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Bioconjugate Chemistry Jan 2018The attachment of two different functionalities in a site-selective fashion represents a great challenge in protein chemistry. We report site specific dual...
The attachment of two different functionalities in a site-selective fashion represents a great challenge in protein chemistry. We report site specific dual functionalizations of peptides and proteins capitalizing on reactivity differences of cysteines in their free (thiol) and protected, oxidized (disulfide) forms. The dual functionalization of interleukin 2 and EYFP proceeded with no loss of bioactivity in a stepwise fashion applying maleimide and disulfide rebridging allyl-sulfone groups. In order to ensure broader applicability of the functionalization strategy, a novel, short peptide sequence that introduces a disulfide bridge was designed and site-selective dual labeling in the presence of biogenic groups was successfully demonstrated.
Topics: Allyl Compounds; Animals; Bacterial Proteins; Cell Line; Cysteine; Humans; Interleukin-2; Luminescent Proteins; Maleimides; Mice; Models, Molecular; Peptides; Proteins; Recombinant Proteins; Staining and Labeling; Sulfhydryl Compounds; Sulfones
PubMed: 29231709
DOI: 10.1021/acs.bioconjchem.7b00675 -
Macromolecular Rapid Communications Mar 2015A thiofunctional thiazolidine is introduced as a new low-molar-mass building block for the introduction of cysteine residues via a thiol-ene reaction. Allyl-functional...
A thiofunctional thiazolidine is introduced as a new low-molar-mass building block for the introduction of cysteine residues via a thiol-ene reaction. Allyl-functional polyglycidol (PG) is used as a model polymer to demonstrate polymer-analogue functionalization through reaction with the unsaturated side-chains. A modified trinitrobenzenesulfonic acid (TNBSA) assay is used for the redox-insensitive quantification and a precise final cysteine content can be predetermined at the polymerization stage. Native chemical ligation at cysteine-functional PG is performed as a model reaction for a chemoselective peptide modification of this polymer. The three-step synthesis of the thiofunctional thiazolidine reactant, together with the standard thiol-ene coupling and the robust quantification assay, broadens the toolbox for thiol-ene chemistry and offers a generic and straightforward approach to cysteine-functional materials.
Topics: Allyl Compounds; Cysteine; Oxidation-Reduction; Peptide Fragments; Polymerization; Polymers; Propylene Glycols; Sulfhydryl Compounds; Surface Properties; Trinitrobenzenesulfonic Acid
PubMed: 25645319
DOI: 10.1002/marc.201400703 -
Journal of the American Chemical Society Apr 2016The enantioselective, intermolecular hydroallylation of vinylarenes employing allylic phosphate electrophiles has been achieved through a copper hydride catalyzed...
The enantioselective, intermolecular hydroallylation of vinylarenes employing allylic phosphate electrophiles has been achieved through a copper hydride catalyzed process. The protocol described herein can be applied to a diverse set of vinylarene substrates and allows for the installation of the parent allyl group as well as a range of 2-substituted allylic fragments.
Topics: Allyl Compounds; Benzene Derivatives; Catalysis; Copper; Styrene; Vinyl Compounds
PubMed: 27042864
DOI: 10.1021/jacs.6b02527 -
Food & Function Aug 2023Aging is a major cause of bone loss and osteoporosis. Diallyl trisulfide (DATS), one of the main organic sulfides in garlic oil, has been shown to alleviate arthritis in...
Aging is a major cause of bone loss and osteoporosis. Diallyl trisulfide (DATS), one of the main organic sulfides in garlic oil, has been shown to alleviate arthritis in mice. However, further research is still needed to determine how DATS affects bone formation and bone loss in aging mice. Here, we established a mouse model of natural aging for dietary DATS intervention. DATS treatment improved the bone microstructure, including the disorganized arrangement of bone trabeculae and promoted collagen synthesis, as confirmed by micro-CT and histological analyses. The abundance of beneficial bacteria for bone formation, such as Clostridiaceae and Erysipelotrichaceae, and the microbial diversity and community richness were all altered by DATS, according to 16S rRNA sequencing data. 14 potential biomarkers and 9 important metabolic pathways were examined using serum metabolomics analysis. Additionally, there has been a significant reduction in sphingosine, which is directly associated with bone metabolism. The level of sphingosine and relative abundance of were found to be negatively correlated by correlation analysis, indicating that bacteria may regulate bone reconstruction influencing metabolites. Furthermore, and gene expression levels increased in bones, which may be related to the ameliorative mechanism of DATS. Our results suggested that DATS may prevent age-related bone loss by upregulating osteogenic gene expression through altering gut microbes and serum metabolism.
Topics: Mice; Animals; Gastrointestinal Microbiome; RNA, Ribosomal, 16S; Sphingosine; Sulfides; Allyl Compounds; Aging; Garlic; Apoptosis
PubMed: 37540026
DOI: 10.1039/d3fo01840g -
Organic & Biomolecular Chemistry May 2019Organic azides are useful synthetic intermediates, which demonstrate broad reactivity. Unlike most organic azides, allylic azides can spontaneously rearrange to form a... (Review)
Review
Organic azides are useful synthetic intermediates, which demonstrate broad reactivity. Unlike most organic azides, allylic azides can spontaneously rearrange to form a mixture of isomers. This rearrangement has been named the Winstein rearrangement. Using allylic azides can result in low yields and azide racemization in some synthetic contexts due to the Winstein rearrangement. Effort has been made to understand the mechanism of the Winstein rearrangement and to take advantage of this process. Several guiding principles can be used to identify which azides will produce a mixture of isomers and which will resist rearrangement. Selective reaction conditions can be used to differentiate the azide isomers in a dynamic manner. This review covers all aspects of allylic azides including their synthesis, their reactivity, the mechanism of the Winstein rearrangement, and reactions that can selectively elaborate an azide isomer. This review covers the literature from Winstein's initial report to early 2019.
Topics: Allyl Compounds; Azides; Cycloaddition Reaction; Isomerism; Models, Chemical; Oxidation-Reduction
PubMed: 30969292
DOI: 10.1039/c8ob03178a -
Organic Letters Jun 2023A highly enantioselective formal α-allylic alkylation of acrylonitrile is developed using 4-cyano-3-oxotetrahydrothiophene (c-THT) as a safe and easy-to-handle...
A highly enantioselective formal α-allylic alkylation of acrylonitrile is developed using 4-cyano-3-oxotetrahydrothiophene (c-THT) as a safe and easy-to-handle surrogate of acrylonitrile. This two-step process consists of an Ir(I)/(,olefin)-catalyzed branched-selective allylic alkylation using easily accessible branched -allylic alcohols as the allylic electrophile followed by retro-Dieckmann/retro-Michael fragmentation and is shown to be applicable for the enantioselective synthesis of α-allylic acrylates as well as α-allylic acrolein.
Topics: Allyl Compounds; Iridium; Acrylonitrile; Stereoisomerism; Catalysis; Alkylation
PubMed: 37311003
DOI: 10.1021/acs.orglett.3c01552 -
Bioorganic & Medicinal Chemistry Letters Feb 2016N,N-Diallyltryptamine (DALT) and 5-methoxy-N,N-diallyltryptamine (5-MeO-DALT) are two tryptamines synthesized and tested by Alexander Shulgin. In self-experiments,...
N,N-Diallyltryptamine (DALT) and 5-methoxy-N,N-diallyltryptamine (5-MeO-DALT) are two tryptamines synthesized and tested by Alexander Shulgin. In self-experiments, 5-MeO-DALT was reported to be psychoactive in the 12-20mg range, while the unsubstituted compound DALT had few discernible effects in the 42-80 mg range. Recently, 5-MeO-DALT has been used in nonmedical settings for its psychoactive effects, but these effects have been poorly characterized and little is known of its pharmacological properties. We extended the work of Shulgin by synthesizing additional 5-substituted-DALTs. We then compared them to DALT and 5-MeO-DALT for their binding affinities at 45 cloned receptors and transporter proteins. Based on in vitro binding affinity, we identified 27 potential receptor targets for the 5-substituted-DALT compounds. Five of the DALT compounds had affinity in the 10-80 nM range for serotonin 5-HT1A and 5-HT2B receptors, while the affinity of DALT itself at 5-HT1A receptors was slightly lower at 100 nM. Among the 5-HT2 subtypes, the weakest affinity was at 5-HT2A receptors, spanning 250-730 nM. Five of the DALT compounds had affinity in the 50-400 nM range for serotonin 5-HT1D, 5-HT6, and 5-HT7 receptors; again, it was the unsubstituted DALT that had the weakest affinity at all three subtypes. The test drugs had even weaker affinity for 5-HT1B, 5-HT1E, and 5-HT5A subtypes and little or no affinity for the 5-HT3 subtype. These compounds also had generally nanomolar affinities for adrenergic α2A, α2B, and α2C receptors, sigma receptors σ1 and σ2, histamine H1 receptors, and norepinephrine and serotonin uptake transporters. They also bound to other targets in the nanomolar-to-low micromolar range. Based on these binding results, it is likely that multiple serotonin receptors, as well as several nonserotonergic sites are important for the psychoactive effects of DALT drugs. To learn whether any quantitative structure-affinity relationships existed, we evaluated correlations among physicochemical properties of the congeneric 5-substituted-DALT compounds. The descriptors included electronic (σp), hydrophobic (π), and steric (CMR) parameters. The binding affinity at 5-HT1A, 5-HT1D, 5-HT7, and κ opioid receptors was positively correlated with the steric volume parameter CMR. At α2A, α2B, and α2C receptors, and at the histamine H1 receptor, binding affinity was correlated with the Hammett substituent parameter σp; higher affinity was associated with larger σp values. At the σ2 receptor, higher affinity was correlated with increasing π. These correlations should aid in the development of more potent and selective drugs within this family of compounds.
Topics: Allyl Compounds; Binding Sites; Kinetics; Protein Binding; Quantitative Structure-Activity Relationship; Receptors, Opioid; Receptors, Serotonin; Receptors, sigma; Tryptamines
PubMed: 26739781
DOI: 10.1016/j.bmcl.2015.12.053 -
Pharmacological Reviews Oct 2017Over the last decade, hydrogen sulfide (HS) has emerged as an important endogenous gasotransmitter in mammalian cells and tissues. Similar to the previously... (Review)
Review
Over the last decade, hydrogen sulfide (HS) has emerged as an important endogenous gasotransmitter in mammalian cells and tissues. Similar to the previously characterized gasotransmitters nitric oxide and carbon monoxide, HS is produced by various enzymatic reactions and regulates a host of physiologic and pathophysiological processes in various cells and tissues. HS levels are decreased in a number of conditions (e.g., diabetes mellitus, ischemia, and aging) and are increased in other states (e.g., inflammation, critical illness, and cancer). Over the last decades, multiple approaches have been identified for the therapeutic exploitation of HS, either based on HS donation or inhibition of HS biosynthesis. HS donation can be achieved through the inhalation of HS gas and/or the parenteral or enteral administration of so-called fast-releasing HS donors (salts of HS such as NaHS and NaS) or slow-releasing HS donors (GYY4137 being the prototypical compound used in hundreds of studies in vitro and in vivo). Recent work also identifies various donors with regulated HS release profiles, including oxidant-triggered donors, pH-dependent donors, esterase-activated donors, and organelle-targeted (e.g., mitochondrial) compounds. There are also approaches where existing, clinically approved drugs of various classes (e.g., nonsteroidal anti-inflammatories) are coupled with HS-donating groups (the most advanced compound in clinical trials is ATB-346, an HS-donating derivative of the non-steroidal anti-inflammatory compound naproxen). For pharmacological inhibition of HS synthesis, there are now several small molecule compounds targeting each of the three HS-producing enzymes cystathionine--synthase (CBS), cystathionine--lyase, and 3-mercaptopyruvate sulfurtransferase. Although many of these compounds have their limitations (potency, selectivity), these molecules, especially in combination with genetic approaches, can be instrumental for the delineation of the biologic processes involving endogenous HS production. Moreover, some of these compounds (e.g., cell-permeable prodrugs of the CBS inhibitor aminooxyacetate, or benserazide, a potentially repurposable CBS inhibitor) may serve as starting points for future clinical translation. The present article overviews the currently known HS donors and HS biosynthesis inhibitors, delineates their mode of action, and offers examples for their biologic effects and potential therapeutic utility.
Topics: Allyl Compounds; Animals; Disulfides; Humans; Hydrogen Sulfide; Molecular Targeted Therapy; Sulfides
PubMed: 28978633
DOI: 10.1124/pr.117.014050 -
Angewandte Chemie (International Ed. in... Aug 2015An organocatalytic and highly regio-, diastereo-, and enantioselective intermolecular haloetherification and haloesterification reaction of allyl amides is reported. A...
An organocatalytic and highly regio-, diastereo-, and enantioselective intermolecular haloetherification and haloesterification reaction of allyl amides is reported. A variety of alkene substituents and substitution patterns are compatible with this chemistry. Notably, electronically unbiased alkene substrates exhibit exquisite regio- and diastereoselectivity for the title transformation. We also demonstrate that the same catalytic system can be used in both chlorination and bromination reactions of allyl amides with a variety of nucleophiles with little or no modification.
Topics: Allyl Compounds; Amides; Catalysis; Esterification; Ethers; Halogenation; Stereoisomerism
PubMed: 26110812
DOI: 10.1002/anie.201502341 -
Chemical Society Reviews Nov 2015The transition metal-catalyzed allylic substitution of unactivated allylic substrates (allylic alcohols, allylic ethers and allylic amines) is rapidly becoming an... (Review)
Review
The transition metal-catalyzed allylic substitution of unactivated allylic substrates (allylic alcohols, allylic ethers and allylic amines) is rapidly becoming an important area of research. There are several advantages to using these substrates in allylic substitution reactions: the use of unactivated alcohols minimizes the production of waste by-products and reaction steps; and allylic ethers and allylic amines are useful substrates because of their stability and their presence in numerous biologically active compounds. Research in this field has therefore gained widespread attention for promoting the development of efficient and environmentally benign procedures for the formation of C-C, C-N and C-O bonds.
Topics: Alcohols; Allyl Compounds; Amines; Catalysis; Ethers; Ketones; Molecular Structure; Transition Elements
PubMed: 26293479
DOI: 10.1039/c5cs00144g