Recent developments in the synthesis and applications of phosphinic peptide analogs

Talma, Michał; Maślanka, Marta; Mucha, Artur

doi:10.1016/j.bmcl.2019.02.034

Cited by 23 publications

(25 citation statements)

References 81 publications

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“…Critical relevance of its activity for cancer progression caused intensive studies to be undertaken to develop new drugs directed towards this enzyme, including enzyme inhibitors and APN-targeted carrier constructs [15,16]. As a consequence, a variety of APN inhibitors have been developed [17][18][19][20][21][22][23].…”

Section: Introductionmentioning

confidence: 99%

Phosphonic Acid Analogs of Fluorophenylalanines as Inhibitors of Human and Porcine Aminopeptidases N: Validation of the Importance of the Substitution of the Aromatic Ring

et al. 2020

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A library of phosphonic acid analogs of phenylalanine substituted with fluorine, chlorine and trifluoromethyl moieties on the aromatic ring was synthesized and evaluated for inhibitory activity against human (hAPN) and porcine (pAPN) aminopeptidases. Fluorogenic screening indicated that these analogs are micromolar or submicromolar inhibitors, both enzymes being more active against hAPN. In order to better understand the mode of the action of the most active compounds, molecular modeling was used. It confirmed that aminophosphonic portion of the enzyme is bound nearly identically in the case of all the studied compounds, whereas the difference in activity results from the placement of aromatic side chain of an inhibitor. Interestingly, both enantiomers of the individual compounds are usually bound quite similarly.

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Section: Introductionmentioning

confidence: 99%

Phosphonic Acid Analogs of Fluorophenylalanines as Inhibitors of Human and Porcine Aminopeptidases N: Validation of the Importance of the Substitution of the Aromatic Ring

et al. 2020

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“…Phosphinic dipeptides are generally acknowledged as transition-state analog inhibitors of metallo-aminopeptidases [1][2][3], a large and homogenous class of exopeptidases that specifically cleave the N-terminal amino acid residues of polypeptides and proteins and contain metal ion(s) in their active sites. Being ubiquitously distributed in subcellular organelles, cytoplasm, and cellular membranes throughout all of the biological kingdoms, these enzymes perform critical roles in physiological processes and diseases.…”

Section: Introductionmentioning

confidence: 99%

“…Mammalian, protozoan, and bacterial enzymes of the M01 and M17 families have probably been the most comprehensively studied metallo-aminopeptidases with phosphinic dipeptides [2,5].…”

Section: Introductionmentioning

confidence: 99%

“…Mammalian, protozoan, and bacterial enzymes of the M01 and M17 families have probably been the most comprehensively studied metallo-aminopeptidases with phosphinic dipeptides [2,5]. Alanine aminopeptidase (aminopeptidase N, APN, M01.001, EC 3.4.11.2) and leucine aminopeptidase (LAP, M17.001, EC 3.4.11.1) can be considered as the prototypical representatives.…”

Section: Introductionmentioning

confidence: 99%

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P1′ Residue-Oriented Virtual Screening for Potent and Selective Phosphinic (Dehydro) Dipeptide Inhibitors of Metallo-Aminopeptidases

Talma

Mucha

2020

Biomolecules

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Designing side chain substituents complementary to enzyme binding pockets is of great importance in the construction of potent and selective phosphinic dipeptide inhibitors of metallo-aminopeptidases. Proper structure selection makes inhibitor construction more economic, as the development process typically consists of multiple iterative preparation/bioassay steps. On the basis of these principles, using noncomplex computation and modeling methodologies, we comprehensively screened 900 commercial precursors of the P1′ residues of phosphinic dipeptide and dehydrodipeptide analogs to identify the most promising ligands of 52 metallo-dependent aminopeptidases with known crystal structures. The results revealed several nonproteinogenic residues with an improved energy of binding compared with the best known inhibitors. The data are discussed taking into account the selectivity and stereochemical implications of the enzymes. Using this approach, we were able to identify nontrivial structural elements substituting the recognized phosphinic peptidomimetic scaffold of metallo-aminopeptidase inhibitors.

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“…The synthesized extended transition state analogs were tested with porcine, human, and plant M1 and M17 aminopeptidases. Mammalian leucine (M1, Ss LAP) and alanyl aminopeptidases (M1, Ss APN and Hs APN) were targeted as inhibition of these enzymes with phosphorus-modified dipeptide analogues was probably the most thoroughly studied [ 17 , 18 ]. LAP and APN are multifunctional broad-band specificity aminopeptidases of known structures, mechanisms of action, and recognized therapeutic potential [ 19 , 20 , 21 ].…”

Section: Resultsmentioning

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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Recent developments in the synthesis and applications of phosphinic peptide analogs

Cited by 23 publications

References 81 publications

Phosphonic Acid Analogs of Fluorophenylalanines as Inhibitors of Human and Porcine Aminopeptidases N: Validation of the Importance of the Substitution of the Aromatic Ring

Phosphonic Acid Analogs of Fluorophenylalanines as Inhibitors of Human and Porcine Aminopeptidases N: Validation of the Importance of the Substitution of the Aromatic Ring

P1′ Residue-Oriented Virtual Screening for Potent and Selective Phosphinic (Dehydro) Dipeptide Inhibitors of Metallo-Aminopeptidases

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

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