10 research outputs found
Nickel Hydroxo Complexes as Intermediates in Nickel-Catalyzed Suzuki–Miyaura Cross-Coupling
The
synthesis, characterization, and reactivity of intermediates
formed in the Ni-catalyzed Suzuki–Miyaura cross-coupling (SMC)
of an aryl chloride are described. Oxidative addition of 1-chloro-4-trifluoromethylbenzene
(<b>1</b>) to a mixture of NiÂ(cod)<sub>2</sub> and PCy<sub>3</sub> afforded NiClÂ(4-CF<sub>3</sub>Ph)Â(PCy<sub>3</sub>)<sub>2</sub> (<b>2</b>), which then cleanly provided dimeric [NiÂ(4-CF<sub>3</sub>Ph)Â(μ–OH)Â(PCy<sub>3</sub>)]<sub>2</sub> (<b>3</b>) by reaction with aqueous KOH. Reactivity studies of <b>2</b> and <b>3</b> with phenylboronic acid (<b>4</b>) revealed
that, while <b>2</b> affords only traces of the biphenyl coupling
product after 24 h, the same reaction with <b>3</b> is complete
within minutes at room temperature. In contrast, the reaction of <b>3</b> with potassium phenyltrihydroxyborate (<b>6</b>) is
much slower than that with boronic acid <b>4</b>, and significantly
lower yields of the cross-coupling product are obtained. We show that
formation of the hydroxo species <b>3</b> is the rate-determining
step in the present SMC
Nickel Hydroxo Complexes as Intermediates in Nickel-Catalyzed Suzuki–Miyaura Cross-Coupling
The
synthesis, characterization, and reactivity of intermediates
formed in the Ni-catalyzed Suzuki–Miyaura cross-coupling (SMC)
of an aryl chloride are described. Oxidative addition of 1-chloro-4-trifluoromethylbenzene
(<b>1</b>) to a mixture of NiÂ(cod)<sub>2</sub> and PCy<sub>3</sub> afforded NiClÂ(4-CF<sub>3</sub>Ph)Â(PCy<sub>3</sub>)<sub>2</sub> (<b>2</b>), which then cleanly provided dimeric [NiÂ(4-CF<sub>3</sub>Ph)Â(μ–OH)Â(PCy<sub>3</sub>)]<sub>2</sub> (<b>3</b>) by reaction with aqueous KOH. Reactivity studies of <b>2</b> and <b>3</b> with phenylboronic acid (<b>4</b>) revealed
that, while <b>2</b> affords only traces of the biphenyl coupling
product after 24 h, the same reaction with <b>3</b> is complete
within minutes at room temperature. In contrast, the reaction of <b>3</b> with potassium phenyltrihydroxyborate (<b>6</b>) is
much slower than that with boronic acid <b>4</b>, and significantly
lower yields of the cross-coupling product are obtained. We show that
formation of the hydroxo species <b>3</b> is the rate-determining
step in the present SMC
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Uncovering Subtle Ligand Effects of Phosphines Using Gold(I) Catalysis
Herein, we report
the integration of simple linear regressions
with goldÂ(I) catalysis to interrogate the influence of phosphine structure
on metal-catalyzed organic transformations. We demonstrate that observed
product ratios in [4 + 3]/[4 + 2] cycloisomerization processes are
influenced by both steric and electronic properties of the phosphine,
which can be represented by the Au–Cl distance. In contrast,
the observed selectivity of a similar [2 + 3]/[2 + 2] cycloisomerization
is governed by L/B1, a steric parameter. Using this correlation, we
were able to accurately predict the selectivity of a previously untested,
Buchwald-type ligand to enhance selectivity for the same transformation.
This ligand found further utility in increasing the selectivity of
a previously reported gold-catalyzed cycloisomerization/arylation
of 1,6-enynes by ∼1 kcal/mol
An Activity-Based Oxaziridine Platform for Identifying and Developing Covalent Ligands for Functional Allosteric Methionine Sites: Redox-Dependent Inhibition of Cyclin-Dependent Kinase 4
Activity-based protein profiling (ABPP) is a versatile
strategy
for identifying and characterizing functional protein sites and compounds
for therapeutic development. However, the vast majority of ABPP methods
for covalent drug discovery target highly nucleophilic amino acids
such as cysteine or lysine. Here, we report a methionine-directed
ABPP platform using Redox-Activated Chemical Tagging (ReACT), which
leverages a biomimetic oxidative ligation strategy for selective methionine
modification. Application of ReACT to oncoprotein cyclin-dependent
kinase 4 (CDK4) as a representative high-value drug target identified
three new ligandable methionine sites. We then synthesized a methionine-targeting
covalent ligand library bearing a diverse array of heterocyclic, heteroatom,
and stereochemically rich substituents. ABPP screening of this focused
library identified 1oxF11 as a covalent modifier of CDK4 at an allosteric
M169 site. This compound inhibited kinase activity in a dose-dependent
manner on purified protein and in breast cancer cells. Further investigation
of 1oxF11 found prominent cation-Ï€ and H-bonding interactions
stabilizing the binding of this fragment at the M169 site. Quantitative
mass-spectrometry studies validated 1oxF11 ligation of CDK4 in breast
cancer cell lysates. Further biochemical analyses revealed cross-talk
between M169 oxidation and T172 phosphorylation, where M169 oxidation
prevented phosphorylation of the activating T172 site on CDK4 and
blocked cell cycle progression. By identifying a new mechanism for
allosteric methionine redox regulation on CDK4 and developing a unique
modality for its therapeutic intervention, this work showcases a generalizable
platform that provides a starting point for engaging in broader chemoproteomics
and protein ligand discovery efforts to find and target previously
undruggable methionine sites
An Activity-Based Oxaziridine Platform for Identifying and Developing Covalent Ligands for Functional Allosteric Methionine Sites: Redox-Dependent Inhibition of Cyclin-Dependent Kinase 4
Activity-based protein profiling (ABPP) is a versatile
strategy
for identifying and characterizing functional protein sites and compounds
for therapeutic development. However, the vast majority of ABPP methods
for covalent drug discovery target highly nucleophilic amino acids
such as cysteine or lysine. Here, we report a methionine-directed
ABPP platform using Redox-Activated Chemical Tagging (ReACT), which
leverages a biomimetic oxidative ligation strategy for selective methionine
modification. Application of ReACT to oncoprotein cyclin-dependent
kinase 4 (CDK4) as a representative high-value drug target identified
three new ligandable methionine sites. We then synthesized a methionine-targeting
covalent ligand library bearing a diverse array of heterocyclic, heteroatom,
and stereochemically rich substituents. ABPP screening of this focused
library identified 1oxF11 as a covalent modifier of CDK4 at an allosteric
M169 site. This compound inhibited kinase activity in a dose-dependent
manner on purified protein and in breast cancer cells. Further investigation
of 1oxF11 found prominent cation-Ï€ and H-bonding interactions
stabilizing the binding of this fragment at the M169 site. Quantitative
mass-spectrometry studies validated 1oxF11 ligation of CDK4 in breast
cancer cell lysates. Further biochemical analyses revealed cross-talk
between M169 oxidation and T172 phosphorylation, where M169 oxidation
prevented phosphorylation of the activating T172 site on CDK4 and
blocked cell cycle progression. By identifying a new mechanism for
allosteric methionine redox regulation on CDK4 and developing a unique
modality for its therapeutic intervention, this work showcases a generalizable
platform that provides a starting point for engaging in broader chemoproteomics
and protein ligand discovery efforts to find and target previously
undruggable methionine sites
An Activity-Based Oxaziridine Platform for Identifying and Developing Covalent Ligands for Functional Allosteric Methionine Sites: Redox-Dependent Inhibition of Cyclin-Dependent Kinase 4
Activity-based protein profiling (ABPP) is a versatile
strategy
for identifying and characterizing functional protein sites and compounds
for therapeutic development. However, the vast majority of ABPP methods
for covalent drug discovery target highly nucleophilic amino acids
such as cysteine or lysine. Here, we report a methionine-directed
ABPP platform using Redox-Activated Chemical Tagging (ReACT), which
leverages a biomimetic oxidative ligation strategy for selective methionine
modification. Application of ReACT to oncoprotein cyclin-dependent
kinase 4 (CDK4) as a representative high-value drug target identified
three new ligandable methionine sites. We then synthesized a methionine-targeting
covalent ligand library bearing a diverse array of heterocyclic, heteroatom,
and stereochemically rich substituents. ABPP screening of this focused
library identified 1oxF11 as a covalent modifier of CDK4 at an allosteric
M169 site. This compound inhibited kinase activity in a dose-dependent
manner on purified protein and in breast cancer cells. Further investigation
of 1oxF11 found prominent cation-Ï€ and H-bonding interactions
stabilizing the binding of this fragment at the M169 site. Quantitative
mass-spectrometry studies validated 1oxF11 ligation of CDK4 in breast
cancer cell lysates. Further biochemical analyses revealed cross-talk
between M169 oxidation and T172 phosphorylation, where M169 oxidation
prevented phosphorylation of the activating T172 site on CDK4 and
blocked cell cycle progression. By identifying a new mechanism for
allosteric methionine redox regulation on CDK4 and developing a unique
modality for its therapeutic intervention, this work showcases a generalizable
platform that provides a starting point for engaging in broader chemoproteomics
and protein ligand discovery efforts to find and target previously
undruggable methionine sites
An Activity-Based Oxaziridine Platform for Identifying and Developing Covalent Ligands for Functional Allosteric Methionine Sites: Redox-Dependent Inhibition of Cyclin-Dependent Kinase 4
Activity-based protein profiling (ABPP) is a versatile
strategy
for identifying and characterizing functional protein sites and compounds
for therapeutic development. However, the vast majority of ABPP methods
for covalent drug discovery target highly nucleophilic amino acids
such as cysteine or lysine. Here, we report a methionine-directed
ABPP platform using Redox-Activated Chemical Tagging (ReACT), which
leverages a biomimetic oxidative ligation strategy for selective methionine
modification. Application of ReACT to oncoprotein cyclin-dependent
kinase 4 (CDK4) as a representative high-value drug target identified
three new ligandable methionine sites. We then synthesized a methionine-targeting
covalent ligand library bearing a diverse array of heterocyclic, heteroatom,
and stereochemically rich substituents. ABPP screening of this focused
library identified 1oxF11 as a covalent modifier of CDK4 at an allosteric
M169 site. This compound inhibited kinase activity in a dose-dependent
manner on purified protein and in breast cancer cells. Further investigation
of 1oxF11 found prominent cation-Ï€ and H-bonding interactions
stabilizing the binding of this fragment at the M169 site. Quantitative
mass-spectrometry studies validated 1oxF11 ligation of CDK4 in breast
cancer cell lysates. Further biochemical analyses revealed cross-talk
between M169 oxidation and T172 phosphorylation, where M169 oxidation
prevented phosphorylation of the activating T172 site on CDK4 and
blocked cell cycle progression. By identifying a new mechanism for
allosteric methionine redox regulation on CDK4 and developing a unique
modality for its therapeutic intervention, this work showcases a generalizable
platform that provides a starting point for engaging in broader chemoproteomics
and protein ligand discovery efforts to find and target previously
undruggable methionine sites
An Activity-Based Oxaziridine Platform for Identifying and Developing Covalent Ligands for Functional Allosteric Methionine Sites: Redox-Dependent Inhibition of Cyclin-Dependent Kinase 4
Activity-based protein profiling (ABPP) is a versatile
strategy
for identifying and characterizing functional protein sites and compounds
for therapeutic development. However, the vast majority of ABPP methods
for covalent drug discovery target highly nucleophilic amino acids
such as cysteine or lysine. Here, we report a methionine-directed
ABPP platform using Redox-Activated Chemical Tagging (ReACT), which
leverages a biomimetic oxidative ligation strategy for selective methionine
modification. Application of ReACT to oncoprotein cyclin-dependent
kinase 4 (CDK4) as a representative high-value drug target identified
three new ligandable methionine sites. We then synthesized a methionine-targeting
covalent ligand library bearing a diverse array of heterocyclic, heteroatom,
and stereochemically rich substituents. ABPP screening of this focused
library identified 1oxF11 as a covalent modifier of CDK4 at an allosteric
M169 site. This compound inhibited kinase activity in a dose-dependent
manner on purified protein and in breast cancer cells. Further investigation
of 1oxF11 found prominent cation-Ï€ and H-bonding interactions
stabilizing the binding of this fragment at the M169 site. Quantitative
mass-spectrometry studies validated 1oxF11 ligation of CDK4 in breast
cancer cell lysates. Further biochemical analyses revealed cross-talk
between M169 oxidation and T172 phosphorylation, where M169 oxidation
prevented phosphorylation of the activating T172 site on CDK4 and
blocked cell cycle progression. By identifying a new mechanism for
allosteric methionine redox regulation on CDK4 and developing a unique
modality for its therapeutic intervention, this work showcases a generalizable
platform that provides a starting point for engaging in broader chemoproteomics
and protein ligand discovery efforts to find and target previously
undruggable methionine sites
An Activity-Based Oxaziridine Platform for Identifying and Developing Covalent Ligands for Functional Allosteric Methionine Sites: Redox-Dependent Inhibition of Cyclin-Dependent Kinase 4
Activity-based protein profiling (ABPP) is a versatile
strategy
for identifying and characterizing functional protein sites and compounds
for therapeutic development. However, the vast majority of ABPP methods
for covalent drug discovery target highly nucleophilic amino acids
such as cysteine or lysine. Here, we report a methionine-directed
ABPP platform using Redox-Activated Chemical Tagging (ReACT), which
leverages a biomimetic oxidative ligation strategy for selective methionine
modification. Application of ReACT to oncoprotein cyclin-dependent
kinase 4 (CDK4) as a representative high-value drug target identified
three new ligandable methionine sites. We then synthesized a methionine-targeting
covalent ligand library bearing a diverse array of heterocyclic, heteroatom,
and stereochemically rich substituents. ABPP screening of this focused
library identified 1oxF11 as a covalent modifier of CDK4 at an allosteric
M169 site. This compound inhibited kinase activity in a dose-dependent
manner on purified protein and in breast cancer cells. Further investigation
of 1oxF11 found prominent cation-Ï€ and H-bonding interactions
stabilizing the binding of this fragment at the M169 site. Quantitative
mass-spectrometry studies validated 1oxF11 ligation of CDK4 in breast
cancer cell lysates. Further biochemical analyses revealed cross-talk
between M169 oxidation and T172 phosphorylation, where M169 oxidation
prevented phosphorylation of the activating T172 site on CDK4 and
blocked cell cycle progression. By identifying a new mechanism for
allosteric methionine redox regulation on CDK4 and developing a unique
modality for its therapeutic intervention, this work showcases a generalizable
platform that provides a starting point for engaging in broader chemoproteomics
and protein ligand discovery efforts to find and target previously
undruggable methionine sites
An Activity-Based Oxaziridine Platform for Identifying and Developing Covalent Ligands for Functional Allosteric Methionine Sites: Redox-Dependent Inhibition of Cyclin-Dependent Kinase 4
Activity-based protein profiling (ABPP) is a versatile
strategy
for identifying and characterizing functional protein sites and compounds
for therapeutic development. However, the vast majority of ABPP methods
for covalent drug discovery target highly nucleophilic amino acids
such as cysteine or lysine. Here, we report a methionine-directed
ABPP platform using Redox-Activated Chemical Tagging (ReACT), which
leverages a biomimetic oxidative ligation strategy for selective methionine
modification. Application of ReACT to oncoprotein cyclin-dependent
kinase 4 (CDK4) as a representative high-value drug target identified
three new ligandable methionine sites. We then synthesized a methionine-targeting
covalent ligand library bearing a diverse array of heterocyclic, heteroatom,
and stereochemically rich substituents. ABPP screening of this focused
library identified 1oxF11 as a covalent modifier of CDK4 at an allosteric
M169 site. This compound inhibited kinase activity in a dose-dependent
manner on purified protein and in breast cancer cells. Further investigation
of 1oxF11 found prominent cation-Ï€ and H-bonding interactions
stabilizing the binding of this fragment at the M169 site. Quantitative
mass-spectrometry studies validated 1oxF11 ligation of CDK4 in breast
cancer cell lysates. Further biochemical analyses revealed cross-talk
between M169 oxidation and T172 phosphorylation, where M169 oxidation
prevented phosphorylation of the activating T172 site on CDK4 and
blocked cell cycle progression. By identifying a new mechanism for
allosteric methionine redox regulation on CDK4 and developing a unique
modality for its therapeutic intervention, this work showcases a generalizable
platform that provides a starting point for engaging in broader chemoproteomics
and protein ligand discovery efforts to find and target previously
undruggable methionine sites