scholarly journals Selenomethionine as an expressible handle for bioconjugations

2021 ◽  
Vol 118 (8) ◽  
pp. e2005164118
Author(s):  
Dillon T. Flood ◽  
Jordi C. J. Hintzen ◽  
Kyle W. Knouse ◽  
David E. Hill ◽  
Chenxi Lu ◽  
...  
Keyword(s):  
Organic Molecules ◽  
Careful Study ◽  
Selective Chemical ◽  
Site Selective ◽  
Complex Organic

Site-selective chemical bioconjugation reactions are enabling tools for the chemical biologist. Guided by a careful study of the selenomethionine (SeM) benzylation, we have refined the reaction to meet the requirements of practical protein bioconjugation. SeM is readily introduced through auxotrophic expression and exhibits unique nucleophilic properties that allow it to be selectively modified even in the presence of cysteine. The resulting benzylselenonium adduct is stable at physiological pH, is selectively labile to glutathione, and embodies a broadly tunable cleavage profile. Specifically, a 4-bromomethylphenylacetyl (BrMePAA) linker has been applied for efficient conjugation of complex organic molecules to SeM-containing proteins. This expansion of the bioconjugation toolkit has broad potential in the development of chemically enhanced proteins.

scholarly journals Selenomethionine as an Expressible Handle for Bioconjugations

2020 ◽  
Author(s):  
Dillon T. Flood ◽  
Jordi C.J. Hintzen ◽  
Chenxi Lu ◽  
Philip A. Cistrone ◽  
Jason Chen ◽  
...  
Keyword(s):  
Rate Constant ◽  
Chemical Biology ◽  
Organic Molecules ◽  
Protein Ligation ◽  
On Demand ◽  
Physical Organic ◽  
Mechanistic Analysis ◽  
Selective Chemical ◽  
Site Selective ◽  
Complex Organic

<b>Site-selective chemical protein ligation reactions are enabling tools for chemical biology. Herein, we employ a physical organic study to refine the selenomethionine (SeM) benzylation as a practical protein bioconjugation strategy. SeM is readily introduced through auxotrophic expression and exhibits unique nucleophilic properties that allow it to be selectively modified even in the presence of cysteine. The resulting benzylselenonium adduct is stable at physiological pH, selectively labile to glutathione and embodies a broadly tuneable reactivity profile. Guided by a mechanistic analysis of the reaction, a 4-bromomethylphenylacetyl linker is identified for efficient conjugations of complex organic molecules to SeM containing proteins. This optimized benzyl linker exhibits a rate constant of 3x10<sup>-1</sup> M<sup>-1</sup>s<sup>-1</sup>, facilitating efficient conjugation at micromolar concentrations. The selenonium conjugate is further advanced through a linker that can be selectively photo-locked or reductively cleaved on demand. This tool-kit of selenonium forming reagents have broad potential in the development of chemically enhanced proteins.</b>

scholarly journals Selenomethionine as an Expressible Handle for Bioconjugations

2020 ◽  
Author(s):  
Dillon T. Flood ◽  
Jordi C.J. Hintzen ◽  
Chenxi Lu ◽  
Philip A. Cistrone ◽  
Jason Chen ◽  
...  
Keyword(s):  
Rate Constant ◽  
Chemical Biology ◽  
Organic Molecules ◽  
Protein Ligation ◽  
On Demand ◽  
Physical Organic ◽  
Mechanistic Analysis ◽  
Selective Chemical ◽  
Site Selective ◽  
Complex Organic

<b>Site-selective chemical protein ligation reactions are enabling tools for chemical biology. Herein, we employ a physical organic study to refine the selenomethionine (SeM) benzylation as a practical protein bioconjugation strategy. SeM is readily introduced through auxotrophic expression and exhibits unique nucleophilic properties that allow it to be selectively modified even in the presence of cysteine. The resulting benzylselenonium adduct is stable at physiological pH, selectively labile to glutathione and embodies a broadly tuneable reactivity profile. Guided by a mechanistic analysis of the reaction, a 4-bromomethylphenylacetyl linker is identified for efficient conjugations of complex organic molecules to SeM containing proteins. This optimized benzyl linker exhibits a rate constant of 3x10<sup>-1</sup> M<sup>-1</sup>s<sup>-1</sup>, facilitating efficient conjugation at micromolar concentrations. The selenonium conjugate is further advanced through a linker that can be selectively photo-locked or reductively cleaved on demand. This tool-kit of selenonium forming reagents have broad potential in the development of chemically enhanced proteins.</b>

scholarly journals Selenomethionine as an Expressible Handle for Bioconjugations

2020 ◽  
Author(s):  
Dillon T. Flood ◽  
Jordi C.J. Hintzen ◽  
Chenxi Lu ◽  
Philip A. Cistrone ◽  
Jason Chen ◽  
...  
Keyword(s):  
Rate Constant ◽  
Chemical Biology ◽  
Organic Molecules ◽  
Protein Ligation ◽  
On Demand ◽  
Physical Organic ◽  
Mechanistic Analysis ◽  
Selective Chemical ◽  
Site Selective ◽  
Complex Organic

<b>Site-selective chemical protein ligation reactions are enabling tools for chemical biology. Herein, we employ a physical organic study to refine the selenomethionine (SeM) benzylation as a practical protein bioconjugation strategy. SeM is readily introduced through auxotrophic expression and exhibits unique nucleophilic properties that allow it to be selectively modified even in the presence of cysteine. The resulting benzylselenonium adduct is stable at physiological pH, selectively labile to glutathione and embodies a broadly tuneable reactivity profile. Guided by a mechanistic analysis of the reaction, a 4-bromomethylphenylacetyl linker is identified for efficient conjugations of complex organic molecules to SeM containing proteins. This optimized benzyl linker exhibits a rate constant of 3x10<sup>-1</sup> M<sup>-1</sup>s<sup>-1</sup>, facilitating efficient conjugation at micromolar concentrations. The selenonium conjugate is further advanced through a linker that can be selectively photo-locked or reductively cleaved on demand. This tool-kit of selenonium forming reagents have broad potential in the development of chemically enhanced proteins.</b>

scholarly journals Late-stage trifluoromethylthiolation of benzylic C-H bonds

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Wentao Xu ◽  
Wenliang Wang ◽  
Tao Liu ◽  
Jin Xie ◽  
Chengjian Zhu
Keyword(s):  
Continuous Flow ◽  
Large Scale ◽  
Organic Molecules ◽  
Initiation Mechanism ◽  
Radical Initiation ◽  
Simple Protocol ◽  
Synthetic Methodologies ◽  
Site Selective ◽  
Complex Organic ◽  
Fluoroalkyl Group

Abstract The benzylic positions in drugs are sites that readily react with cytochrome P450 oxidases via single-electron oxidation. New synthetic methodologies to incorporate a fluoroalkyl group at the benzylic site are continually being developed, and in this paper, we report a metal-free and site-selective organophotoredox-catalyzed trifluoromethylthiolation of benzylic C-H bonds for a wide variety of alkyl arenes and heteroarenes. The precise and predictive regioselectivity among various C(sp3)-H bonds originates from an inner-sphere benzylic radical initiation mechanism, and avoids the use of external oxidants or hydrogen atom abstractors. Its practicality stems from the trifluoromethylthiolation of a series of drugs and complex organic molecules, which is overwhelmingly selective for benzyl groups. This operationally simple protocol can provide a general and practical access to structurally diverse benzylic trifluoromethyl sulfides produced from ubiquitous benzylic C-H bonds. Large scale trifluoromethylthiolation can be achieved with continuous flow photoredox technology.

scholarly journals Benzylic C−H acylation by cooperative NHC and photoredox catalysis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Qing-Yuan Meng ◽  
Lena Lezius ◽  
Armido Studer
Keyword(s):  
Organic Molecules ◽  
Functional Group ◽  
Photoredox Catalysis ◽  
Diverse Range ◽  
Site Selectivity ◽  
Aryl Ketones ◽  
Direct Acylation ◽  
Selective Acylation ◽  
Site Selective ◽  
Complex Organic

AbstractMethods that enable site selective acylation of sp3 C-H bonds in complex organic molecules are not well explored, particularly if compared with analogous transformations of aromatic and vinylic sp2 C-H bonds. We report herein a direct acylation of benzylic C-H bonds by merging N-heterocyclic carbene (NHC) and photoredox catalysis. The method allows the preparation of a diverse range of benzylic ketones with good functional group tolerance under mild conditions. The reaction can be used to install acyl groups on highly functionalized natural product derived compounds and the C-H functionalization works with excellent site selectivity. The combination of NHC and photoredox catalysis offers options in preparing benzyl aryl ketones.

Imine as a Linchpin Approach for Distal C(sp2)–H Functionalization

2020 ◽  
Author(s):  
Sukdev Bag ◽  
Sadhan Jana ◽  
Sukumar Pradhan ◽  
Suman Bhowmick ◽  
Nupur Goswami ◽  
...  
Keyword(s):  
Organic Molecules ◽  
Bond Activation ◽  
Bond Formation ◽  
Ancillary Ligand ◽  
Significant Challenge ◽  
Site Selectivity ◽  
Directing Group ◽  
Covalently Linked ◽  
Complex Organic ◽  
Post Functionalization

<p>Despite the widespread applications of C–H functionalization, controlling site selectivity remains a significant challenge. Covalently attached directing group (DG) served as an ancillary ligand to ensure proximal <i>ortho</i>-, distal <i>meta</i>- and <i>para</i>-C-H functionalization over the last two decades. These covalently linked DGs necessitate two extra steps for a single C–H functionalization: introduction of DG prior to C–H activation and removal of DG post-functionalization. We introduce here a transient directing group for distal C(<i>sp<sup>2</sup></i>)-H functionalization <i>via</i> reversible imine formation. By overruling facile proximal C-H bond activation by imine-<i>N</i> atom, a suitably designed pyrimidine-based transient directing group (TDG) successfully delivered selective distal C-C bond formation. Application of this transient directing group strategy for streamlining the synthesis of complex organic molecules without any necessary pre-functionalization at the distal position has been explored.</p>

scholarly journals Rational Generation of Lasso Peptides Based on Biosynthetic Gene Mutations and Site-Selective Chemical Modifications

2021 ◽  
Author(s):  
Tan Liu ◽  
Xiaojie Ma ◽  
Jiahui Yu ◽  
Wensheng Yang ◽  
guiyang wang ◽  
...  
Keyword(s):  
Natural Products ◽  
Gene Mutations ◽  
Proteolytic Degradation ◽  
Biosynthetic Gene ◽  
Chemical Modifications ◽  
Lasso Peptides ◽  
Selective Chemical ◽  
Site Selective

Lasso peptides are a unique family of natural products whose structures feature a specific threaded fold, which confers these peptides the resistance to thermal and proteolytic degradation. This stability gives...

scholarly journals A Sustainable Improvement of ω-Bromoalkylphosphonates Synthesis to Access Novel KuQuinones

Organics ◽  
2021 ◽  
Vol 2 (2) ◽  
pp. 107-117
Author(s):  
Mattia Forchetta ◽  
Valeria Conte ◽  
Giulia Fiorani ◽  
Pierluca Galloni ◽  
Federica Sabuzi
Keyword(s):  
Metal Oxides ◽  
Phosphonic Acid ◽  
Organic Molecules ◽  
Building Blocks ◽  
Reaction Conditions ◽  
Phosphonic Acids ◽  
Sustainable Improvement ◽  
Phosphonate Esters ◽  
First Time ◽  
Complex Organic

Owing to the attractiveness of organic phosphonic acids and esters in the pharmacological field and in the functionalization of conductive metal-oxides, the research of effective synthetic protocols is pivotal. Among the others, ω-bromoalkylphosphonates are gaining particular attention because they are useful building blocks for the tailored functionalization of complex organic molecules. Hence, in this work, the optimization of Michaelis–Arbuzov reaction conditions for ω-bromoalkylphosphonates has been performed, to improve process sustainability while maintaining good yields. Synthesized ω-bromoalkylphosphonates have been successfully adopted for the synthesis of new KuQuinone phosphonate esters and, by hydrolysis, phosphonic acid KuQuinone derivatives have been obtained for the first time. Considering the high affinity with metal-oxides, KuQuinones bearing phosphonic acid terminal groups are promising candidates for biomedical and photo(electro)chemical applications.

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