Search Results (26)

Background: Type 2 diabetes mellitus (T2DM) is a prevalent metabolic disease with global implications, necessitating effective management strategies. Dipeptidyl peptidase IV (DPP-4) inhibitors have shown promise as potent agents for T2DM treatment. Methods: This study combines chemical synthesis, molecular modelling, and inhibitory activity assays to characterise the structure–activity relationship of novel isomeric 1,2,4-oxadiazole-substituted derivatives of the 2-azabicyclo[2.2.1]heptane scaffold acylated with (R)-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid. Results: In this article, we demonstrate the efficacy of new compounds as robust inhibitors of DPP-4. The attempts to further modify neogliptin (our lead compound described previously) resulted in a more potent DPP-4 inhibitor 9a (IC₅₀ = 4.3 nM), which did not mediate any substantial inhibition of DPP-8 and DPP-9. Conclusions: This study demonstrates that pseudo peptides incorporating (R)-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid, a 2-aza-bicyclo[2.2.1]heptane moiety, and 1,2,4-oxadiazole substituents act as potent and selective DPP-4 inhibitors. By the stereochemical refinement of oxadiazole derivatives of neogliptin, we discovered compound 9a, a strong candidate for further development in T2DM treatment. Full article

A concise, transition metal-free four-step synthetic pathway has been developed for the synthesis of tetracyclic heterosteroidal compounds, 14-aza-12-oxasteroids, starting from readily available 2-naphthol analogues. After conversion of 2-naphthols to 2-naphthylamines by the Bucherer reaction, subsequent selective C-acetylation was achieved via the Sugasawa reaction and reduction of the acetyl group using borohydride, which resulted into the corresponding amino-alcohols. The naphthalene-based amino-alcohols underwent double dehydrations and double intramolecular cyclization with oxo-acids leading to one-pot formation of a C-N bond, a C-O bond and an amide bond in tandem, to generate two additional rings completing the steroidal framework. A series of 14-aza-12-oxasteroids were synthesized using our developed synthetic strategy in moderate yields, and the structure of one of the final products, 12a-Methyl-11-phenyl-11,12a-dihydro-1H-naphtho[2,1-d]pyrrolo[2,1-b][1,3]oxazin-3(2H)-one, was further confirmed by single crystal X-ray crystallography. Full article

The one-pot multicomponent aza-Morita–Baylis–Hillman (MBH) reaction was performed under green conditions using 1,4-diazabicyclo[2.2.2]octane (DABCO) and Amberlyst^® 15 as a co-catalyst, at ambient temperature and under negligible amounts of non-hazardous solvent. A number of α-methylene-β-amino acid derivatives were produced in good to excellent yields from different arylaldehydes, p-toluenesulfonamide and α,β-unsaturated carbonyl compounds. The environmental benignity of the process is accounted by the low E-factor (0.7) and high atom economy (95%) values obtained. Full article

The cell-penetrating peptide (CPP) penetratin has gained much attention over many years due to its potential role as a transporter for a broad range of cargo into cells. The modification of penetratin has been extensively investigated too. Aza-peptides are peptide analogs in which one or more of the amino residues are replaced by a semicarbazide. This substitution results in conformational restrictions and modifications in hydrogen bonding properties, which affect the structure and may lead to enhanced activity and selectivity of the modified peptide. In this work, the Trp residues of penetratin were substituted by aza-glycine or glycine residues to examine the effect of these modifications on the cellular uptake and the internalization mechanism. The substitution of Trp⁴⁸ or Trp^48,56 dramatically reduced the internalization, showing the importance of Trp⁴⁸ in cellular uptake. Interestingly, while aza-glycine in the position of Trp⁵⁶ increased the cellular uptake, Gly reduced it. The two Trp-modified derivatives showed altered internalization pathways, too. Based on our knowledge, this is the first study about the effect of aza-amino acid substitution on the cell entry of CPPs. Our results suggest that aza-amino acid insertion is a useful modification to change the internalization of a CPP. Full article

Azapeptides have gained much attention due to their ability to enhance the stability and bioavailability of peptide drugs. Their structural preferences, essential to understanding their function and potential application in the peptide drug design, remain largely unknown. In this work, we systematically investigated the conformational preferences of three azaamino acid residues in tripeptide models, Ac-azaXaa-Pro-NHMe [Xaa = Asn (4), Asp (5), Ala (6)], using the popular DFT functionals, B3LYP and B3LYP-D3. A solvation model density (SMD) was used to mimic the solvation effect on the conformational behaviors of azapeptides in water. During the calculation, we considered the impact of the amide bond in the azapeptide models on the conformational preferences of models 4–6. We analyzed the effect of the HB between the side-chain main chain and main-chain main-chain on the conformational behaviors of azapeptides 4–6. We found that the predicted lowest energy conformation for the three models differs depending on the calculation methods. In the gas phase, B3LYP functional indicates that the conformers tttANP-1 and tttADP-1 of azapeptides 4 and 5 correspond to the type I of β-turn, the lowest energy conformation with all-trans amide bonds. Considering the dispersion correction, B3LYP-D3 functional predicts the conformers tctANP-2 and tctADP-3 of azapeptide 4 and 5, which contain the cis amide bond preceding the Pro residue, as the lowest energy conformation in the gas phase. The results imply that azaAsx and Pro residues may involve cis-trans isomerization in the gas phase. In water, the predicted lowest energy conformer of azapeptides 4 and 5 differs from the gas phase results and depends on the calculational method. For azapeptide 6, regardless of calculation methods and phases, tttAAP-1 (β-I turn) is predicted as the lowest energy conformer. The results imply that the effect of the side chain that can form HBs on the conformational preferences of azapeptides 4 and 5 may not be negligible. We compared the theoretical results of azaXaa-Pro models with those of Pro-azaXaa models, showing that incorporating azaamino acid residue in peptides at different positions can significantly impact the folding patterns and stability of azapeptides. Full article

Three AML cell variants (M/A, M/A* from MOLM-13 and S/A from SKM-1) were established for resistance by the same protocol using 5-azacytidine (AZA) as a selection agent. These AZA-resistant variants differ in their responses to other cytosine nucleoside analogs, including 5-aza-2′-deoxycytidine (DAC), as well as in some molecular features. Differences in global DNA methylation, protein levels of DNA methyltransferases, and phosphorylation of histone H2AX were observed in response to AZA and DAC treatment in these cell variants. This could be due to changes in the expression of uridine-cytidine kinases 1 and 2 (UCK1 and UCK2) demonstrated in our cell variants. In the M/A variant that retained sensitivity to DAC, we detected a homozygous point mutation in UCK2 resulting in an amino acid substitution (L220R) that is likely responsible for AZA resistance. Cells administered AZA treatment can switch to de novo synthesis of pyrimidine nucleotides, which could be blocked by inhibition of dihydroorotate dehydrogenase by teriflunomide (TFN). This is shown by the synergistic effect of AZA and TFN in those variants that were cross-resistant to DAC and did not have a mutation in UCK2. Full article

Highly efficient silicone surfactants are typically based on polyether hydrophiles. As part of a program to increase the natural content of silicones, we describe the synthesis of silicone surfactants with amino acid hydrophiles (cysteine, arginine, and lysine). The compounds were prepared using a radial thiol–ene reaction with vinylsilicones for cysteine derivatives and a catalyst-free aza-Michael reaction with arginine and lysine. Short chain surfactants with silicone monomer:hydrophile ratios of 5:1 or less (e.g., telechelic silicones of lysine-linker-(Me₂OSi)_n-linker-lysine n = 10) were ineffective at stabilizing emulsions of silicone oil (D₄): water. However, excellent surfactants were realized as the chain length (n) increased to 25 or 50, stabilizing water-in-oil emulsions with high water content (80% or 90%). The surfactants, especially the longer chain compounds, were stable against pH except <4 or >9 and survived freeze/thaw cycles. These surfactants contain 12–25% natural materials, improving their sustainability compared to those containing synthetic hydrophiles. Full article

Unnatural amino acids with enhanced properties, such as increased complexing ability and luminescence, are considered to be highly attractive building blocks for bioinspired frameworks, such as probes for biomolecule dynamics, sensitive fluorescent chemosensors, and peptides for molecular imaging, among others. Therefore, a novel series of highly emissive heterocyclic alanines bearing a benzo[d]oxazolyl unit functionalized with different heterocyclic π-spacers and (aza)crown ether moieties was synthesized. The new compounds were completely characterized using the usual spectroscopic techniques and evaluated as fluorimetric chemosensors in acetonitrile and aqueous mixtures in the presence of various alkaline, alkaline-earth, and transition metal ions. The different crown ether binding moieties as well as the electronic nature of the π-bridge allowed for fine tuning of the sensory properties of these unnatural amino acids towards Pd²⁺ and Fe³⁺, as seen by spectrofluorimetric titrations. Full article

In this paper, a simple and efficient synthetic route for the preparation of new heterocyclic amino acid derivatives containing azetidine and oxetane rings was described. The starting (N-Boc-azetidin-3-ylidene)acetate was obtained from (N-Boc)azetidin-3-one by the DBU-catalysed Horner–Wadsworth–Emmons reaction, followed by aza-Michael addition with NH-heterocycles to yield the target functionalised 3-substituted 3-(acetoxymethyl)azetidines. Methyl 2-(oxetan-3-ylidene)acetate was obtained in a similar manner, which was further treated with various (N-Boc-cycloaminyl)amines to yield the target 3-substituted 3-(acetoxymethyl)oxetane compounds. The synthesis and diversification of novel heterocyclic amino acid derivatives were achieved through the Suzuki–Miyaura cross-coupling from the corresponding brominated pyrazole–azetidine hybrid with boronic acids. The structures of the novel heterocyclic compounds were confirmed via ¹H-, ¹³C-, ¹⁵N-, and ¹⁹F-NMR spectroscopy, as well as HRMS investigations. Full article

The preparation and characterization of a new chiral tertiary dibenzylamine are described. These molecules are well known in the literature for their high neuropharmacological potential. The general synthetic pathway is based on asymmetric Aza–Michael addition of chiral (R)-N-benzyl-N-(α-methylbenzyl)amide to methyl cyclohex-1-en-carboxilate obtaining the β-amino ester, followed by carboxylic acid hydrolysis and subsequent Barton descarboxylation. Interestingly, it is a general synthetic procedure of a wide range of chiral amines by careful choice of insaturated esters and alkylation of the chiral enolate in the initial reaction. The new tertiary dibenzylamine molecule is fully characterized by NMR Spectroscopy (¹H and ¹³C), as well by High-Resolution Mass Spectrometry and Infrared Spectroscopy. Full article

Peptides are highly potent biological active compounds with excellent selectivity and binding, but they have some drawbacks (e.g., low stability in vivo because of the enzymatic degradation, and fast elimination). To overcome their drawbacks, various peptidomimetics have been gaining ground. Different modifications have been examined, such as the modification of peptide backbone. One such seemingly simple modification is the replacement of the CH^α group by an N atom. These amino acid derivatives are called azaamino acids, and peptides containing azaamino acid are called azapeptides. This exchange results in both steric and electronic differences from the original amino acids, thus affecting the structure and biological activity of the modified peptide. In this review, the synthesis possibilities of azapeptides and the impact of azaamino acid incorporation on the structure and biological activity are presented through examples. Different synthetic solutions for azaamino acid introduction and the various routes to build in the side chain are summarized to illustrate the improvement of the field of azaamino acid chemistry. The influence of the altered electronic and steric properties of N-atom on the structure is described, too. Finally, some examples are given with potent biological activity. Full article

Plants use complex gene regulatory mechanisms to overcome diverse environmental challenges. For instance, cold stress induces rapid and massive transcriptome changes via alternative splicing (AS) to confer cold tolerance in plants. In mammals, mounting evidence suggests chromatin structure can regulate co-transcriptional AS. Recent evidence also supports co-transcriptional regulation of AS in plants, but how dynamic changes in DNA methylation and the chromatin structure influence the AS process upon cold stress remains poorly understood. In this study, we used the DNA methylation inhibitor 5-Aza-2′-Deoxycytidine (5-aza-dC) to investigate the role of stochastic variations in DNA methylation and nucleosome occupancy in modulating cold-induced AS, in Arabidopsis thaliana (Arabidopsis). Our results demonstrate that 5-aza-dC derived stochastic hypomethylation modulates nucleosome occupancy and AS profiles of genes implicated in RNA metabolism, plant hormone signal transduction, and of cold-related genes in response to cold stress. We also demonstrate that cold-induced remodelling of DNA methylation regulates genes involved in amino acid metabolism. Collectively, we demonstrate that sudden changes in DNA methylation via drug treatment can influence nucleosome occupancy levels and modulate AS in a temperature-dependent manner to regulate plant metabolism and physiological stress adaptation. Full article

Compounds that contain (R)-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid substituted with bicyclic amino moiety (2-aza-bicyclo[2.2.1]heptane) were designed using molecular modelling methods, synthesised, and found to be potent DPP-4 (dipeptidyl peptidase-4) inhibitors. Compound 12a (IC50 = 16.8 ± 2.2 nM), named neogliptin, is a more potent DPP-4 inhibitor than vildagliptin and sitagliptin. Neogliptin interacts with key DPP-4 residues in the active site and has pharmacophore parameters similar to vildagliptin and sitagliptin. It was found to have a low cardiotoxic effect compared to sitagliptin, and it is superior to vildagliptin in terms of ADME properties. Moreover, compound 12a is stable in aqueous solutions due to its low intramolecular cyclisation potential. These findings suggest that compound 12a has unique properties and can act as a template for further type 2 diabetes mellitus drug development. Full article

In order to develop novel bioactive substances with potent activities, some new valine-derived compounds incorporating a 4-(phenylsulfonyl)phenyl fragment, namely, acyclic precursors from N-acyl-α-amino acids and N-acyl-α-amino ketones classes, and heterocycles from the large family of 1,3-oxazole-based compounds, were synthesized. The structures of the new compounds were established using elemental analysis and spectral (UV-Vis, FT-IR, MS, NMR) data, and their purity was checked by reversed-phase HPLC. The newly synthesized compounds were evaluated for their antimicrobial and antibiofilm activities, for toxicity on D. magna, and by in silico studies regarding their potential mechanism of action and toxicity. The 2-aza-3-isopropyl-1-[4-(phenylsulfonyl)phenyl]-1,4-butanedione 4b bearing a p-tolyl group in 4-position exhibited the best antibacterial activity against the planktonic growth of both Gram-positive and Gram-negative strains, while the N-acyl-α-amino acid 2 and 1,3-oxazol-5(4H)-one 3 inhibited the Enterococcus faecium biofilms. Despite not all newly synthesized compounds showing significant biological activity, the general scaffold allows several future optimizations for obtaining better novel antimicrobial agents by the introduction of various substituents on the phenyl moiety at position 5 of the 1,3-oxazole nucleus. Full article

A new methodology for the asymmetric synthesis of enantiomerically enriched 3-aroyl pyroglutamic acid derivatives has been developed through effective 5-exo-tet cyclization of N-chloroacetyl aroylalanines. The three-step sequence starts with the synthesis of N-substituted (S,S)-2-amino-4-aryl-4-oxobutanoic acids via highly diastereoselective tandem aza-Michael addition and crystallization-induced diastereomer transformation (CIDT). Their N-chloroacetylation followed by base-catalyzed cyclization and ultimate acid-catalyzed removal of chiral auxiliary without loss of stereochemical integrity furnishes the target substituted pyroglutamic acids. Finally, several series of their benzyl amides were prepared as 3-aroyl analogs of known P2X7 antagonists. Full article