103321-53-5Relevant articles and documents
Synthesis and in vitro stability of amino acid prodrugs of 6-β-naltrexol for microneedle-enhanced transdermal delivery
Eldridge, Joshua A.,Milewski, Mikolaj,Stinchcomb, Audra L.,Crooks, Peter A.
, p. 5212 - 5215 (2014)
A small library of amino acid ester prodrugs of 6-β-naltrexol (NTXOL, 1) was prepared in order to investigate the candidacy of these prodrugs for microneedle-enhanced transdermal delivery. Six amino acid ester prodrugs were synthesized (6a-f). 6b, 6d, and 6e were stable enough at skin pH (pH 5.0) to move forward to studies in 50% human plasma. The lead compound (6e) exhibited the most rapid bioconversion to NTXOL in human plasma (t1/2 = 2.2 ± 0.1 h).
Efficient amide bond formation through a rapid and strong activation of carboxylic acids in a microflow reactor
Fuse, Shinichiro,Mifune, Yuto,Takahashi, Takashi
, p. 851 - 855 (2014)
The development of highly efficient amide bond forming methods which are devoid of side reactions, including epimerization, is important, and such a method is described herein and is based on the concept of rapid and strong activation of carboxylic acids. Various carboxylic acids are rapidly (0.5 s) converted into highly active species, derived from the inexpensive and less-toxic solid triphosgene, and then rapidly (4.3 s) reacted with various amines to afford the desired peptides in high yields (74 %-quant.) without significant epimerization (≤3 %). Our process can be carried out at ambient temperature, and only CO2 and HCl salts of diisopropylethyl amine are generated. In the long history of peptide synthesis, a significant number of active coupling reagents have been abandoned because the highly active electrophilic species generated are usually susceptible to side reactions such as epimerization. The concept presented herein should renew interest in the use of these reagents. In the fast lane: The title reaction is described for the synthesis of peptides. Various carboxylic acids including easily epimerizable amino acids were rapidly converted into highly electrophilic species, and then reacted with various amines, including less nucleophilic N-methyl amino acids, to afford the desired peptides in high yields without significant epimerization. Copyright
Enantiopure 5-CF3-Proline: Synthesis, Incorporation in Peptides, and Tuning of the Peptide Bond Geometry
Sanchez, Clément A.,Gadais, Charlène,Chaume, Grégory,Girard, Sylvaine,Chelain, Evelyne,Brigaud, Thierry
, p. 382 - 387 (2021)
The straightforward synthesis of enantiopure 5-(R)-and 5-(S)-trifluoromethylproline is reported. The key steps are a Ruppert-Prakash reagent addition on l-pyroglutamic esters followed by an elimination reaction and a selective reduction. The solution-phase and solid-phase incorporation of this unprotected enantiopure fluorinated amino acid in a short peptide chain was demonstrated. Compared to proline, the CF3 group provides a decrease of the trans to cis amide bond isomerization energy and an increase of the cis conformer population.
Discovery of nanomolar desmuramylpeptide agonists of the innate immune receptor nucleotide-binding oligomerization domain-containing protein 2 (NOD2) possessing immunostimulatory properties
Gobec, Martina,Toma?i?, Tihomir,?timac, Adela,Frkanec, Ru?a,Trontelj, Jurij,Anderluh, Marko,Mlinari?-Ra??an, Irena,Jakopin, ?iga
, p. 2707 - 2724 (2018)
Muramyl dipeptide (MDP), a fragment of bacterial peptidoglycan, has long been known as the smallest fragment possessing adjuvant activity, on the basis of its agonistic action on the nucleotide-binding oligomerization domain-containing protein 2 (NOD2). There is a pressing need for novel adjuvants, and NOD2 agonists provide an untapped source of potential candidates. Here, we report the design, synthesis, and characterization of a series of novel acyl tripeptides. A pivotal structural element for molecular recognition by NOD2 has been identified, culminating in the discovery of compound 9, the most potent desmuramylpeptide NOD2 agonist to date. Compound 9 augmented pro-inflammatory cytokine release from human peripheral blood mononuclear cells in synergy with lipopolysaccharide. Furthermore, it was able to induce ovalbumin-specific IgG titers in a mouse model of adjuvancy. These findings provide deeper insights into the structural requirements of desmuramylpeptides for NOD2-activation and highlight the potential use of NOD2 agonists as adjuvants for vaccines.
N-Amination Converts Amyloidogenic Tau Peptides into Soluble Antagonists of Cellular Seeding
Del Valle, Juan R.,Lin, Yu-Shan,Makwana, Kamlesh M.,Miao, Jiayuan,Sarnowski, Matthew P.
, p. 3928 - 3938 (2021/10/29)
The spread of neurofibrillary tangles composed of tau protein aggregates is a hallmark of Alzheimer's and related neurodegenerative diseases. Early oligomerization of tau involves conformational reorganization into parallel β-sheet structures and supramolecular assembly into toxic fibrils. Despite the need for selective inhibitors of tau propagation, β-rich protein assemblies are inherently difficult to target with small molecules. Here, we describe a minimalist approach to mimic the aggregation-prone modules within tau. We carried out a backbone residue scan and show that amide N-amination completely abolishes the tendency of these peptides to self-aggregate, rendering them soluble mimics of ordered β-strands from the tau R2 and R3 domains. Several N-amino peptides (NAPs) inhibit tau fibril formation in vitro. We further demonstrate that NAPs 12 and 13 are effective at blocking the cellular seeding of endogenous tau by interacting with monomeric or fibrillar forms of extracellular tau. Peptidomimetic 12 is serum stable, non-toxic to neuronal cells, and selectivity inhibits the fibrilization of tau over Aβ42. Structural analysis of our lead NAPs shows considerable conformational constraint imposed by the N-amino groups. The described backbone N-amination approach provides a rational basis for the mimicry of other aggregation-prone peptides that drive pathogenic protein assembly.
