Biological Evaluation and X-ray Co-crystal Structures of Cyclohexylpyrrolidine Ligands for Trypanothione Reductase, an Enzyme from the Redox Metabolism of Trypanosoma

doi:https://doi.org/10.1002/cmdc.201800067

Title: Biological Evaluation and X-ray Co-crystal Structures of Cyclohexylpyrrolidine Ligands for Trypanothione Reductase, an Enzyme from the Redox Metabolism of Trypanosoma

Authors:

De Gasparo, Raoul ^[1]; Brodbeck-Persch, Elke ^[1]; Bryson, Steve ^[2]; Hentzen, Nina B. ^[1]; Kaiser, Marcel ^[3];

^[2]; Krauth-Siegel, R. Luise ^[4];

^[1]

Laboratorium für Organische Chemie, ETH Zürich, Vladimir-Prelog-Weg 3 8093 Zürich Switzerland
Departments of Biochemistry, Medical Biophysics, and Molecular Genetics, University of Toronto, Medical Sciences Building, #5358, 1 King's College Circle Toronto ON M5S 1A8 Canada; The Campbell Family Institute for Cancer Research, University Health Network, 101 College Street Toronto ON M5G 1L7 Canada
Swiss Tropical and Public Health Institute, Socinstrasse 57 4002 Basel Switzerland; University of Basel, Petersplatz 1 4003 Basel Switzerland
Biochemie-Zentrum Heidelberg (BZH), Universität Heidelberg, Im Neuenheimer Feld 328 69120 Heidelberg Germany

Publication Date:: 2018-04-06

Research Org.:: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Org.:: NCINIGMS

OSTI Identifier:: 1498318

Resource Type:: Journal Article

Journal Name:: ChemMedChem(Print)

Additional Journal Information:: Journal Volume: 13; Journal Issue: 9; Journal ID: ISSN 1860-7179

Publisher:: ChemPubSoc Europe

Country of Publication:: United States

Language:: ENGLISH

Citation Formats


                    De Gasparo, Raoul, Brodbeck-Persch, Elke, Bryson, Steve, Hentzen, Nina B., Kaiser, Marcel, Pai, Emil F., Krauth-Siegel, R. Luise, and Diederich, François. Biological Evaluation and X-ray Co-crystal Structures of Cyclohexylpyrrolidine Ligands for Trypanothione Reductase, an Enzyme from the Redox Metabolism of Trypanosoma.  United States: N. p., 2018. 
        Web.  doi:10.1002/cmdc.201800067.

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                    De Gasparo, Raoul, Brodbeck-Persch, Elke, Bryson, Steve, Hentzen, Nina B., Kaiser, Marcel, Pai, Emil F., Krauth-Siegel, R. Luise, & Diederich, François. Biological Evaluation and X-ray Co-crystal Structures of Cyclohexylpyrrolidine Ligands for Trypanothione Reductase, an Enzyme from the Redox Metabolism of Trypanosoma.  United States.  https://doi.org/10.1002/cmdc.201800067

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                    De Gasparo, Raoul, Brodbeck-Persch, Elke, Bryson, Steve, Hentzen, Nina B., Kaiser, Marcel, Pai, Emil F., Krauth-Siegel, R. Luise, and Diederich, François. Fri .  
        "Biological Evaluation and X-ray Co-crystal Structures of Cyclohexylpyrrolidine Ligands for Trypanothione Reductase, an Enzyme from the Redox Metabolism of Trypanosoma".  United States.  https://doi.org/10.1002/cmdc.201800067.

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@article{osti_1498318,

  title        = {Biological Evaluation and X-ray Co-crystal Structures of Cyclohexylpyrrolidine Ligands for Trypanothione Reductase, an Enzyme from the Redox Metabolism of Trypanosoma},

  author       = {De Gasparo, Raoul and Brodbeck-Persch, Elke and Bryson, Steve and Hentzen, Nina B. and Kaiser, Marcel and Pai, Emil F. and Krauth-Siegel, R. Luise and Diederich, François},

  abstractNote = {},

  doi          = {10.1002/cmdc.201800067},

  url          = {https://www.osti.gov/biblio/1498318},
  journal      = {ChemMedChem(Print)},

  issn         = {1860-7179},

  number       = 9,

  volume       = 13,

  place        = {United States},

  year         = {2018},

  month        = {4}

}

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Title: Biological Evaluation and X-ray Co-crystal Structures of Cyclohexylpyrrolidine Ligands for Trypanothione Reductase, an Enzyme from the Redox Metabolism of Trypanosoma

Citation Formats

Alkalinization of the food vacuole of malaria parasites by quinoline drugs and alkylamines is not correlated with their antimalarial activity journal, August 1989

Substrate specificity of the flavoprotein trypanothione disulfide reductase from Crithidia fasciculata journal, June 1987

Dithiolproteine als Hüter des intrazellulären Redoxmilieus bei Parasiten: alte und neue Wirkstoff-Targets bei Trypanosomiasis und Malaria journal, January 2005

Fast Calculation of Molecular Polar Surface Area as a Sum of Fragment-Based Contributions and Its Application to the Prediction of Drug Transport Properties journal, October 2000

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Passive Permeability and P-Glycoprotein-Mediated Efflux Differentiate Central Nervous System (CNS) and Non-CNS Marketed Drugs journal, December 2002

Conformational adaptation to surroundings of PCP, TCP and BTCP molecules. A tentative explanation for different biochemical specificities journal, October 1991

Suzuki-Miyaura Cross-Coupling Reactions in a Solkane365/227/Ethanol Blend at Ambient Temperature journal, February 2012

One-Pot Desulfonylative Alkylation of N-Sulfonyl Azacycles Using Alkoxides Generated by Phase-Transfer Catalysis journal, December 2009

Trypanothione reductase from Trypanosoma cruzi. Catalytic properties of the enzyme and inhibition studies with trypanocidal compounds journal, March 1989

Management of trypanosomiasis and leishmaniasis journal, November 2012

Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015 journal, October 2016

Treatment options for second-stage gambiense human African trypanosomiasis journal, September 2014

Molecular Recognition in Chemical and Biological Systems journal, January 2015

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Oxetanes in Drug Discovery: Structural and Synthetic Insights journal, April 2010

Conjugation of Quinones with Natural Polyamines: Toward an Expanded Antitrypanosomatid Profile journal, November 2012

Reactions of Oxetan-3- tert -butylsulfinimine for the Preparation of Substituted 3-Aminooxetanes journal, March 2010

Transfer of activation from indoles to alcohols: A new method for the synthesis of aminoethylindoles journal, March 1995

Dihydroquinazolines as a Novel Class of Trypanosoma brucei Trypanothione Reductase Inhibitors: Discovery, Synthesis, and Characterization of their Binding Mode by Protein Crystallography journal, October 2011

Inhibition of the Cysteine Protease Human Cathepsin L by Triazine Nitriles: Amide⋅⋅⋅Heteroarene π-Stacking Interactions and Chalcogen Bonding in the S3 Pocket journal, January 2017

Synthesis and Evaluation of 1-(1-(Benzo[ b ]thiophen-2-yl)cyclohexyl)piperidine (BTCP) Analogues as Inhibitors of Trypanothione Reductase journal, June 2009

XDS journal, January 2010

2-Amino diphenylsulfides as new inhibitors of trypanothione reductase journal, December 1995

Dithiol Proteins as Guardians of the Intracellular Redox Milieu in Parasites: Old and New Drug Targets in Trypanosomes and Malaria-Causing Plasmodia journal, January 2005

Aromatische Ringe in chemischer und biologischer Erkennung: Energien und Strukturen journal, April 2011

Bromination of 3-phenylthiophene journal, February 1967

Trypanosomatidae Diseases: From the Current Therapy to the Efficacious Role of Trypanothione Reductase in Drug Discovery journal, May 2013

Antimalarial drugs inhibiting hemozoin (β-hematin) formation: A mechanistic update journal, February 2007

The Cation−π Interaction journal, June 2012

Folding of the four domains and dimerization are impaired by the Gly446.fwdarw.Glu exchange in human glutathione reductase. Implications for the design of antiparasitic drugs journal, April 1993

A Survey of the Role of Noncovalent Sulfur Interactions in Drug Design journal, March 2015

The Chemistry of N -Substituted Benzotriazoles; Part II. 1 The Preparation of Tertiary Amines Containing Tertiary-Alkyl Groups from Ketones, Secondary Amines, and Organometallic Reagents journal, January 1989

Inhibition of Leishmania infantum Trypanothione Reductase by Azole-Based Compounds: a Comparative Analysis with Its Physiological Substrate by X-ray Crystallography journal, June 2013

Improved Inhibitors of Trypanothione Reductase by Combination of Motifs: Synthesis, Inhibitory Potency, Binding Mode, and Antiprotozoal Activities journal, December 2010

Metabolism and Functions of Trypanothione in the Kinetoplastida journal, October 1992

Molekulare Erkennung in chemischen und biologischen Systemen journal, February 2015

Synthesis, Inhibition Potency, Binding Mode, and Antiprotozoal Activities of Fluorescent Inhibitors of Trypanothione Reductase Based on Mepacrine-Conjugated Diaryl Sulfide Scaffolds journal, October 2009

PHENIX: a comprehensive Python-based system for macromolecular structure solution journal, January 2010

Efficient Stacking on Protein Amide Fragments journal, January 2013

Predicting and Tuning Physicochemical Properties in Lead Optimization: Amine Basicities journal, August 2007

Crystal structure of Trypanosoma cruzi trypanothione reductase in complex with trypanothione, and the structure-based discovery of new natural product inhibitors journal, January 1999

Pentafluorosulfanyl as a Novel Building Block for Enzyme Inhibitors: Trypanothione Reductase Inhibition and Antiprotozoal Activities of Diarylamines journal, January 2009

Aromatic Rings in Chemical and Biological Recognition: Energetics and Structures journal, April 2011

Molecular characterization of the trypanothione reductase gene from Crithidia fasciculata and Trypanosoma brucei: comparison with other flavoprotein disulphide oxidoreductases with respect to substrate specificity and catalytic machanism journal, November 1992

Anti-trypanosomatid drug discovery: an ongoing challenge and a continuing need journal, February 2017

Thiol redox biology of trypanosomatids and potential targets for chemotherapy journal, March 2016

Regioselective palladium-catalyzed cross-coupling reactions in the synthesis of novel 2,3-disubstituted thiophene derivatives journal, September 2001

Inhibition of Leishmania infantum trypanothione reductase by diaryl sulfide derivatives journal, January 2017

A gold-containing drug against parasitic polyamine metabolism: the X-ray structure of trypanothione reductase from Leishmania infantum in complex with auranofin reveals a dual mechanism of enzyme inhibition journal, August 2011

Selective N-alkylation of pyrrolopyrimidines and indoles by “transfer of activation” journal, August 1998

Trypanosomes lacking trypanothione reductase are avirulent and show increased sensitivity to oxidative stress: Trypanosomes lacking trypanothione reductase journal, February 2000

MAB, a generally applicable molecular force field for structure modelling in medicinal chemistry journal, June 1995

Preparation of Tertiary Alkyl Carbinamines, Propargylamines, and α -Heteroarylamines by Ketone-Based Aminoalkylation journal, January 2005

Charge is the major discriminating factor for glutathione reductase versus trypanothione reductase inhibitors journal, August 1996

Kinetoplastids: related protozoan pathogens, different diseases journal, April 2008

Inhibition of Trypanosoma cruzi Trypanothione Reductase by Acridines: Kinetic Studies and Structure−Activity Relationships journal, December 1999

Phaser crystallographic software journal, July 2007

Alkalinization of the food vacuole of malaria parasites by quinoline drugs and alkylamines is not correlated with their antimalarial activity
journal, August 1989

Substrate specificity of the flavoprotein trypanothione disulfide reductase from Crithidia fasciculata
journal, June 1987

Dithiolproteine als Hüter des intrazellulären Redoxmilieus bei Parasiten: alte und neue Wirkstoff-Targets bei Trypanosomiasis und Malaria
journal, January 2005

Fast Calculation of Molecular Polar Surface Area as a Sum of Fragment-Based Contributions and Its Application to the Prediction of Drug Transport Properties
journal, October 2000

Crystal structure of theTrypanosoma cruzi trypanothione reductase·mepacrine complex
journal, January 1996

Diaryl sulfide-based inhibitors of trypanothione reductase: inhibition potency, revised binding mode and antiprotozoal activities
journal, January 2008

Passive Permeability and P-Glycoprotein-Mediated Efflux Differentiate Central Nervous System (CNS) and Non-CNS Marketed Drugs
journal, December 2002

Conformational adaptation to surroundings of PCP, TCP and BTCP molecules. A tentative explanation for different biochemical specificities
journal, October 1991

Suzuki-Miyaura Cross-Coupling Reactions in a Solkane365/227/Ethanol Blend at Ambient Temperature
journal, February 2012

One-Pot Desulfonylative Alkylation of N-Sulfonyl Azacycles Using Alkoxides Generated by Phase-Transfer Catalysis
journal, December 2009

Trypanothione reductase from Trypanosoma cruzi. Catalytic properties of the enzyme and inhibition studies with trypanocidal compounds
journal, March 1989

Management of trypanosomiasis and leishmaniasis
journal, November 2012

Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015
journal, October 2016

Treatment options for second-stage gambiense human African trypanosomiasis
journal, September 2014

Molecular Recognition in Chemical and Biological Systems
journal, January 2015

Two Interacting Binding Sites for Quinacrine Derivatives in the Active Site of Trypanothione Reductase: A TEMPLATE FOR DRUG DESIGN
journal, April 2004

Oxetanes in Drug Discovery: Structural and Synthetic Insights
journal, April 2010

Conjugation of Quinones with Natural Polyamines: Toward an Expanded Antitrypanosomatid Profile
journal, November 2012

Reactions of Oxetan-3- tert -butylsulfinimine for the Preparation of Substituted 3-Aminooxetanes
journal, March 2010

Transfer of activation from indoles to alcohols: A new method for the synthesis of aminoethylindoles
journal, March 1995

Dihydroquinazolines as a Novel Class of Trypanosoma brucei Trypanothione Reductase Inhibitors: Discovery, Synthesis, and Characterization of their Binding Mode by Protein Crystallography
journal, October 2011

Inhibition of the Cysteine Protease Human Cathepsin L by Triazine Nitriles: Amide⋅⋅⋅Heteroarene π-Stacking Interactions and Chalcogen Bonding in the S3 Pocket
journal, January 2017

Synthesis and Evaluation of 1-(1-(Benzo[ b ]thiophen-2-yl)cyclohexyl)piperidine (BTCP) Analogues as Inhibitors of Trypanothione Reductase
journal, June 2009

XDS
journal, January 2010

2-Amino diphenylsulfides as new inhibitors of trypanothione reductase
journal, December 1995

Dithiol Proteins as Guardians of the Intracellular Redox Milieu in Parasites: Old and New Drug Targets in Trypanosomes and Malaria-Causing Plasmodia
journal, January 2005

Aromatische Ringe in chemischer und biologischer Erkennung: Energien und Strukturen
journal, April 2011

Bromination of 3-phenylthiophene
journal, February 1967

Trypanosomatidae Diseases: From the Current Therapy to the Efficacious Role of Trypanothione Reductase in Drug Discovery
journal, May 2013

Antimalarial drugs inhibiting hemozoin (β-hematin) formation: A mechanistic update
journal, February 2007

The Cation−π Interaction
journal, June 2012

Folding of the four domains and dimerization are impaired by the Gly446.fwdarw.Glu exchange in human glutathione reductase. Implications for the design of antiparasitic drugs
journal, April 1993

A Survey of the Role of Noncovalent Sulfur Interactions in Drug Design
journal, March 2015

The Chemistry of N -Substituted Benzotriazoles; Part II. ¹ The Preparation of Tertiary Amines Containing Tertiary-Alkyl Groups from Ketones, Secondary Amines, and Organometallic Reagents
journal, January 1989

Inhibition of Leishmania infantum Trypanothione Reductase by Azole-Based Compounds: a Comparative Analysis with Its Physiological Substrate by X-ray Crystallography
journal, June 2013

Improved Inhibitors of Trypanothione Reductase by Combination of Motifs: Synthesis, Inhibitory Potency, Binding Mode, and Antiprotozoal Activities
journal, December 2010

Metabolism and Functions of Trypanothione in the Kinetoplastida
journal, October 1992

Molekulare Erkennung in chemischen und biologischen Systemen
journal, February 2015

Synthesis, Inhibition Potency, Binding Mode, and Antiprotozoal Activities of Fluorescent Inhibitors of Trypanothione Reductase Based on Mepacrine-Conjugated Diaryl Sulfide Scaffolds
journal, October 2009

PHENIX: a comprehensive Python-based system for macromolecular structure solution
journal, January 2010

Efficient Stacking on Protein Amide Fragments
journal, January 2013

Predicting and Tuning Physicochemical Properties in Lead Optimization: Amine Basicities
journal, August 2007

Crystal structure of Trypanosoma cruzi trypanothione reductase in complex with trypanothione, and the structure-based discovery of new natural product inhibitors
journal, January 1999

Pentafluorosulfanyl as a Novel Building Block for Enzyme Inhibitors: Trypanothione Reductase Inhibition and Antiprotozoal Activities of Diarylamines
journal, January 2009

Aromatic Rings in Chemical and Biological Recognition: Energetics and Structures
journal, April 2011

Molecular characterization of the trypanothione reductase gene from Crithidia fasciculata and Trypanosoma brucei: comparison with other flavoprotein disulphide oxidoreductases with respect to substrate specificity and catalytic machanism
journal, November 1992

Anti-trypanosomatid drug discovery: an ongoing challenge and a continuing need
journal, February 2017

Thiol redox biology of trypanosomatids and potential targets for chemotherapy
journal, March 2016

Regioselective palladium-catalyzed cross-coupling reactions in the synthesis of novel 2,3-disubstituted thiophene derivatives
journal, September 2001

Inhibition of Leishmania infantum trypanothione reductase by diaryl sulfide derivatives
journal, January 2017

A gold-containing drug against parasitic polyamine metabolism: the X-ray structure of trypanothione reductase from Leishmania infantum in complex with auranofin reveals a dual mechanism of enzyme inhibition
journal, August 2011

Selective N-alkylation of pyrrolopyrimidines and indoles by “transfer of activation”
journal, August 1998

Trypanosomes lacking trypanothione reductase are avirulent and show increased sensitivity to oxidative stress: Trypanosomes lacking trypanothione reductase
journal, February 2000

MAB, a generally applicable molecular force field for structure modelling in medicinal chemistry
journal, June 1995

Preparation of Tertiary Alkyl Carbinamines, Propargylamines, and α -Heteroarylamines by Ketone-Based Aminoalkylation
journal, January 2005

Charge is the major discriminating factor for glutathione reductase versus trypanothione reductase inhibitors
journal, August 1996

Kinetoplastids: related protozoan pathogens, different diseases
journal, April 2008

Inhibition of Trypanosoma cruzi Trypanothione Reductase by Acridines: Kinetic Studies and Structure−Activity Relationships
journal, December 1999

Phaser crystallographic software
journal, July 2007