Amide Motif Research Articles

Deciphering Spectroscopic Signatures of Competing Ca2+ - Peptide Interactions.

Calcium-protein interactions are of paramount importance in biochemistry. They are a key element in a number of biological processes, such as neuronal signaling. Therefore, an understanding of the interaction at the molecular level is highly desirable. Here, we study the zwitterionic model peptide l-alanyl-l-alanine (2Ala), which has two distinct and competing binding sites for Ca2+: The carbonyl of the peptide bond and the C-terminus, the carboxylate group. We perform linear and two-dimensional IR spectroscopy experiments and find that the spectroscopic signatures of both moieties in the IR spectra change in amplitude and peak position upon the addition of CaCl2: A blueshift of the asymmetric carboxylate band and a redshift for the amide I mode. Ab initio molecular dynamics simulations confirm the direct interaction of the Ca2+ ion at both the carboxylate and the amide CO site leading to different spectral responses. The blueshift of the asymmetric carboxylate band is caused by a localization of the charge, leading to a decoupling of the CO stretching modes of the carboxylate group. The slight redshift of the amide I mode of 2Ala upon the addition of CaCl2 contrasts the blueshift that has been observed for isolated amide motifs, such as N-methylacetamide (NMA). This difference is caused by the smaller number of water molecules being replaced by the Ca2+ ion for 2Ala's amide compared to less sterically hindered, isolated amide carbonyls, in conjunction with vibrational Stark effects. Our results highlight the importance of considering potential competing binding sites, such as the amide CO backbone, the termini and residues, as well as the nature of the hydration of both peptide and ion, when exploring ions' interacting with small peptides and larger proteins.

Synthesis and Antibacterial Activities of Linezolid Analogues with C5‐thioether/N,S‐acetal Amide

AbstractThe modification on the C5‐side chain in Linezolid analogues development is sporadic owing to the fact that trivial alternation on this position always leads to significant loss of antibacterial activity and in many cases to complete inactivity. The present work focused on constructing the potent yet relatively unexplored C5‐side chain of Linezolid, therefore various C5‐thioethers were synthesized and evaluated for their antibacterial activities. The most potent candidates, hydroxyl thioether (R)‐5 a, (R)‐10 a, and (R)‐5 r which featuring a linear N,S‐acetal amide motif at the C5 side chain, shown strong antibacterial activities with no observable cytotoxicity.

Thermally and mechanically robust self-healing supramolecular polyurethanes featuring aliphatic amide end caps

A series of supramolecular polyurethanes (SPUs) were designed and synthesised with synergetic multifunctional hydrogen bonding aliphatic amide end-caps. Hydrogen bonding between the urethane, urea, and amide motifs in the polymers afford strong dynamic association between polymer chains in the solid state. Phase separation of the apolar and polar components of the polyurethanes also serves to reinforce their thermal and mechanical properties. The supramolecular polyurethane with bisamide-morpholine end caps associates via multiple hydrogen bonds and exhibits enhanced tensile and thermal properties when compared to the other materials. Variable-temperature infrared spectroscopy (VT-IR) and atomic force microscopy (AFM), were carried out to study the phase morphology of the polymers and revealed a correlation between increased phase separation and the introduction of amide motifs in the end-caps. These SPUs also exhibit excellent healing abilities, requiring temperatures >200 °C to recover their physical properties.

Photocatalyzed sulfoximination/amidation of (Het)arylethenes tethered N-tosyl amide: a versatile entry to sulfoximidoyl β- and γ-lactams

Lactamization through C–N bond formation between CC and amide motifs enables access to various sulfoximidoyl lactams via a 1,2-diamination process.

Nanoscale iodophoric poly(vinyl amide) coatings for the complexation and release of iodine for antimicrobial surfaces

Wound infection exacerbated by multidrug-resistant (MDR) bacteria has necessitated the need for wound dressing materials with embedded antimicrobial property to prevent the development of chronic wounds. Iodine (I2), typically as a poly(vinyl pyrrolidone)-I2 (PVP–I) complex, is a widely used antiseptic agent in wound care owing to its efficacy, safety, and low probability to cause further resistance. Despite extensive research on PVP–I formulations, there is potentially a large selection of poly(vinyl amide)s that have remained largely unexplored as iodophoric materials, particularly as coatings for wound dressings and medical devices. Therefore, in this study we prepared a series of stable, cross-linked poly(vinyl amide) coatings via plasma polymerization and studied their structure–property relationships for the complexation and release of I2. Plasma polymerized poly(N-vinyl-2-pyrrolidone) (pPVP), poly(N-methyl-N-vinylacetamide) (pPMVA) and poly(N-vinylcaprolactam) (pPVCl) nanoscale coatings were prepared with uniform thicknesses of 330–340 nm and low surface roughness. Complexation of I2 as polyiodides resulted in a significant increase in the pPVCl coating thickness in phosphate buffered saline (PBS), consistent with the Hofmeister effect. Raman spectroscopy confirmed that the I2 was complexed exclusively as the triiodide ion (I3-) in all coatings, which was confirmed by synchrotron X-ray photoelectron spectroscopy (XPS) experiments. Nuclear magnetic resonance (NMR) spectroscopy of poly(vinyl amides) was employed to further prove that the complexing species was hydrogen triiodide (HI3). The loading of I2 species increased from pPVP < pPMVA < pPVCl, with percentage elemental compositions of 1.3, 1.8, and 2.9%, respectively, which correlated with the extent of nitrogen loss during polymerization and oxidation, and was also in agreement with determined negative zeta potential values. However, quantification of the released I2 species over 5 h showed that the greatest release was observed from pPMVA (121.3 µg.cm−2), with pPVP (77.4 µg.cm−2) and pPVCl (74.6 µg.cm−2) releasing a similar amount, highlighting that I2 release from poly(vinyl amide) coatings is a function of the loading and composition of the polymer, not just the I2 complexing amide motif. The I2 complexed pPMVA coated wound dressings were highly effective against Gram-negative Pseudomonas aeruginosa and Gram-positive Staphylococcus aureus, the two major strains associated with wound infection, reducing bacterial viability by up to 4 and 7 (log10 reduction) orders of magnitude. Overall, the poly(vinyl amide) coatings are promising iodophors for the prevention and treatment of wound infections.

Fatty Acid-Activated Proton Transport by Bisaryl Anion Transporters Depolarises Mitochondria and Reduces the Viability of MDA-MB-231 Breast Cancer Cells.

In respiring mitochondria, the proton gradient across the inner mitochondrial membrane is used to drive ATP production. Mitochondrial uncouplers, which are typically weak acid protonophores, can disrupt this process to induce mitochondrial dysfunction and apoptosis in cancer cells. We have shown that bisaryl urea-based anion transporters can also mediate mitochondrial uncoupling through a novel fatty acid-activated proton transport mechanism, where the bisaryl urea promotes the transbilayer movement of deprotonated fatty acids and proton transport. In this paper, we investigated the impact of replacing the urea group with squaramide, amide and diurea anion binding motifs. Bisaryl squaramides were found to depolarise mitochondria and reduce MDA-MB-231 breast cancer cell viability to similar extents as their urea counterpart. Bisaryl amides and diureas were less active and required higher concentrations to produce these effects. For all scaffolds, the substitution of the bisaryl rings with lipophilic electron-withdrawing groups was required for activity. An investigation of the proton transport mechanism in vesicles showed that active compounds participate in fatty acid-activated proton transport, except for a squaramide analogue, which was sufficiently acidic to act as a classical protonophore and transport protons in the absence of free fatty acids.

Enhancing Substrate-Metal Catalyst Affinity via Hydrogen Bonding: Pd(II)-Catalyzed β-C(sp3)-H Bromination of Free Carboxylic Acids.

The achievement of sufficient substrate-metal catalyst affinity is a fundamental challenge for the development of synthetically useful C-H activation reactions of weakly coordinating native substrates. While hydrogen bonding has been harnessed to bias site selectivity in existing C(sp2)-H activation reactions, the potential for designing catalysts with hydrogen bond donors (HBDs) to enhance catalyst-substrate affinity and, thereby, facilitate otherwise unreactive C(sp3)-H activation remains to be demonstrated. Herein, we report the discovery of a ligand scaffold containing a remote amide motif that can form a favorable meta-macrocyclic hydrogen bonding interaction with the aliphatic acid substrate. The utility of this ligand scaffold is demonstrated through the development of an unprecedented C(sp3)-H bromination of α-tertiary and α-quaternary free carboxylic acids, which proceeds in exceedingly high mono-selectivity. The geometric relationship between the NHAc hydrogen bond donor and the coordinating quinoline ligand is crucial for forming the meta-macrocyclophane-like hydrogen bonding interaction, which provides a guideline for the future design of catalysts employing secondary interactions.

Site-Selective Arylation of Carboxamides from Unprotected Peptides.

The amidated peptides are an important class of biologically active compounds due to their unique biological properties and wide applications as potential peptide drugs and biomarkers. Despite the abundance of free amide motifs (Asn, Gln, and C-terminal amide) in native peptides, late-stage modification of the amide unit in naturally occurring peptides remains very rare because of the intrinsically weak nucleophilicity of amides and the interference of multiple competing nucleophilic residues, which generally lead to undesired side reactions. Herein, chemoselective arylation of amides in unprotected polypeptides has been developed under an air atmosphere to afford the N-aryl amide peptides bearing various functional motifs. Its success relies on the combination of gold catalysis and silver salt to differentiate the relative inert amide among a collection of reactive nucleophilic amino acid residues (e.g., -NH2, -OH, and -COOH), favoring the C-N bond coupling toward amides over other more nucleophilic groups. Experimental and DFT studies reveal a crucial role of the silver cation, which serves as a transient coordination mask of the more reactive reaction sites, overcoming the inherently low reactivity of amides. The excellent biocompatibility of this strategy has been applied to functionalize a wide range of peptide drugs and complex peptides. The application could be further extended to peptide labeling and peptide stapling.

Atroposelective Synthesis of Axially Chiral Styrenes by Platinum- Catalyzed Stereoselective Hydrosilylation of Internal Alkynes.

Hydrofunctionalization of alkynes is one of the most efficient ways to access axially chiral styrenes with open-chained olefins. While great advances have been achieved for 1-alkynylnaphthalen-2-ols and analogues, atroposelective hydrofunctionalization of unactivated internal alkynes lags. Herein we reported a platinum-catalyzed atroposelective hydrosilylation of unactivated internal alkynes for the first time. With monodentate TADDOL-derived phosphonite L1 used as a chiral ligand, various axially chiral styrenes were achieved in excellent enantioselectivities with high E-selectivities. Control experiments showed that the NH-arylamide groups have significant effects on both the yields and enantioselectivities and could act as directing groups. The potential utilities of the products were shown by the transformations of the amide motifs of the products.

Atroposelective Synthesis of Axially Chiral Styrenes by Platinum‐ Catalyzed Stereoselective Hydrosilylation of Internal Alkynes

AbstractHydrofunctionalization of alkynes is one of the most efficient ways to access axially chiral styrenes with open‐chained olefins. While great advances have been achieved for 1‐alkynylnaphthalen‐2‐ols and analogues, atroposelective hydrofunctionalization of unactivated internal alkynes lags. Herein we reported a platinum‐catalyzed atroposelective hydrosilylation of unactivated internal alkynes for the first time. With monodentate TADDOL‐derived phosphonite L1 used as a chiral ligand, various axially chiral styrenes were achieved in excellent enantioselectivities with high E‐selectivities. Control experiments showed that the NH‐arylamide groups have significant effects on both the yields and enantioselectivities and could act as directing groups. The potential utilities of the products were shown by the transformations of the amide motifs of the products.

Ionizable Lipid with Supramolecular Chemistry Features for RNA Delivery In Vivo.

Lipid nanoparticles (LNPs) and ribonucleic acid (RNA) technology are highly versatile tools that can be deployed for diagnostic, prophylactic, and therapeutic applications. In this report, supramolecular chemistry concepts are incorporated into the rational design of a new ionizable lipid, C3-K2-E14, for systemic administration. This lipid incorporates a cone-shaped structure intended to facilitate cell bilayer disruption, and three tertiary amines to improve RNA binding. Additionally, hydroxyl and amide motifs are incorporated to further enhance RNA binding and improve LNP stability. Optimization of messenger RNA (mRNA) and small interfering RNA (siRNA) formulation conditions and lipid ratios produce LNPs with favorable diameter (<150nm), polydispersity index (<0.15), and RNA encapsulation efficiency (>90%), all of which are preserved after 2months at 4 or 37°C storage in ready-to-use liquid form. The lipid and formulated LNPs are well-tolerated in animals and show no deleterious material-induced effects. Furthermore, 1week after intravenous LNP administration, fluorescent signal from tagged RNA payloads are not detected. To demonstrate the long-term treatment potential for chronic diseases, repeated dosing of C3-K2-E14 LNPs containing siRNA that silences the colony stimulating factor-1 (CSF-1) gene can modulate leukocyte populations in vivo, further highlighting utility.

Design and Structural Optimization of Methionine Adenosyltransferase 2A (MAT2A) Inhibitors with High In Vivo Potency and Oral Bioavailability.

Inhibition of methionine adenosyltransferase 2A (MAT2A) in cancers with a deletion of methylthioadenosine phosphorylase (MTAP) gene leads to synthetic lethality, thus receiving significant interest in the field of precise cancer treatment. Herein, we report the discovery of a tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine fragment which occupies the MAT2A allosteric pocket. The lead compound 8 exhibited extremely high potency to inhibit MAT2A enzymatic activity (IC50 = 18 nM) and proliferation of MTAP-null cancer cells (IC50 = 52 nM). 8 had a favorable pharmacokinetic profile with a bioavailability of 116% in mice. More importantly, introducing an amide motif (28) to the core structure raised the plasma drug exposure from 11 718 to 41 192 ng·h·mL-1. 28 displayed a significantly better in vivo potency than AG-270, which is being evaluated in clinical trails, and induced -52% tumor regression in a xenograft MTAP-depleted colon tumor model.

Poly(N-acryloyl glycinamide-co-N-acryloxysuccinimide) Nanoparticles: Tunable Thermo-Responsiveness and Improved Bio-Interfacial Adhesion for Cell Function Regulation.

Poly(N-acryloyl glycinamide) (PNAGA) can form high-strength hydrogen bonds (H-bonds) through the dual amide motifs in the side chain, allowing the polymer to exhibit gelation behavior and an upper critical solution temperature (UCST) property. These features make PNAGA a candidate platform for biomedical devices. However, most applications focused on PNAGA hydrogels, while few focused on PNAGA nanoparticles. Improving the UCST tunability and bio-interfacial adhesion of the PNAGA nanoparticles may expand their applications in biomedical fields. To address the issues, we established a reactive H-bond-type P(NAGA-co-NAS) copolymer via reversible addition-fragmentation chain transfer polymerization of NAGA and N-acryloxysuccinimide (NAS) monomers. The UCST behaviors and the bio-interfacial adhesion toward the proteins and cells along with the potential application of the copolymer nanoparticles were investigated in detail. Taking advantage of the enhanced H-bonding and reactivity, the copolymer exhibited a tunable UCST in a broad temperature range, showing thermo-reversible transition between nanoparticles (PNPs) and soluble chains; the PNPs efficiently bonded proteins into nano-biohybrids while keeping the secondary structure of the protein, and more importantly, they also exhibited good adhesion ability to the cell membrane and significantly inhibited cell-specific propagation. These features suggest broad prospects for the P(NAGA-co-NAS) nanoparticles in the fields of biosensors, protein delivery, cell surface decoration, and cell-specific function regulation.

Total Synthesis of (E/Z) des‐Hydroxy Triticone A and B

AbstractThe first total synthesis of des‐hydroxy triticone A and B was achieved in 12 steps. The highly chemoselective, base mediated iodolactamization of olefins with N‐OMe amide motif is a key highlight of the synthesis.

Regioselective reductive transamination of peptidic amides enabled by a dual Zr(IV)–H catalysis

<h2>Summary</h2> An amide group, which is a common structural motif of peptides and biologically active molecules, is a highly attractive target for catalytic transformations. Despite its high synthetic potential, the chemical inertness of the amide bond, owing to its resonance stabilization, has rendered this approach challenging. Existing catalytic modes essentially include metal-catalyzed carbon–nitrogen bond activation, transamidation, and catalytic amide reduction. Herein, we report an unprecedented protocol of catalytic reductive transamination of amides to amines of exchanged identities. Through the intermediacy of aminals, combinations of amides with a wide range of external amines lead to a variety of mono- and diamines in good yields with high compatibility of functional groups and retentions of chirality. Regioselective post-modifications of oligomeric peptide derivatives bearing multiple amide motifs have also been realized, and the origin of site-selectivity has been explained by both experimental studies together with DFT calculations.

Magnetic MCR-Functionalized Graphene Oxide Complexed with Copper Nano-Particles: An Efficient and Recyclable Nanocatalyst for Ullmann C–N Coupling Reaction

In this study, we report the synthesis of Cu nanoparticle modified dithiocarbamate (DTC)-functionalized magnetic graphene oxide (GO) nanocatalyst through a one-pot three component reaction. It has an excellent affinity for copper nanoparticles due to its DTC ligand amide motif. The structure of the synthesized catalysts was confirmed by using FT-IR, TGA, CHNS, SEM, XRD, EDS mapping, and ICP. The catalytic activity of the synthesized nanocatalyst was investigated in Ullmann cross-coupling reaction for the synthesis of N-aryl amines, which resulted in high reaction yields, easy workup, and short reaction times. The catalyst is separated easily by a magnetic field and can be reused for at least five successive runs without significant loss of catalytic activity. The nature of the supported DTC on the GO’s surface improved the catalytic activity of the graphene, provided homogeneity to the catalyst, and enhanced the capability of coordination with copper ions. Facile catalyst recovery and reusability, simple setup procedure, generality of the method and high turnover number (TON) make this procedure an environmentally benign approach for preparing the titled compounds. Based on the findings of this study, it appears that the catalytic system introduced can be used to prepare other beneficial heterocyclic compounds.

Synthesis and Characterization of Novel Isosorbide‐Based Polyester Derivatives Decorated with α‐Acyloxy Amides

AbstractThe synergy of multicomponent reactions (MCRs) and metathesis chemistry is applied for the synthesis of bio‐based functional isosorbide polymers (i.e., polyesters) decorated with α‐acyloxy amide motif. The chemical structure of the polyesters that are not accessible by any other conventional methodologies is characterized in‐depth via nuclear magnetic resonance, size‐exclusion chromatography, and attenuated total reflectance infrared spectroscopy. It is also observed that the “biomass‐derived” carbon % of the polymers varied between 66.2 and 76.9. Moreover, the thermal properties of the novel isosorbide‐based polymers are investigated via thermogravimetric analysis and differential scanning calorimetry, revealing that the polymers are in the amorphous state, identified by the glass transition temperature (Tg) values below the human body temperature. The mechanical properties and the biocompatibility of the functional novel polyester derivative with the highest “biomass‐derived” carbon % are evaluated via dynamic mechanical analysis and cytotoxicity test. The exemplary polymer is biocompatible with chondrocyte cells in the conditions used in the tests. In summary, the complementary nature of isosorbide derivatives with MCRs and metathesis chemistry is utilized to illustrate the potential utility of isosorbide as a building block for polymers with prospective biomedical application (namely, as novel cartilage materials).

Effect of a Novel Lubricant Embedded with Alcohol Ether, Amide and Amine Motifs for Silicate Drilling Fluid on Bit Balling and Lubrication: an Experimental Study

Effect of a Novel Lubricant Embedded with Alcohol Ether, Amide and Amine Motifs for Silicate Drilling Fluid on Bit Balling and Lubrication: an Experimental Study

Identification of novel benzothiopyranones with ester and amide motifs derived from active metabolite as promising leads against Mycobacterium tuberculosis.

We reported three distinct series of novel benzothiopyranones, derived from an active metabolite (M-1) of anti-TB agent 6b. These small molecules were evaluated for their biological activities against a range of Mycobacterium tuberculosis (M.tuberculosis) strains. Preliminary druggability evaluation demonstrated that M-1 showed good aqueous solubility and hepatocyte stability. Benzothiopyranones with acyl, sulfonyl and phosphoryl groups exhibited potent invitro inhibitory activity against M.tuberculosis H37Rv and low cytotoxicity. In particular, compound 3d, containing a benzoate fragment, displayed marked metabolic stability and potent invitro activity against drug-resistant tuberculosis clinical strains. Further druggability evaluation based on the identified compounds 3d, 4e and 5b is ongoing for the discovery of promising anti-TB agents.

Front Cover: Identification of Novel Histone Deacetylase 6‐Selective Inhibitors Bearing 3,3,3‐Trifluorolactic Amide (TFLAM) Motif as a Zinc Binding Group (ChemBioChem 22/2021)

This picture shows the 3,3,3-trifluorolactic amide (TFLAM) motif which chelates the zinc ion of histone deacetylase 6 (HDAC6). To identify non-hydroxamate HDAC6 inhibitors for the treatment of cancer and immunological diseases, the TFMAL motif was discovered by screening a metal chelator chemical library. Subsequent structure-based drug design led to the discovery of compounds that exhibit sufficient HDAC6 inhibitory activity and selectivity in both in vitro and in cellulo experiments. More information can be found in the Communication by T. Suzuki et al.