A phosphonamidate dipeptide analog as an inhibitor of carboxypeptidase A

Jacobsen, Neil E.; Bartlett, Paul A.

doi:10.1021/ja00393a026

Cited by 219 publications

(102 citation statements)

References 3 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…7À10,14 At pH values >7.0, 0960-894X/00/$ -see front matter # 2000 Elsevier Science Ltd. All rights reserved. P I I : S 0 9 6 0 -8 9 4 X ( 0 0 ) 0 0 1 8 6 -4 phosphonamidate 1 is stable for over a week at 4 o C, in agreement with previous studies by Bartlett 10 To assess the inhibition properties of these compounds, steady-state kinetic studies were conducted using recombinant VanX and the continuous assay for VanX activity recently reported by our lab. 15 In excellent agreement with Walsh and co-workers, 1 the phosphonate 3 is a competitive inhibitor of VanX with a K i of 400 AE 8 mM at pH 7.0.…”

supporting

confidence: 85%

“…The monomethyl ester 9 was obtained by partial base-catalyzed hydrolysis of dimethyl ester 8 and was subsequently converted by treatment with thionyl chloride in dichloromethane to chlorophosphonate 10. This strategy revealed the key intermediate chlorophosphonate 10 could be coupled with d-lactic acid methyl ester or d-alanine methyl ester and converted using previously published procedures 8,10,14 to aord the phosphonate 3 and phosphonamidate 1. Similar synthetic Schemes are thoroughly precedented in the literature.…”

mentioning

confidence: 99%

“…The crystal structure of VanX demonstrated that the comparable N±H in substrate d-Ala-d-Ala is hydrogen bonded to the backbone carbonyl of Tyr109. 6 To extend the synthetic route in Scheme 1 to generate additional potential inhibitors of VanX, chlorophosphonate 10 was coupled with methyl mercaptoacetate and deprotected using standard procedures 8,10,14 to yield the phosphothioate 2. This compound was shown to be stable for over a week at 4 C and at pH 7.0.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Phosphonamidate and phosphothioate dipeptides as potential inhibitors of VanX

Yang

Brandt

Chatwood

et al. 2000

Bioorganic & Medicinal Chemistry Letters

View full text Add to dashboard Cite

supporting

confidence: 85%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Phosphonamidate and phosphothioate dipeptides as potential inhibitors of VanX

Yang

Brandt

Chatwood

et al. 2000

Bioorganic & Medicinal Chemistry Letters

View full text Add to dashboard Cite

“…9,10 These biological properties mostly are associated with the tetrahedral structure of the phosphonyl group acting as a "transition-state" analogue. 11 Because of their ability to mimic transition states of hydrolysis, phosphonic acid derivatives having heterocycles at the α-positions have been shown to be inhibitors of various enzymes, including HIV-protease and human collagenase. 12 At present, the literature concerning the synthesis and application of α-aminophosphonates is very extensive, comprising more than six thousand publications.…”

Section: Introductionmentioning

confidence: 99%

Methods for the synthesis of α-heterocyclic/heteroaryl-α-aminophosphonic acids and their esters

Ali¹,

Abdel‐Kariem²

2015

Arkivoc

View full text Add to dashboard Cite

show abstract

“…A series of compounds ranging from simple carboxylates to large polypeptides [I, 2, 6 -91 have been shown to possess various inhibitory properties towards CPA-catalyzed reactions. Among those compounds, analogs of dipeptide and tripeptide substrates containing phosphonate or phosphonamidate groups in place of the peptide link are known to be the most potent inhibitors [2,4]. The tight binding of this class of compounds in explained by their structural analogy to the transition state of the enzymatic reaction [4,.…”

mentioning

confidence: 99%

X‐ray diffraction study of the interaction between carboxypeptidase A and (S)‐(+)‐1‐amino‐2‐phenylethyl phosphonic acid

Mangani

Carloni

Orioli

1992

European Journal of Biochemistry

View full text Add to dashboard Cite

The structure of the carboxypeptidase A complex with the inhibitor (5')-(+)-I-amino-2-phenylethylphosphonic acid has been determined at 0.23 nm resolution. The AF map shows electrondensity peaks both in the S1 and s', sites, where the inhibitor molecule can be modeled in two different orientations with approximate 50% occupancy. In the proposed model, the phosphonate group binds to the zinc ion in a monodentate fashion. Other anchoring groups for the inhibitor molecule are Argl27 (hydrogen bonds with the phosphonate oxygen atoms) and Glu270 (hydrogen bond with the amino group in one of the two orientations).A recent spectroscopic investigation of the complex between cobalt(I1) carboxypeptidase A and (5')-(+)-I -amino-2-phenylethylphosphonic acid is essentially in agreement with our results.The study of inhibitors of carboxypeptidase A (CPA) has received considerable attention owing to their importance in contributing to the elucidation of the mechanism of action of the enzyme, and consequently to constitute a valid model for the design of drugs against pathologies in which other zinc proteases of unknown structure (e. g. angiotensin-converting enzyme, collagenase) are involved [I -41. In this respect, highresolution crystallographic studies of several CPA-inhibitor complexes have led to the recent formulation of a mechanistic proposal for the CPA-catalyzed hydrolysis of peptides [ 5 ] .Together with spectroscopic studies, these investigations have highlighted the structural features of the active-site cavity of the enzyme, which are responsible for the binding of the inhibitor: the S; pocket, specific for a PI hydrophobic side chain; Argl45 which binds a terminal carboxylate; Glu270 which can interact both with amino or amide nitrogens, hydroxyl groups and intact carboxylates; the zinc ion itself, which has the ability to coordinate phosphate, carboxylate and sulphydryl groups. A series of compounds ranging from simple carboxylates to large polypeptides [I, 2, 6 - A recent spectroscopic study on the complex between the title compound and the cobalt derivative of CPA [18] has shown that substitution of the carboxylate group of D-phenylalanine (DPhe) by a phosphonate group causes a 1000-fold increase in the Ki of the inhibitor. A new type of binding for the phosphonic amino acid has been suggested in which the aromatic side chain does not lie in the S; hydrophobic pocket, but is bound in the adjacent S, site. In view of the unique behavior of this inhibitor molecule, we have undertaken an X-ray structural investigation on the complex between CPA and the (S)-(+)-l-amino-2-phenylethylphosphonic acid (Phe-P). MATERIALS AND METHODSAll the reagents used were of analytical grade. Phe-P, which is the analog of DPhe with a phosphate group in place of the carboxylic group (Scheme l), was a generous gift of Prof. H. Kozlowsky [18, 191. Bovine CPA, prepared by the method of Cox [20], was purchased from Sigma Chemical Co. and used without further purification. CPA was crystallized in space group P21 [21] (a = 5.160 nm, b = ...

show abstract

A phosphonamidate dipeptide analog as an inhibitor of carboxypeptidase A

Cited by 219 publications

References 3 publications

Phosphonamidate and phosphothioate dipeptides as potential inhibitors of VanX

Phosphonamidate and phosphothioate dipeptides as potential inhibitors of VanX

Methods for the synthesis of α-heterocyclic/heteroaryl-α-aminophosphonic acids and their esters

X‐ray diffraction study of the interaction between carboxypeptidase A and (S)‐(+)‐1‐amino‐2‐phenylethyl phosphonic acid

Contact Info

Product

Resources

About