The Experts below are selected from a list of 8514 Experts worldwide ranked by ideXlab platform
James E Petersson - One of the best experts on this subject based on the ideXlab platform.
-
improved modeling of Thioamide fret quenching by including conformational restriction and coulomb coupling
Journal of Physical Chemistry B, 2020Co-Authors: Jimin Yoon, John J Ferrie, James E PeterssonAbstract:Thioamide-containing amino acids have been shown to quench a wide range of fluorophores through distinct mechanisms. Here, we quantitatively analyze the mechanism through which the Thioamide functional group quenches the fluorescence of p-cyanophenylalanine (Cnf), tyrosine (Tyr), and tryptophan (Trp). By comparing PyRosetta simulations to published experiments performed on polyproline ruler peptides, we corroborate previous findings that both Cnf and Tyr quenching occurs via Forster resonance energy transfer (FRET), while Trp quenching occurs through an alternate mechanism such as Dexter transfer. Additionally, optimization of the peptide sampling scheme and comparison of Thioamides attached to the peptide backbone and side chain revealed that the significant conformational restriction associated with the Thioamide moiety results in a high sensitivity of the apparent FRET efficiency to underlying conformational differences. Moreover, by computing FRET efficiencies from structural models using a variety of approaches, we find that quantitative accuracy in the role of Coulomb coupling is required to explain contributions to the observed quenching efficiency from individual structures on a detailed level. Last, we demonstrate that these additional considerations improve our ability to predict Thioamide quenching efficiencies observed during binding of Thioamide-labeled peptides to fluorophore-labeled variants of calmodulin.
-
studies of Thioamide effects on serine protease activity enable two site stabilization of cancer imaging peptides
ACS Chemical Biology, 2020Co-Authors: Taylor M. Barrett, Chunxiao Liu, Xing S Chen, Sam Giannakoulias, Hoang Anh T Phan, Jieliang Wang, Keith E Keenan, Richard J Karpowicz, James E PeterssonAbstract:Thioamide substitutions in peptides can be used as fluorescence quenchers in protease sensors and as stabilizing modifications of hormone analogs. To guide these applications in the context of serine proteases, we here examine the cleavage of several model substrates, scanning a Thioamide between the P3 and P3' positions, and identify perturbing positions for Thioamide substitution. While all serine proteases tested were affected by P1 thioamidation, certain proteases were also significantly affected by other Thioamide positions. We demonstrate how these findings can be applied by harnessing the combined P3/P1 effect of a single Thioamide on kallikrein proteolysis to protect two key positions in a neuropeptide Y-based imaging probe, increasing its serum half-life to >24 h while maintaining potency for binding to Y1 receptor expressing cells. Such stabilized peptide probes could find application in imaging cell populations in animal models or even in clinical applications such as fluorescence-guided surgery.
-
fluorescent probes for studying Thioamide positional effects on proteolysis reveal insight into resistance to cysteine proteases
ChemBioChem, 2019Co-Authors: Taylor M. Barrett, Chunxiao Liu, Xing Chen, John J Ferrie, James E PeterssonAbstract:Thioamide substitutions of the peptide backbone have been shown to reduce proteolytic degradation, and this property can be used to generate competitive protease inhibitors and to stabilize peptides toward degradation in vivo. Here, we present a straightforward sensor design that allows a systematic study of the positional effects of Thioamide substitution by using real-time fluorescence. Thioamide scanning in peptide substrates of five papain family cysteine proteases demonstrates that a Thioamide at or near the scissile bond can slow proteolysis in all cases, but that the magnitude of the effects varies with position and protease in spite of high sequence homology. Mechanistic investigation of papain proteolysis reveals that the Thioamide effects derive from reductions in both affinity (KM ) and turnover number (kcat ). Computational modeling allows these effects to be understood based on disruption of key enzyme-substrate hydrogen bonds, providing a model for future rational use of Thioamides to confer cysteine protease resistance.
-
thieme chemistry journals awardees where are they now improved fmoc deprotection methods for the synthesis of Thioamide containing peptides and proteins
Synlett, 2017Co-Authors: Miklos D Szantaikis, Taylor M. Barrett, Christopher R Walters, Eileen M Hoang, James E PeterssonAbstract:Site-selective incorporation of Thioamides into peptides and proteins provides a useful tool for a wide range of applications. Current incorporation methods suffer from low yields as well as epimerization. Here, we describe how the use of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) rather than piperidine in fluorenylmethyloxycarbonyl (Fmoc) deprotection reduces epimerization and increases yields of Thioamide-containing peptides. Furthermore, we demonstrate that the use of DBU avoids byproduct formation when synthesizing peptides containing side-chain Thioamides.
-
the effects of Thioamide backbone substitution on protein stability a study in α helical β sheet and polyproline ii helical contexts
Chemical Science, 2017Co-Authors: Christopher R Walters, Miklos D Szantaikis, Yitao Zhang, Zachary E Reinert, Seth W Horne, David M Chenoweth, James E PeterssonAbstract:Thioamides are single atom substitutions of the peptide bond that serve as versatile probes of protein structure. Effective use of Thioamides requires a robust understanding of the impact that the substitution has on a protein of interest. However, the thermodynamic effects of Thioamide incorporation have only been studied in small structural motifs, and their influence on secondary structure in the context of full-length proteins is not known. Here we describe a comprehensive survey of Thioamide substitutions in three benchmark protein systems (calmodulin, the B1 domain of protein G, and collagen) featuring the most prevalent secondary structure motifs: α-helix, β-sheet, and polyproline type II helix. We find that in most cases, effects on thermostability can be understood in terms of the positioning and local environment of the Thioamide relative to proximal structural elements and hydrogen bonding networks. These observations set the stage for the rational design of Thioamide substituted proteins with predictable stabilities.
Masakatsu Shibasaki - One of the best experts on this subject based on the ideXlab platform.
-
Asymmetric Synthesis Using Thioamides
Chemistry of Thioamides, 2019Co-Authors: Naoya Kumagai, Masakatsu ShibasakiAbstract:Following the preceding chapter in which synthesis and transformation of Thioamides were introduced, this chapter provides an overview of state-of-the-art asymmetric catalysis to elicit the hidden reactivity of Thioamide functionality, thereby engaging Thioamide substrates in catalytic transformations to produce more elaborate Thioamide compounds. The designed catalytic systems, comprising a soft Lewis acid and Bronsted base, chemoselectively activate Thioamides in both a nucleophilic and electrophilic fashion, leading to a number of bimolecular reactions rendered catalytic and enantioselective. The last section showcases the synthetic application of these catalytic processes to demonstrate their practical utility.
-
direct catalytic asymmetric aldol reaction of Thioamide with an α vinyl appendage
Chemistry: A European Journal, 2018Co-Authors: Jin Cui, Naoya Kumagai, Akimichi Ohtsuki, Takumi Watanabe, Masakatsu ShibasakiAbstract:The direct catalytic asymmetric aldol reaction is an emerging catalytic methodology that provides atom-economical access to functionalized chiral building blocks. Thioamides are useful aldol donors due to their high-fidelity chemoselective enolization and divergent post-aldol transformations. Herein we describe the incorporation of an α-vinyl appendage on a Thioamide, which expands the utility of aldol adducts for natural product synthesis. This vinylated Thioamide was not accommodated under the previously identified catalyst settings, but the newly developed catalytic conditions furnished aldol products containing the pendant vinyl group.
-
Direct Catalytic Asymmetric Aldol Reaction of Thioamide with an α‐Vinyl Appendage
Chemistry – A European Journal, 2018Co-Authors: Jin Cui, Naoya Kumagai, Akimichi Ohtsuki, Takumi Watanabe, Masakatsu ShibasakiAbstract:The direct catalytic asymmetric aldol reaction is an emerging catalytic methodology that provides atom-economical access to functionalized chiral building blocks. Thioamides are useful aldol donors due to their high-fidelity chemoselective enolization and divergent post-aldol transformations. Herein we describe the incorporation of an α-vinyl appendage on a Thioamide, which expands the utility of aldol adducts for natural product synthesis. This vinylated Thioamide was not accommodated under the previously identified catalyst settings, but the newly developed catalytic conditions furnished aldol products containing the pendant vinyl group.
-
Direct Catalytic Asymmetric Conjugate Addition of Saturated and Unsaturated Thioamides.
ChemInform, 2015Co-Authors: Nilanjana Majumdar, Naoya Kumagai, Akira Saito, Liang Yin, Masakatsu ShibasakiAbstract:It is found that the Thioamide moiety is crucial to promote both the efficient enolization of thiolactam pronucleophiles and the subsequent stereoselective conjugate addition to α,β-unsaturated Thioamides.
-
Direct Catalytic Asymmetric Conjugate Addition of Saturated and Unsaturated Thioamides
Organic Letters, 2015Co-Authors: Nilanjana Majumdar, Naoya Kumagai, Akira Saito, Liang Yin, Masakatsu ShibasakiAbstract:Direct catalytic asymmetric conjugate addition of thiolactams to α,β-unsaturated Thioamides was efficiently promoted by a soft Lewis acid/hard Bronsted base cooperative catalyst in a highly stereocontrolled manner. Thioamide functionality was crucial to promote both the efficient enolization of thiolactam pronucleophiles and the subsequent stereoselective conjugate addition to α,β-unsaturated Thioamides. Differential manipulation of the two Thioamide functionalities of the product highlights the synthetic utility of the present catalytic system.
Toshiaki Murai - One of the best experts on this subject based on the ideXlab platform.
-
intramolecular cyclization of in situ generated adducts formed between Thioamide dianions and thioformamides leading to generation of 5 amino 2 thiazolines and 5 aminothiazoles and their fluorescence properties
Organic Letters, 2011Co-Authors: Toshiaki Murai, Fumihiko Hori, Toshifumi MaruyamaAbstract:Reactions of Thioamide dianions, derived from secondary N-arylmethyl Thioamides using BuLi, with thioformamides followed by the addition of iodine to yield 5-amino-2-thiazolines are described. Treatment of the 5-amino-2-thiazolines with iodine leads to a highly efficient production of 5-aminothiazoles. When N,N-diarylthioformamides are employed in this process, fluorescent 5-N,N-diarylthiazoles are obtained.
-
Thioamide dianions derived from n arylmethyl Thioamides generation and application as carbon nucleophiles adjacent to the nitrogen atom
Pure and Applied Chemistry, 2010Co-Authors: Toshiaki MuraiAbstract:This review illustrates the ready availability of Thioamide dianions and their versa- tility as carbon nucleophiles adjacent to the nitrogen atom. The products derived from the ad- dition of Thioamide dianions to a range of electrophiles can participate in a cyclization reac- tion to form nitrogen-containing heterocycles. The electronic properties of Thioamide dianions are also considered.
-
Silylation and alkylation of Thioamide dianions of N-arylmethyl secondary Thioamides, and reduction of the resulting Thioamides leading to secondary and primary amines
Journal of Sulfur Chemistry, 2009Co-Authors: Toshiaki Murai, Tadashi Michigami, Mai Yamaguchi, Noriko MizuhataAbstract:N-arylmethyl aromatic Thioamides were reacted with n-BuLi (2 equivalents), and then treated with silylpropyl chloride and silyl chlorides. As a result, these electrophiles were introduced to the carbon atom adjacent to the nitrogen atom of Thioamides via Thioamide dianions. The efficiency of the reaction was largely influenced by the substituents on the aromatic ring of Thioamides. The reaction of Thioamides having pyridyl groups was not always successful and depended on the position of the nitrogen atom of these groups. Reduction of the resulting Thioamides with LiAlH4 proceeded smoothly to give the corresponding secondary N-1-silylarylmethyl amines in good yields. In contrast, the reduction of Thioamides bearing pyridyl groups gave complex mixtures. In these cases, the use of DIBAH successfully gave the desired secondary amines.
-
n thioacyl 1 3 amino alcohols synthesis via ring opening of oxiranes with Thioamide dianions and applications as key intermediates leading to stereochemically defined 5 6 dihydro 4h 1 3 oxazines and 1 3 amino alcohols
Journal of Organic Chemistry, 2005Co-Authors: Toshiaki Murai, Hideo Aso, Hiroaki Sano, Hiroyasu Kawai, Fumitoshi ShibaharaAbstract:N-Thioacyl 1,3-amino alcohols were synthesized via the ring-opening of oxiranes with Thioamide dianions generated from N-benzyl Thioamides and BuLi in a highly regio- and stereoselective manner. The diastereomers of N-thioacyl 1,3-amino alcohols were readily separated by column chromatography to give stereochemically defined N-thioacyl 1,3-amino alcohols. They underwent intramolecular cyclization with Bu4F and EtI to give 5,6-dihydro-4H-1,3-oxazines. The reaction was specific with anti-N-thioacyl 1,3-amino alcohols, and cis-5,6-dihydro-4H-1,3-oxazines were obtained with high efficiency, whereas the reaction of a syn-alcohol gave a thioimidate as a major product. The reduction of N-thioacyl 1,3-amino alcohols with LiAlH4gave N-alkyl 1,3-amino alcohols in high yields. The use of optically active propylene oxide as a starting material gave the corresponding oxazine and alcohols in optically pure forms.
-
Reaction and characterization of Thioamide dianions derived from N-benzyl Thioamides.
The Journal of Organic Chemistry, 2003Co-Authors: Toshiaki Murai, Hideo Aso, Yoshiharu Tatematsu, Yoshiaki Itoh, Hisayuki Niwa, Shinzi KatoAbstract:Thioamide dianions were generated by the highly efficient reaction of N-benzyl Thioamides with 2 equiv of BuLi. Alkylation, allylation, and silylation took place selectively at the carbon atom adjacent to the nitrogen atom of the Thioamide dianions. Oxiranes and an aldehyde were also used as electrophiles in the reaction of Thioamide dianions to form N-thioacyl 1,3- or 1,2-amino alcohols. The insertion reaction of elemental sulfur to a Thioamide dianion and subsequent ethylation afforded a N-thioacyl hemithioaminal. NMR studies on the Thioamide mono- and dianions derived from N-benzyl 2-methoxythiobenzamide showed a linear relationship between the chemical shifts of all carbon atoms of Thioamide mono- and dianions. The results also suggested that the negative charge at the benzylic carbon atom of the dianion is not fully delocalized. The charge distribution patterns of the dianion are consistent with those of π polarization.
Naoya Kumagai - One of the best experts on this subject based on the ideXlab platform.
-
Asymmetric Synthesis Using Thioamides
Chemistry of Thioamides, 2019Co-Authors: Naoya Kumagai, Masakatsu ShibasakiAbstract:Following the preceding chapter in which synthesis and transformation of Thioamides were introduced, this chapter provides an overview of state-of-the-art asymmetric catalysis to elicit the hidden reactivity of Thioamide functionality, thereby engaging Thioamide substrates in catalytic transformations to produce more elaborate Thioamide compounds. The designed catalytic systems, comprising a soft Lewis acid and Bronsted base, chemoselectively activate Thioamides in both a nucleophilic and electrophilic fashion, leading to a number of bimolecular reactions rendered catalytic and enantioselective. The last section showcases the synthetic application of these catalytic processes to demonstrate their practical utility.
-
direct catalytic asymmetric aldol reaction of Thioamide with an α vinyl appendage
Chemistry: A European Journal, 2018Co-Authors: Jin Cui, Naoya Kumagai, Akimichi Ohtsuki, Takumi Watanabe, Masakatsu ShibasakiAbstract:The direct catalytic asymmetric aldol reaction is an emerging catalytic methodology that provides atom-economical access to functionalized chiral building blocks. Thioamides are useful aldol donors due to their high-fidelity chemoselective enolization and divergent post-aldol transformations. Herein we describe the incorporation of an α-vinyl appendage on a Thioamide, which expands the utility of aldol adducts for natural product synthesis. This vinylated Thioamide was not accommodated under the previously identified catalyst settings, but the newly developed catalytic conditions furnished aldol products containing the pendant vinyl group.
-
Direct Catalytic Asymmetric Aldol Reaction of Thioamide with an α‐Vinyl Appendage
Chemistry – A European Journal, 2018Co-Authors: Jin Cui, Naoya Kumagai, Akimichi Ohtsuki, Takumi Watanabe, Masakatsu ShibasakiAbstract:The direct catalytic asymmetric aldol reaction is an emerging catalytic methodology that provides atom-economical access to functionalized chiral building blocks. Thioamides are useful aldol donors due to their high-fidelity chemoselective enolization and divergent post-aldol transformations. Herein we describe the incorporation of an α-vinyl appendage on a Thioamide, which expands the utility of aldol adducts for natural product synthesis. This vinylated Thioamide was not accommodated under the previously identified catalyst settings, but the newly developed catalytic conditions furnished aldol products containing the pendant vinyl group.
-
Direct Catalytic Asymmetric Conjugate Addition of Saturated and Unsaturated Thioamides.
ChemInform, 2015Co-Authors: Nilanjana Majumdar, Naoya Kumagai, Akira Saito, Liang Yin, Masakatsu ShibasakiAbstract:It is found that the Thioamide moiety is crucial to promote both the efficient enolization of thiolactam pronucleophiles and the subsequent stereoselective conjugate addition to α,β-unsaturated Thioamides.
-
Direct Catalytic Asymmetric Conjugate Addition of Saturated and Unsaturated Thioamides
Organic Letters, 2015Co-Authors: Nilanjana Majumdar, Naoya Kumagai, Akira Saito, Liang Yin, Masakatsu ShibasakiAbstract:Direct catalytic asymmetric conjugate addition of thiolactams to α,β-unsaturated Thioamides was efficiently promoted by a soft Lewis acid/hard Bronsted base cooperative catalyst in a highly stereocontrolled manner. Thioamide functionality was crucial to promote both the efficient enolization of thiolactam pronucleophiles and the subsequent stereoselective conjugate addition to α,β-unsaturated Thioamides. Differential manipulation of the two Thioamide functionalities of the product highlights the synthetic utility of the present catalytic system.
Ryo Yazaki - One of the best experts on this subject based on the ideXlab platform.
-
cooperative activation of alkyne and Thioamide functionalities direct catalytic asymmetric conjugate addition of terminal alkynes to α β unsaturated Thioamides
Chemistry-an Asian Journal, 2011Co-Authors: Ryo Yazaki, Naoya Kumagai, Masakatsu ShibasakiAbstract:A detailed study of the direct catalytic asymmetric conjugate addition of terminal alkynes to α,β-unsaturated Thioamides is described. A soft Lewis acid/hard Bronsted base cooperative catalyst, comprising [Cu(CH(3)CN)(4)]PF(6), bisphosphine ligand, and Li(OC(6)H(4)-p-OMe) simultaneously activated both substrates to compensate for the low reactivity of copper alkynylide. A series of control experiments revealed that the intermediate copper-Thioamide enolate functioned as a Bronsted base to generate copper alkynylide from the terminal alkyne, thus driving the catalytic cycle through an efficient proton transfer between substrates. These findings led to the identification of a more convenient catalyst using potassium hexamethyldisilazane (KHMDS) as the Bronsted base, which was particularly effective for the reaction of silylacetylenes. Divergent transformation of the Thioamide functionality and a concise enantioselective synthesis of a GPR40 receptor agonist AMG-837 highlighted the synthetic utility of the present catalysis.
-
Direct Catalytic Asymmetric Conjugate Addition of Terminal Alkynes to α,β-Unsaturated Thioamides
Journal of the American Chemical Society, 2010Co-Authors: Ryo Yazaki, Naoya Kumagai, Masakatsu ShibasakiAbstract:Direct catalytic asymmetric conjugate addition of terminal alkynes to α,β-unsaturated Thioamides under proton transfer conditions is described. Soft Lewis acid/hard Bronsted base cooperative catalysis is crucial for simultaneous activation of terminal alkynes and Thioamides, affording the β-alkynylThioamides in a highly enantioselective manner. Control experiments suggested that the intermediate copper Thioamide enolate can work as Bronsted base to drive the catalytic cycle via proton transfer. The divergent transformation of the Thioamide functionality highlights the synthetic utility of the alkynylation products.
-
direct catalytic asymmetric aldol reactions of Thioamides toward a stereocontrolled synthesis of 1 3 polyols
Journal of the American Chemical Society, 2009Co-Authors: Mitsutaka Iwata, Naoya Kumagai, Ryo Yazaki, Yuta Suzuki, Masakatsu ShibasakiAbstract:A direct catalytic asymmetric aldol reaction of Thioamides with a soft Lewis acid/hard Bronsted base cooperative catalytic system comprising (R,R)-Ph-BPE/[Cu(CH3CN)4]PF6/LiOAr is described. Highly chemoselective deprotonative activation of Thioamides allows for a direct aldol reaction of α-nonbranched aliphatic aldehydes, which are susceptible to self-condensation. Facile reduction of the Thioamide functionality and a catalyst-controlled second aldol reaction provides 1,3-diols in a highly stereoselective manner.
