Unusual activity pattern of leucine aminopeptidase inhibitors based on phosphorus containing derivatives of methionine and norleucine

Pícha, Jan; Liboska, Radek; Budêšínský, Miloś; Jiráček, Jiřı́; Pawełczak, Małgorzata; Mucha, Artur

doi:10.3109/14756366.2010.482047

Cited by 12 publications

(7 citation statements)

References 49 publications

(71 reference statements)

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“…... (15) And this equation is the same as equation (11) which we had already obtained with the assumption that the rate-determining step is relative to the sixth step. Furthermore, in the fifth step the solvent with the high dielectric constant (1, 2-dichloroethane) must be able to stabilize the dipolar intermediate I 3 which has full positive and negative charges and reduces the rate of reaction.…”

Section: (11)mentioning

confidence: 94%

“…They efficiently block bimetallic Zn-related aminopeptidases, i.e. leucine, alanine and methionine aminopeptidase [13][14][15] . The same electrostatic interaction between a negatively charged phosphonate group and the amino acid residue NH3 + , together with some hydrophobic interactions, was used in host-guest type recognition of amino acids by various calixarene derivatives 16,17 .…”

Section: 3rmentioning

confidence: 99%

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A Mechanistic Investigation of Stable Phosphonate Ester Derived from 3, 4 dichloro Aniline: A Kinetics Study and Theoretical Calculations

Habibi‐Khorassani¹,

Maghsoodluo²,

Ebrahimi³

et al. 2012

Orientjchem.

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For the first time, kinetic studies were made of the reactions between triphenyl phosphite 1, dialkyl acetylenedicarboxylates 2 in the presence of NH-acid, such as 3, 4-dicholoro aniline (as a protic/nucleophilic reagent) 3 for the generation of compound 4 with gauche arrangement and [(2S * , 3S * ) or (2R * , 3R * )] configuration. To determine the kinetic parameters of the reaction, monitoring was conducted using UV spectrophotometery. The second order fits were automatically drawn and the values of the second order rate constant (k 2 ) were automatically calculated using standard equations within the program. All reactions were repeated at different temperature ranges, the dependence of the second order rate constant (Ln k 2 ) and (Ln k 2 /T) on the reciprocal temperature were in good agreement with Arrhenius and Eyring equations, respectively. This provided the relevant plots to calculate the kinetic and activation parameters (Ea, ΔH # , ΔS # and ΔG # ) of all reactions. Furthermore, useful information was obtained from studying the of the effect of solvent, structure of reactants (dialkyl acetylenedicarboxylates) and also concentration of reactants on the reaction rates. The proposed mechanism was confirmed according to the obtained results and steady state approximation. The first and third steps (k 2 , k 3 ) of all reactions were recognized as rate determining and a fast steps, respectively on the basis of experimental data. Herein, theoretical calculations have been employed for the assignment of the most stable isomers ([(2S

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Section: (11)mentioning

confidence: 94%

Section: 3rmentioning

confidence: 99%

A Mechanistic Investigation of Stable Phosphonate Ester Derived from 3, 4 dichloro Aniline: A Kinetics Study and Theoretical Calculations

Habibi‐Khorassani¹,

Maghsoodluo²,

Ebrahimi³

et al. 2012

Orientjchem.

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“…The current studies followed the methodologies of the enzyme kinetic experiments, with calculation of the inhibition constants, and the mechanism of inhibition, which are presented in detail in our previous papers: For microsomal alanyl aminopeptidase from porcine kidney [ 27 , 28 , 29 ], recombinant human alanine aminopeptidase [ 30 ], leucine aminopeptidase from porcine kidney [ 27 , 28 , 31 ], and leucine aminopeptidase from barley seeds ( Hv APN) [ 22 , 28 , 29 ].…”

Section: Methodsmentioning

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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“…As far as metalloprotease targets are concerned, inhibition of leucine and alanyl aminopeptidases (LAP and APN) seems to be the most recognized example of biological activity of phosphinic dipeptide analogues [ 45 , 46 , 99 , 108 , 109 , 110 , 111 ]. LAP and APN are multifunctional broad-band specificity aminopeptidases involved in biological functions in both eukaryotic and prokaryotic cells.…”

Section: Applications and Conclusionmentioning

confidence: 99%

Synthesis and Modifications of Phosphinic Dipeptide Analogues

Mucha

2012

Molecules

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Pseudopeptides containing the phosphinate moiety (-P(O)(OH)CH2-) have been studied extensively, mainly as transition state analogue inhibitors of metalloproteases. The key synthetic aspect of their chemistry is construction of phosphinic dipeptide derivatives bearing appropriate side-chain substituents. Typically, this synthesis involves a multistep preparation of two individual building blocks, which are combined in the final step. As this methodology does not allow simple variation of the side-chain structure, many efforts have been dedicated to the development of alternative approaches. Recent achievements in this field are summarized in this review. Improved methods for the formation of the phosphinic peptide backbone, including stereoselective and multicomponent reactions, are presented. Parallel modifications leading to the structurally diversified substituents are also described. Finally, selected examples of the biomedical applications of the title compounds are given.

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Unusual activity pattern of leucine aminopeptidase inhibitors based on phosphorus containing derivatives of methionine and norleucine

Cited by 12 publications

References 49 publications

A Mechanistic Investigation of Stable Phosphonate Ester Derived from 3, 4 dichloro Aniline: A Kinetics Study and Theoretical Calculations

A Mechanistic Investigation of Stable Phosphonate Ester Derived from 3, 4 dichloro Aniline: A Kinetics Study and Theoretical Calculations

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

Synthesis and Modifications of Phosphinic Dipeptide Analogues

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