Dipeptidyl Enoates As Potent Rhodesain Inhibitors That Display a Dual Mode of Action

Publication type:
Journal article
Metadata:
Autoren
  • Santiago Royo
  • Santiago Rodriguez
  • Tanja Schirmeister
  • Jochen Kesselring
  • Marcel Kaiser
  • Florenci V Gonzalez
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000360499400005&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1002/cmdc.201500204
eISSN
1860-7187
Externe Identifier
  • Clarivate Analytics Document Solution ID: CQ3JY
  • PubMed Identifier: 26179752
ISSN
1860-7179
Ausgabe der Veröffentlichung
9
Zeitschrift
CHEMMEDCHEM
Schlüsselwörter
  • dipeptidyl enoates
  • inhibitors
  • rhodesain
  • sleeping sickness
  • trypanosomiasis
Paginierung
1484 - 1487
Datum der Veröffentlichung
2015
Status
Published
Titel
Dipeptidyl Enoates As Potent Rhodesain Inhibitors That Display a Dual Mode of Action
Sub types
  • Article
Ausgabe der Zeitschrift
10

Data source: Web of Science (Lite)

Other metadata sources:
Abstract
<jats:title>Abstract</jats:title><jats:p>Dipeptidyl enoates were prepared through a high‐yielding two‐step synthetic route. They have a dipeptidic structure with a 4‐oxoenoate moiety as a warhead with multiple reactive sites. Dipeptidyl enoates were screened against rhodesain and human cathepsins B and L, and were found to be potent and selective inhibitors of rhodesain. Among them (<jats:italic>S</jats:italic>,<jats:italic>E</jats:italic>)‐ethyl 5‐((<jats:italic>S</jats:italic>)‐2‐{[(benzyloxy)carbonyl]amino}‐3‐phenylpropanamido)‐7‐methyl‐4‐oxooct‐2‐enoate (<jats:bold>6</jats:bold>) was the most potent, with an IC<jats:sub>50</jats:sub> value of 16.4 n<jats:sc>M</jats:sc> and <jats:italic>k</jats:italic><jats:sub>inact</jats:sub>/<jats:italic>K</jats:italic><jats:sub>i</jats:sub>=1.6×10<jats:sup>6</jats:sup> <jats:sc>M</jats:sc><jats:sup>−1</jats:sup> s<jats:sup>−1</jats:sup> against rhodesain. These dipeptidyl enoates display a reversible mode of inhibition at very low concentrations and an irreversible mode at higher concentrations. Inhibition kinetics data, supported by docking studies, suggest a dual mode of action via attack of cysteine thiolate at two reactive positions.</jats:p>
Autoren
  • Santiago Royo
  • Santiago Rodríguez
  • Tanja Schirmeister
  • Jochen Kesselring
  • Marcel Kaiser
  • Florenci V González
DOI
10.1002/cmdc.201500204
eISSN
1860-7187
ISSN
1860-7179
Ausgabe der Veröffentlichung
9
Zeitschrift
ChemMedChem
Sprache
en
Online publication date
2015
Paginierung
1484 - 1487
Datum der Veröffentlichung
2015
Status
Published
Herausgeber
Wiley
Herausgeber URL
http://dx.doi.org/10.1002/cmdc.201500204
Datum der Datenerfassung
2023
Titel
Dipeptidyl Enoates As Potent Rhodesain Inhibitors That Display a Dual Mode of Action
Ausgabe der Zeitschrift
10

Data source: Crossref

Abstract
Dipeptidyl enoates were prepared through a high-yielding two-step synthetic route. They have a dipeptidic structure with a 4-oxoenoate moiety as a warhead with multiple reactive sites. Dipeptidyl enoates were screened against rhodesain and human cathepsins B and L, and were found to be potent and selective inhibitors of rhodesain. Among them (S,E)-ethyl 5-((S)-2-{[(benzyloxy)carbonyl]amino}-3-phenylpropanamido)-7-methyl-4-oxooct-2-enoate (6) was the most potent, with an IC50 value of 16.4 nM and kinact /Ki =1.6×10(6)  M(-1)  s(-1) against rhodesain. These dipeptidyl enoates display a reversible mode of inhibition at very low concentrations and an irreversible mode at higher concentrations. Inhibition kinetics data, supported by docking studies, suggest a dual mode of action via attack of cysteine thiolate at two reactive positions.
Addresses
  • Departament de Química Inorgànica i Orgànica, Universitat Jaume I, 12080 Castelló (Spain).
Autoren
  • Santiago Royo
  • Santiago Rodríguez
  • Tanja Schirmeister
  • Jochen Kesselring
  • Marcel Kaiser
  • Florenci V González
DOI
10.1002/cmdc.201500204
eISSN
1860-7187
Externe Identifier
  • PubMed Identifier: 26179752
Open access
false
ISSN
1860-7179
Ausgabe der Veröffentlichung
9
Zeitschrift
ChemMedChem
Schlüsselwörter
  • Humans
  • Trypanosomiasis, African
  • Cathepsin B
  • Cysteine Endopeptidases
  • Dipeptides
  • Cysteine Proteinase Inhibitors
  • Trypanocidal Agents
  • Drug Evaluation, Preclinical
  • Inhibitory Concentration 50
  • Structure-Activity Relationship
  • Kinetics
  • Cathepsin L
  • Molecular Targeted Therapy
  • Chemistry Techniques, Synthetic
  • Molecular Docking Simulation
Sprache
eng
Medium
Print-Electronic
Online publication date
2015
Paginierung
1484 - 1487
Datum der Veröffentlichung
2015
Status
Published
Datum der Datenerfassung
2015
Titel
Dipeptidyl Enoates As Potent Rhodesain Inhibitors That Display a Dual Mode of Action.
Sub types
  • Research Support, Non-U.S. Gov't
  • Journal Article
Ausgabe der Zeitschrift
10

Data source: Europe PubMed Central

Abstract
Dipeptidyl enoates were prepared through a high-yielding two-step synthetic route. They have a dipeptidic structure with a 4-oxoenoate moiety as a warhead with multiple reactive sites. Dipeptidyl enoates were screened against rhodesain and human cathepsins B and L, and were found to be potent and selective inhibitors of rhodesain. Among them (S,E)-ethyl 5-((S)-2-{[(benzyloxy)carbonyl]amino}-3-phenylpropanamido)-7-methyl-4-oxooct-2-enoate (6) was the most potent, with an IC50 value of 16.4 nM and kinact /Ki =1.6×10(6)  M(-1)  s(-1) against rhodesain. These dipeptidyl enoates display a reversible mode of inhibition at very low concentrations and an irreversible mode at higher concentrations. Inhibition kinetics data, supported by docking studies, suggest a dual mode of action via attack of cysteine thiolate at two reactive positions.
Autoren
  • Santiago Royo
  • Santiago Rodríguez
  • Tanja Schirmeister
  • Jochen Kesselring
  • Marcel Kaiser
  • Florenci V González
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/26179752
DOI
10.1002/cmdc.201500204
eISSN
1860-7187
Ausgabe der Veröffentlichung
9
Zeitschrift
ChemMedChem
Schlüsselwörter
  • dipeptidyl enoates
  • inhibitors
  • rhodesain
  • sleeping sickness
  • trypanosomiasis
  • Cathepsin B
  • Cathepsin L
  • Chemistry Techniques, Synthetic
  • Cysteine Endopeptidases
  • Cysteine Proteinase Inhibitors
  • Dipeptides
  • Drug Evaluation, Preclinical
  • Humans
  • Inhibitory Concentration 50
  • Kinetics
  • Molecular Docking Simulation
  • Molecular Targeted Therapy
  • Structure-Activity Relationship
  • Trypanocidal Agents
  • Trypanosomiasis, African
Sprache
eng
Country
Germany
Paginierung
1484 - 1487
Datum der Veröffentlichung
2015
Status
Published
Datum, an dem der Datensatz öffentlich gemacht wurde
2016
Titel
Dipeptidyl Enoates As Potent Rhodesain Inhibitors That Display a Dual Mode of Action.
Sub types
  • Journal Article
  • Research Support, Non-U.S. Gov't
Ausgabe der Zeitschrift
10

Data source: PubMed

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