealed canonical modes of interactions for mono-metallic alanyl aminopeptidases, and distorted modes for di-metallic leucine aminopeptidases (with C-terminal carboxylate, not phosphinate, involved in metal coordination). In general, the method can be dedicated to examine P1′-S1′ complementarity in searching for non-evident structures of specific residues as the key fragments of perspective ligands.

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A three-component Mannich-type condensation leading to phosphinic dipeptides—extended transition state analogue inhibitors of aminopeptidases

Cited by 12 publications

References 30 publications

An integrated approach to the ligand binding specificity of Neisseria meningitidis M1 alanine aminopeptidase by fluorogenic substrate profiling, inhibitory studies and molecular modeling

An integrated approach to the ligand binding specificity of Neisseria meningitidis M1 alanine aminopeptidase by fluorogenic substrate profiling, inhibitory studies and molecular modeling

Bis(aminomethyl)phosphinic Acid, a Highly Promising Scaffold for the Development of Bacterial Urease Inhibitors

N-Benzyl Residues as the P1′ Substituents in Phosphorus-Containing Extended Transition State Analog Inhibitors of Metalloaminopeptidases

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