Mechanistic Study on C–C Bond Formation of a Nickel(I) Monocarbonyl Species with Alkyl Iodides: Experimental and Computational Investigations

Unlike C-N bond formation with classical dirhodium(II)-nitrenoids as the key intermediate, dirhodium(II)-catalyzed 1,2-and 1,3-diamination reactions are realized by a free radical mechanism. A mechanistic study revealed that the reactions undergo...

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Mechanism of Covalent Binding of Ibrutinib to Bruton’s Tyrosine Kinase revealed by QM/MM Calculations

10.26434/chemrxiv.13149893 ◽

2020 ◽

Author(s):

Angus Voice ◽

Gary Tresadern ◽

Rebecca Twidale ◽

Herman Van Vlijmen ◽

Adrian Mulholland

Keyword(s):

Tyrosine Kinase ◽

Covalent Binding ◽

Bond Formation ◽

Covalent Bond ◽

Covalent Modification ◽

Mechanistic Study ◽

Bruton’S Tyrosine Kinase ◽

Bruton's Tyrosine Kinase ◽

Covalent Inhibitors ◽

Covalent Bond Formation

Ibrutinib is the first covalent inhibitor of Bruton’s tyrosine kinase (BTK) to be used in the treatment of B-cell cancers. Understanding the mechanism of covalent inhibition is crucial for the design of safer and more selective covalent inhibitors that target BTK. There are questions surrounding the precise mechanism of covalent bond formation in BTK as there is no appropriate active site residue that can act as a base to deprotonate the cysteine thiol prior to covalent bond formation. To address this, we have investigated several mechanistic pathways of covalent modification of C481 in BTK by ibrutinib using QM/MM reaction simulations. The lowest energy pathway we identified involves a direct proton transfer from C481 to the acrylamide warhead in ibrutinib, followed by covalent bond formation to form an enol intermediate. There is a subsequent rate-limiting keto-enol tautomerisation step (DG‡=10.5 kcal mol-1) to reach the inactivated BTK/ibrutinib complex. Our results represent the first mechanistic study of BTK inactivation by ibrutinib to consider multiple mechanistic pathways. These findings should aid in the design of covalent drugs that target BTK and related proteins.

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A mechanistic study supports a two-step mechanism for peptide bond formation on the ribosome

Physical Chemistry Chemical Physics ◽

10.1039/c3cp51082d ◽

2013 ◽

Vol 15 (36) ◽

pp. 14931 ◽

Cited By ~ 10

Author(s):

Byung Jin Byun ◽

Young Kee Kang

Keyword(s):

Bond Formation ◽

Peptide Bond ◽

Mechanistic Study ◽

Peptide Bond Formation ◽

Step Mechanism

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Mechanism of Covalent Binding of Ibrutinib to Bruton’s Tyrosine Kinase revealed by QM/MM Calculations

10.26434/chemrxiv.13149893.v1 ◽

2020 ◽

Author(s):

Angus Voice ◽

Gary Tresadern ◽

Rebecca Twidale ◽

Herman Van Vlijmen ◽

Adrian Mulholland

Keyword(s):

Tyrosine Kinase ◽

Covalent Binding ◽

Bond Formation ◽

Covalent Bond ◽

Covalent Modification ◽

Mechanistic Study ◽

Bruton’S Tyrosine Kinase ◽

Bruton's Tyrosine Kinase ◽

Covalent Inhibitors ◽

Covalent Bond Formation

Ibrutinib is the first covalent inhibitor of Bruton’s tyrosine kinase (BTK) to be used in the treatment of B-cell cancers. Understanding the mechanism of covalent inhibition is crucial for the design of safer and more selective covalent inhibitors that target BTK. There are questions surrounding the precise mechanism of covalent bond formation in BTK as there is no appropriate active site residue that can act as a base to deprotonate the cysteine thiol prior to covalent bond formation. To address this, we have investigated several mechanistic pathways of covalent modification of C481 in BTK by ibrutinib using QM/MM reaction simulations. The lowest energy pathway we identified involves a direct proton transfer from C481 to the acrylamide warhead in ibrutinib, followed by covalent bond formation to form an enol intermediate. There is a subsequent rate-limiting keto-enol tautomerisation step (DG‡=10.5 kcal mol-1) to reach the inactivated BTK/ibrutinib complex. Our results represent the first mechanistic study of BTK inactivation by ibrutinib to consider multiple mechanistic pathways. These findings should aid in the design of covalent drugs that target BTK and related proteins.

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Mechanistic Study of Ni and Cu Dual Catalyst for Asymmetric C–C Bond Formation; Asymmetric Coupling of 1,3-Dienes with C-nucleophiles to Construct Vicinal Stereocenters

ACS Catalysis ◽

10.1021/acscatal.1c01626 ◽

2021 ◽

pp. 6643-6655

Author(s):

Jingzhao Xia ◽

Takahiro Hirai ◽

Shoichiro Katayama ◽

Haruki Nagae ◽

Wanbin Zhang ◽

...

Keyword(s):

Bond Formation ◽

Mechanistic Study ◽

Asymmetric Coupling

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Unraveling the Role of a Flexible Tetradentate Ligand in the Aerobic Oxidative Carbon–Carbon Bond Formation with Palladium Complexes: A Computational Mechanistic Study

Journal of the American Chemical Society ◽

10.1021/jacs.7b11701 ◽

2018 ◽

Vol 140 (11) ◽

pp. 3929-3939 ◽

Cited By ~ 3

Author(s):

Qian Peng ◽

Zengwei Wang ◽

Snežana D. Zarić ◽

Edward N. Brothers ◽

Michael B. Hall

Keyword(s):

Bond Formation ◽

Palladium Complexes ◽

Mechanistic Study ◽

Tetradentate Ligand ◽

Carbon Bond ◽

Carbon Carbon Bond

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Synthesis of higher carboxylic acids from ethers, CO2 and H2

Nature Communications ◽

10.1038/s41467-019-13463-0 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 5

Author(s):

Ying Wang ◽

Qingli Qian ◽

Jingjing Zhang ◽

Bernard Baffour Asare Bediako ◽

Zhenpeng Wang ◽

...

Keyword(s):

Carboxylic Acid ◽

Carboxylic Acids ◽

Catalytic System ◽

Acid Synthesis ◽

Alternative Strategy ◽

Mechanistic Study ◽

Rwgs Reaction ◽

Alkyl Iodides

AbstractSynthesis of higher carboxylic acids using CO2 and H2 is of great importance, because CO2 is an attractive renewable C1 resource and H2 is a cheap and clean reductant. Herein we report a route to produce higher carboxylic acids via reaction of ethers with CO2 and H2. We show that the reaction can be efficiently catalyzed by an IrI4 catalyst with LiI as promoter at 170 °C, 5 MPa of CO2 and 2 MPa of H2. The catalytic system applies to various ether substrates. The mechanistic study indicates that the ethers are converted to olefins, which are further transformed into alkyl iodides. The higher carboxylic acids are produced by carbonylation of alkyl iodides with CO generated in situ via RWGS reaction. This report offers an alternative strategy of higher carboxylic acid synthesis and CO2 transformation.

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