Cis-configured aziridines are new pseudo-irreversible dual-mode inhibitors of Candida albicans secreted aspartic protease 2

Publikationstyp:
Zeitschriftenaufsatz
Metadaten:
Autoren
  • Bjoern Degel
  • Peter Staib
  • Sebastian Rohrer
  • Josef Scheiber
  • Erika Martina
  • Christian Buechold
  • Knut Baumann
  • Joachim Morschhaeuser
  • Tanja Schirmeister
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000254022600012&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1002/cmdc.200700101
eISSN
1860-7187
Externe Identifier
  • Clarivate Analytics Document Solution ID: 274SY
  • PubMed Identifier: 18038380
ISSN
1860-7179
Ausgabe der Veröffentlichung
2
Zeitschrift
CHEMMEDCHEM
Schlüsselwörter
  • aspartic proteases
  • aziridines
  • Candida albicans
  • epoxides
  • inhibitors
Paginierung
302 - 315
Datum der Veröffentlichung
2008
Status
Published
Titel
Cis-configured aziridines are new pseudo-irreversible dual-mode inhibitors of <i>Candida albicans</i> secreted aspartic protease 2
Sub types
  • Article
Ausgabe der Zeitschrift
3

Datenquelle: Web of Science (Lite)

Andere Metadatenquellen:
Abstract
<jats:title>Abstract</jats:title><jats:p>A series of <jats:italic>cis</jats:italic>‐configured epoxides and aziridines containing hydrophobic moieties and amino acid esters were synthesized as new potential inhibitors of the secreted aspartic protease 2 (SAP2) of <jats:italic>Candida albicans</jats:italic>. Enzyme assays revealed the <jats:italic>N</jats:italic>‐benzyl‐3‐phenyl‐substituted aziridines <jats:bold>11</jats:bold> and <jats:bold>17</jats:bold> as the most potent inhibitors, with second‐order inhibition rate constants (<jats:italic>k</jats:italic><jats:sub>2</jats:sub>) between 56 000 and 121 000 <jats:sc>M</jats:sc><jats:sup>−1</jats:sup><jats:italic> </jats:italic>min<jats:sup>−1</jats:sup>. The compounds were shown to be pseudo‐irreversible dual‐mode inhibitors: the intermediate esterified enzyme resulting from nucleophilic ring opening was hydrolyzed and yielded amino alcohols as transition‐state‐mimetic reversible inhibitors. The results of docking studies with the ring‐closed aziridine forms of the inhibitors suggest binding modes mainly dominated by hydrophobic interactions with the S1, S1′, S2, and S2′ subsites of the protease, and docking studies with the processed amino alcohol forms predict additional hydrogen bonds of the new hydroxy group to the active site Asp residues. <jats:italic>C. albicans</jats:italic> growth assays showed the compounds to decrease SAP2‐dependent growth while not affecting SAP2‐independent growth.</jats:p>
Autoren
  • Björn Degel
  • Peter Staib
  • Sebastian Rohrer
  • Josef Scheiber
  • Erika Martina
  • Christian Büchold
  • Knut Baumann
  • Joachim Morschhäuser
  • Tanja Schirmeister
DOI
10.1002/cmdc.200700101
eISSN
1860-7187
ISSN
1860-7179
Ausgabe der Veröffentlichung
2
Zeitschrift
ChemMedChem
Sprache
en
Online publication date
2008
Paginierung
302 - 315
Datum der Veröffentlichung
2008
Status
Published
Herausgeber
Wiley
Herausgeber URL
http://dx.doi.org/10.1002/cmdc.200700101
Datum der Datenerfassung
2023
Titel
<i>Cis</i>‐Configured Aziridines Are New Pseudo‐Irreversible Dual‐Mode Inhibitors of <i>Candida albicans</i> Secreted Aspartic Protease 2
Ausgabe der Zeitschrift
3

Datenquelle: Crossref

Abstract
A series of cis-configured epoxides and aziridines containing hydrophobic moieties and amino acid esters were synthesized as new potential inhibitors of the secreted aspartic protease 2 (SAP2) of Candida albicans. Enzyme assays revealed the N-benzyl-3-phenyl-substituted aziridines 11 and 17 as the most potent inhibitors, with second-order inhibition rate constants (k(2)) between 56,000 and 121,000 M(-1) min(-1). The compounds were shown to be pseudo-irreversible dual-mode inhibitors: the intermediate esterified enzyme resulting from nucleophilic ring opening was hydrolyzed and yielded amino alcohols as transition-state-mimetic reversible inhibitors. The results of docking studies with the ring-closed aziridine forms of the inhibitors suggest binding modes mainly dominated by hydrophobic interactions with the S1, S1', S2, and S2' subsites of the protease, and docking studies with the processed amino alcohol forms predict additional hydrogen bonds of the new hydroxy group to the active site Asp residues. C. albicans growth assays showed the compounds to decrease SAP2-dependent growth while not affecting SAP2-independent growth.
Addresses
  • Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
Autoren
  • Björn Degel
  • Peter Staib
  • Sebastian Rohrer
  • Josef Scheiber
  • Erika Martina
  • Christian Büchold
  • Knut Baumann
  • Joachim Morschhäuser
  • Tanja Schirmeister
DOI
10.1002/cmdc.200700101
eISSN
1860-7187
Externe Identifier
  • PubMed Identifier: 18038380
Open access
false
ISSN
1860-7179
Ausgabe der Veröffentlichung
2
Zeitschrift
ChemMedChem
Schlüsselwörter
  • Candida albicans
  • Amino Alcohols
  • Epoxy Compounds
  • Aziridines
  • Amino Acids
  • Fungal Proteins
  • Cysteine Proteinase Inhibitors
  • Antifungal Agents
  • Crystallography, X-Ray
  • Binding Sites
  • Substrate Specificity
  • Hydrolysis
  • Kinetics
  • Stereoisomerism
  • Hydrogen-Ion Concentration
  • Aspartic Acid Endopeptidases
  • Hydrophobic and Hydrophilic Interactions
Sprache
eng
Medium
Print
Paginierung
302 - 315
Datum der Veröffentlichung
2008
Status
Published
Datum der Datenerfassung
2007
Titel
Cis-Configured aziridines are new pseudo-irreversible dual-mode inhibitors of Candida albicans secreted aspartic protease 2.
Sub types
  • Research Support, Non-U.S. Gov't
  • Journal Article
Ausgabe der Zeitschrift
3

Datenquelle: Europe PubMed Central

Abstract
A series of cis-configured epoxides and aziridines containing hydrophobic moieties and amino acid esters were synthesized as new potential inhibitors of the secreted aspartic protease 2 (SAP2) of Candida albicans. Enzyme assays revealed the N-benzyl-3-phenyl-substituted aziridines 11 and 17 as the most potent inhibitors, with second-order inhibition rate constants (k(2)) between 56,000 and 121,000 M(-1) min(-1). The compounds were shown to be pseudo-irreversible dual-mode inhibitors: the intermediate esterified enzyme resulting from nucleophilic ring opening was hydrolyzed and yielded amino alcohols as transition-state-mimetic reversible inhibitors. The results of docking studies with the ring-closed aziridine forms of the inhibitors suggest binding modes mainly dominated by hydrophobic interactions with the S1, S1', S2, and S2' subsites of the protease, and docking studies with the processed amino alcohol forms predict additional hydrogen bonds of the new hydroxy group to the active site Asp residues. C. albicans growth assays showed the compounds to decrease SAP2-dependent growth while not affecting SAP2-independent growth.
Autoren
  • Björn Degel
  • Peter Staib
  • Sebastian Rohrer
  • Josef Scheiber
  • Erika Martina
  • Christian Büchold
  • Knut Baumann
  • Joachim Morschhäuser
  • Tanja Schirmeister
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/18038380
DOI
10.1002/cmdc.200700101
eISSN
1860-7187
Ausgabe der Veröffentlichung
2
Zeitschrift
ChemMedChem
Schlüsselwörter
  • Amino Acids
  • Amino Alcohols
  • Antifungal Agents
  • Aspartic Acid Endopeptidases
  • Aziridines
  • Binding Sites
  • Candida albicans
  • Crystallography, X-Ray
  • Cysteine Proteinase Inhibitors
  • Epoxy Compounds
  • Fungal Proteins
  • Hydrogen-Ion Concentration
  • Hydrolysis
  • Hydrophobic and Hydrophilic Interactions
  • Kinetics
  • Stereoisomerism
  • Substrate Specificity
Sprache
eng
Country
Germany
Paginierung
302 - 315
Datum der Veröffentlichung
2008
Status
Published
Datum, an dem der Datensatz öffentlich gemacht wurde
2008
Titel
Cis-Configured aziridines are new pseudo-irreversible dual-mode inhibitors of Candida albicans secreted aspartic protease 2.
Sub types
  • Journal Article
  • Research Support, Non-U.S. Gov't
Ausgabe der Zeitschrift
3

Datenquelle: PubMed

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