Cyclic Moiety Research Articles

Synthesis of Novel 2(3H)-Benzoxazolone Mannich Bases as Potential Agents for Future Studies of Cancer Treatment

Aims: In this study, a series of new Mannich bases of 2(3H)-benzoxazolone derivatives containing substituted cyclic amine moieties with a potential to show cytotoxic activity have been prepared. In order to develop effective anticancer agents against various cancer cell lines, it is essential to study the structure activity relationship and the effect of different substituents on the activity of heterocyclic scaffolds which were known to have cytotoxic activities.
 Study Design: In silico and experimental design.
 Place and Duration of Study: Pharmaceutical Chemistry Department, Faculty of Pharmacy, Near East University, Nicosia, Cyprus, between January 2019- September 2020.
 Methodology: In this work, 2(3H)-benzoxazolone derivatives were prepared by Mannich reaction. The synthesis and structural characterization of the compounds were performed experimentally by FT-IR, 1H NMR, 13C NMR spectra and elemental analysis. In silico prediction of cell line cytotoxicity with PASS based CLC-Pred tool was performed to predict cytotoxicity of the compounds against different tumor cell lines.
 Results: In silico prediction results for the compounds showed that all benzoxazolone derivatives have cytotoxic activity against different cell lines and tumor types. It was clearly understood that the cytotoxicity of the compounds was affected by the substituents on their piperazine moieties and by the substituents on benzoxazolone core structure.
 Conclusion: In conclusion, newly synthesized Mannich bases of benzoxazolone derivatives were reported for the first time which may have a potential to show anticancer activities at different cancer cell lines. The efficiency of new compounds against cancer could be found via PASS based CLC-Pred database and could be further investigated by in vivo experimental cytotoxicity studies in the future to design new anticancer drug candidates.

The molecular mechanism of P450-catalyzed amination of the pyrrolidine derivative of lidocaine: insights from multiscale simulations.

Nitrogen heterocycles are key and prevalent motifs in drugs. Evolved variants of cytochrome P450BM3 (CYP102A1) from Bacillus megaterium employ high-valent oxo-iron(iv) species to catalyze the synthesis of imidazolidine-4-ones via an intramolecular C–H amination. Herein, we use multi-scale simulations, including classical molecular dynamics (MD) simulations, quantum mechanical/molecular mechanical (QM/MM) calculations and QM calculations, to reveal the molecular mechanism of the intramolecular C–H amination of the pyrrolidine derivative of lidocaine bearing cyclic amino moieties catalyzed by the variant RP/FV/EV of P450BM3, which bears five mutations compared to wild type. Our calculations show that overall catalysis includes both the enzymatic transformation in P450 and non-enzymatic transformation in water solution. The enzymatic transformation involves the exclusive hydroxylation of the C–H bond of the pyrrolidine derivative of lidocaine, leading to the hydroxylated intermediate, during which the substrate radical would be bypassed. The following dehydration and C–N coupling reactions are found to be much favored in aqueous situation compared to that in the non-polar protein environment. The present findings expand our understanding of the P450-catalyzed C(sp3)–H amination reaction.

Thermodynamically stable structure of hydroxy alkane sulfonate surfactant monomers in water achieving high water solubility and a low CMC.

Although sodium internal olefin sulfonates (IOSs) derived from petrochemicals are known to act as anionic surfactants, these compounds have few practical applications and their interfacial properties have not been examined in detail because they have complex compositions and are challenging to prepare. However, IOSs obtained from vegetable oils have recently been applied to detergents. The present work represents the first study of the IOS sodium 5-hydroxyhexadecane-4-sulfonate (C16-4S-5OH) as a pure substance. The properties of C16-4S-5OH in aqueous solution were assessed by differential scanning calorimetry, equilibrium surface tension measurements, Fourier transform infrared spectroscopy and proton nuclear magnetic resonance spectroscopy. This compound was found to have a low Krafft point and a low CMC, both of which are necessary for a modern sustainable surfactant. Although these two characteristics are normally difficult to achieve simultaneously, this work demonstrated that C16-4S-5OH in aqueous solution has a highly fixed stereostructure that enables both properties to be achieved. The C16 main carbon chain of this compound acts as a C12 and a C4 chain both oriented in the same direction, while the hydrophilic sulfo and hydroxy head groups form a rigid cyclic moiety including two carbons of the C16 alkyl chain based on hydrogen bonding. This highly fixed molecular structure of the C16-4S-5OH in water is maintained in the monomer and micellar states below and above the CMC, respectively.

Recent advances in transition metal-catalyzed (1,n) annulation using (de)-hydrogenative coupling with alcohols.

(1,n) annulation reactions using (de)-hydrogenative coupling with alcohols or diols represent a straightforward technique for the synthesis of cyclic moieties. Utilization of such renewable resources for chemical transformations in a one-pot manner is the main focus, which avoids generation of stoichiometric waste. Application of such (1,n) annulation approaches drives the catalysis research in a more sustainable way and generates dihydrogen and water as by-products. This feature article highlights the recent (from 2015 to March 2021) progress in the synthesis of stereo-selective cycloalkanes and cycloalkenes, saturated and unsaturated N-heterocycles (cyclic amine, imide, lactam, tetrahydro β-carboline, quinazoline, quinazolinone, 1,3,5-triazines etc.) and other N-heterocycles with the formation of multiple bonds in a one pot operation. Mechanistic studies, new catalytic approaches, and synthetic applications including drug synthesis and post-drug derivatization, scope, and limitations are discussed.

Withanolide-Type Steroids from Withania aristata as Potential Anti-Leukemic Agents.

Leukemia is a blood or bone marrow cancer with increasing incidence in developed regions of the world. Currently, there is an ongoing need for novel and safe anti-leukemic agents, as no fully effective chemotherapy is available to treat this life-threatening disease. Herein, are reported the isolation, structural elucidation, and anti-leukemic evaluation of twenty-nine withanolide-type steroids (1–29) from Withania aristata. Among them, the new isolated withanolides, withaperoxidins A–D (1–4) have an unusual six-membered cyclic peroxide moiety on the withasteroid skeleton as a structural novelty. Their structures have been elucidated by means of spectroscopic analyses, including 2D NMR experiments. In addition, extensive structure–activity relationships and in silico ADME studies were employed to understand the pharmacophore and pharmacokinetic properties of this series of withasteroids. Compounds 15, 16, and 22 together with withaferin A (14) were identified as having improved antiproliferative effect (IC50 ranging from 0.2 to 0.7 μM) on human leukemia HL-60 cell lines compared with the reference drug, etoposide. This cytotoxic potency was also coupled with good selectivity index (SI 33.0–9.2) on non-tumoral Vero cell line and in silico drug likeness. These findings revealed that these natural withasteroids are potential candidates as chemotherapeutic agents in the treatment of leukemia.

Detection of U-87 Tumor Cells by RGD-Functionalized/Gd-Containing Giant Unilamellar Vesicles in Magnetization Transfer Contrast Magnetic Resonance Images.

The targeting of tumor cells and their visualization with magnetic resonance imaging (MRI) is an important task in biomedicine. The low sensitivity of this technique is a significant drawback and one that may hamper the detection of the imaging reporters used.To overcome this sensitivity issue, this work explores the synergy between 2 strategies: (1) arginine, glycine, aspartic acid peptide (RGD)-functionalized giant unilamellar vesicles (GUVs) loaded with Gd complexes to accumulate large amounts of MRI contrast agent at the targeting site; and (2) the use of magnetization transfer contrast (MTC), which is a sensitive MRI technique for the detection of Gd complexes in the tumor region. Giant unilamellar vesicles were prepared using the gentle swelling method, and the cyclic RGD targeting moiety was introduced onto the external membrane. Paramagnetic Gd-containing complexes and the fluorescent probe rhodamine were both part of the vesicle membranes and Gd-complexes were also the payload within the inner aqueous cavity. Giant unilamellar vesicles that were loaded with the imaging reporters, but devoid of the RGD targeting moiety, were used as controls. U-87 MG human glioblastoma cells, which are known to overexpress the targets for RGD moieties, were used. In the in vivo experiments, U-87 MG cells were subcutaneously injected into nu/nu mice, and the generated tumors were imaged using MRI, 15 days after cell administration. Magnetic resonance imaging was carried out at 7 T, and T2W, T1W, and MTC/Z-spectra were acquired. Confocal microscopy images and Inductively Coupled Plasma Mass Spectrometry (ICP-MS) were used for result validation. In vitro results show that RGD GUVs specifically bind to U-87 MG cells. Microscopy demonstrates that (1) RGD GUVs were anchored onto the external surface of the tumor cells without any internalization; (2) a low number of GUVs per cell were clustered at specific regions; and (3) there is no evidence for macrophage uptake or cell toxicity. The MRI of cell pellets after incubation with RGD GUVs and untargeted ctrl-GUVs was performed. No difference in T1 signal was detected, whereas a 15% difference in MT contrast is present between the RGD GUV-treated cells and the ctrl-GUV-treated cells.Magnetic resonance imaging scans of tumor-bearing mice were acquired before and after (t = 0, 4 hours and 24 hours) the administration of RGD GUVs and ctrl-GUVs. A roughly 16% MTC difference between the 2 groups was observed after 4 hours. Immunofluorescence analyses and ICP-MS analyses (for Gd-detection) of the explanted tumors confirmed the specific accumulation of RGD GUVs in the tumor region. RGD GUVs seem to be interesting carriers that can facilitate the specific accumulation of MRI contrast agents at the tumor region. However, the concentration achieved is still below the threshold needed for T1w-MRI visualization. Conversely, MTC proved to be sufficiently sensitive for the visualization of detectable contrast between pretargeting and posttargeting images.

Tracking and Recovery of Metal Desorption from Organized Films of Polyguanamine Derivatives having Cyclic Moieties

AbstractMetal desorption behavior of polyguanamine derivatives having cyclic moieties (c‐PGs), with metal‐scavenging abilities, organized into molecular films was investigated, and a recovery technique was realized. Cadmium (a toxic metal), palladium (a precious metal), and neodymium (a rare earth metal) were studied, along with sodium (a cationic metal). A monolayer of c‐PGs forming on an aqueous metal solution surface effectively scavenges cations from the subphase owing to the relative basicity of the cyclic moiety. X‐ray photoelectron spectroscopy revealed that cadmium and palladium (both divalent cations) were desorbed by simple 30–60 min ultrasonication of their Langmuir–Blodgett multilayers. Conversely, the desorption of neodymium, a trivalent cation, was very slow. Sodium, a monovalent cation, was difficult to collect. Its valence and monolayer condensation on the aqueous sodium buffer were remarkable, indicating that coordinated sodium ions escape during the monolayer condensation.

Lipophilic ion aromaticity is not important for permeability across lipid membranes

To clarify the contribution of charge delocalization in a lipophilic ion to the efficacy of its permeation through a lipid membrane, we compared the behavior of alkyl derivatives of triphenylphosphonium, tricyclohexylphosphonium and trihexylphosphonium both in natural and artificial membranes. Exploring accumulation of the lipophilic cations in response to inside-negative membrane potential generation in mitochondria by using an ion-selective electrode revealed similar mitochondrial uptake of butyltricyclohexylphosphonium (C4TCHP) and butyltriphenylphosphonium (C4TPP). Fluorescence correlation spectroscopy also demonstrated similar membrane potential-dependent accumulation of fluorescein derivatives of tricyclohexyldecylphosphonium and decyltriphenylphosphonium in mitochondria. The rate constant of lipophilic cation translocation across the bilayer lipid membrane (BLM), measured by the current relaxation method, moderately increased in the following sequence: trihexyltetradecylphosphonium ([P6,6,6,14]) < triphenyltetradecylphosphonium (C14TPP) < tricyclohexyldodecylphosphonium (C12TCHP). In line with these results, measurements of the BLM stationary conductance indicated that membrane permeability for C4TCHP is 2.5 times higher than that for C4TPP. Values of the difference in the free energy of ion solvation in water and octane calculated using the density functional theory and the polarizable continuum solvent model were similar for methyltriphenylphosphonium, tricyclohexylmethylphosphonium and trihexylmethylphosphonium. Our results prove that both cyclic and aromatic moieties are not necessary for lipophilic ions to effectively permeate through lipid membranes.

Design and Validation of Linkers for Site-Specific Preparation of Antibody-Drug Conjugates Carrying Multiple Drug Copies Per Cysteine Conjugation Site.

First-generation cysteine-based site-specific antibody–drug conjugates (ADCs) are limited to one drug per cysteine. However, certain applications require a high drug to antibody ratio (DAR), such as when low-potency payloads are used. Higher drug load can be achieved using classical cysteine conjugation methods, but these result in heterogeneity, suboptimal efficacy and pharmacokinetics. Here, we describe the design, synthesis and validation of heterobifunctional linkers that can be used for the preparation of ADCs with a DAR of two, three and four in a site-specific manner per single cysteine conjugation site, resulting in site-specific ADCs with a DAR of four, six and eight. The designed linkers carry a sulfhydryl-specific iodoacetyl reactive group, and multiple cyclic diene moieties which can efficiently react with maleimide-carrying payloads through the Diels–Alder reaction. As a proof of concept, we synthesized site-specific DAR four, six and eight ADCs carrying tubulysin (AZ13601508) using engineered antibodies with a cysteine inserted after position 239 in the antibody CH2 domain. We evaluated and compared the in vitro cytotoxicity of ADCs obtained via the site-specific platform described herein, with ADCs prepared using classical cysteine conjugation. Our data validated a novel cysteine-based conjugation platform for the preparation of site-specific ADCs with high drug load for therapeutic applications.

Sustainable antimicrobial modified chitosan and its nanoparticles hydrogels: Synthesis and characterization

The target of the present study is the development of sustainable chitosan and chitosan nanoparticles-based heterocyclic compound hydrogels with antimicrobial properties. Sustainable antimicrobial new modified chitosan hydrogel (CS-3) was synthesized by the reaction of chitosan (CS) with 2-([4-[(1, 3-dioxoisoindolin-2-ylimino) methyl] phenyl] methyleneamino) isoindoline-1, 3-dione (3) via ring opening of cyclic imide moiety in compound (3). However, the modified chitosan nanoparticles hydrogel (CS-3 NPs) were prepared in-situ by an ionotropic gelation technique using sodium tripolyphosphate (TPP) as the cross-linking agent. The prepared hydrogels were characterized by FTIR, SEM, TEM, TGA, DSC and elemental analysis. The hydrogels were tested versus eight pathogenic strains of Gram +ve and Gram −ve bacteria and two fungi. The results revealed that hydrogels (CS-3) and (CS-3 NPs) showed higher antimicrobial activities than virgin (CS) and (CS-NPs). However, hydrogel (CS-3 NPs) showed the highest Minimal Inhibitory Concentration (MIC) and Minimal Bactericidal Concentration (MBC) especially with Gram +ve bacteria (S. pyogenes) at 19.5 and 39 μg/ml compared to the standard antibiotic Ciprofloxacin at 19 and 38 μg/ml respectively.

Facile Synthesis of 6-Phenyl-6h-chromeno [4, 3-b] Quinoline Derivatives using NaHSO4@SiO2 Re-usable Catalyst and Their Antibacterial Activity Study Correlated by Molecular Docking Studies

Background: Heterocyclic compounds containing heteroatoms (O, N and S) as part of five or six-membered cyclic moieties exhibited various potential applications, such as pharmaceutical drugs, agrochemical products and organic materials. Among many known heterocyclic moieties, quinoline and its derivatives are one of the privileged scaffolds found in many natural products. In general, quinoline derivatives could be prepared by utilizing ortho-substituted anilines and carbonyl compounds containing a reactive α-methylene group of well-known reaction routes like Friedlander synthesis, Niemantowski synthesis and Pfitzinger synthesis. Moreover, polysubstituted quinolones and their derivatives also had shown considerable interest in the fields of organic and pharmaceutical chemistry in recent years. Objective: The main objective of our research work is towards the design and synthesis of divergent biological-oriented, proactive analogues with potential pharmacological value inspired by the anti-tubercular activity of 2-phenylquinoline analogues. In this study, we have been interested in the design and synthesis of bioactive, 2, 4-diphenyl, 8-arylated quinoline analogues. Methods: 6-phenyl-6h-chromeno [4, 3-b] quinoline derivatives were synthesized from 4-chloro-2- phenyl-2H-chromene-3-carbaldehyde and various substituted aromatic anilines as starting materials using sodium bisulfate embedded SiO2 re-usable catalyst. All these fifteen new compound structures confirmed by spectral data 1H &amp; 13C NMR, Mass, CHN analysis etc. Furthermore, all these new compounds antibacterial activity strains recorded using the paper disc method. The compound molecular structures were designed using molecular docking study by utilizing the crystallographic parameters of S. Areus Murb protein. Results: A series of fifteen new quinoline derivatives synthesized in moderate to good yields using sodium bisulfate embedded SiO2 re-usable catalyst. The molecular structures of these newly synthesized compounds elucidated by the combination of spectral data along with the elemental analysis. These compounds antibacterial activity study have shown moderate to good activity against, Escherichia coli (Gram-negative) and Staphylococcus aureus (gram-positive) organisms. These antibacterial activity results were also a very good correlation with molecular docking studies. Conclusion: In this study, fifteen new quinoline derivatives synthesized and structures confirmed by spectral data. In fact, all the compounds have shown moderate to good antibacterial activity. In general, the compounds containing the electron donor group at R1 position (R1 = OMe) and the acceptor group at R2 positions (R2 = F or Cl) had shown good antibacterial activity. These antibacterial activity results were also a very good correlation with molecular docking studies showing strong binding energies with the highest value being, -12.45 Kcal mol-1 with S. aureus MurB receptor.

Solubilization and Stabilization of Membrane Proteins by Cycloalkane-Modified Amphiphilic Polymers.

Membrane proteins (MPs) need to be extracted from biological membranes and purified in their native state for most structural and functional in vitro investigations. Amphiphilic copolymers, such as amphipols (APols), have emerged as very useful alternatives to detergents for keeping MPs water-soluble under their native form. However, classical APols, such as poly(acrylic acid) (PAA) derivatives, seldom enable direct MP extraction. Poly(styrene maleic anhydride) copolymers (SMAs), which bear aromatic rings as hydrophobic side groups, have been reported to be more effective extracting agents. In order to test the hypothesis of the role of cyclic hydrophobic moieties in membrane solubilization by copolymers, we have prepared PAA derivatives comprising cyclic rather than linear aliphatic side groups (CyclAPols). As references, APol A8-35, SMAs, and diisobutylene maleic acid (DIBMA) were compared with CyclAPols. Using as models the plasma membrane of Escherichia coli and the extraction-resistant purple membrane from Halobacterium salinarum, we show that CyclAPols combine the extraction efficiency of SMAs with the stabilization afforded to MPs by classical APols such as A8-35.

Effects of Amino Group Substitution on the Photophysical Properties and Stability of Near-Infrared Fluorescent P-Rhodamines.

A series of phosphine oxide-bridged rhodamines (P-rhodamines) bearing various acyclic and cyclic amine moieties, including dimethyl- and diethylamine, azetidine, pyrrolidine and 7-azabicyclo[2,2,1]heptane (7ABH), have been synthesized. The photophysical properties as well as chemical and photostability of these dyes have been studied in detail. Among these dyes, the 7ABH-substituted dye shows stronger fluorescence in the near-infrared (NIR) region, relative to the other P-rhodamines. This dye could be applied to live-cell imaging, wherein lysosomes were selectively stained in a pH-independent manner. It was also found that the ring fusion of the amine moieties gives rise to remarkably redshifted spectra, with absorption and emission maxima at 770 and 820 nm, respectively, spectrally close to that of indocyanine green (ICG). Importantly, the ring-fused P-rhodamines showed much higher photostability than ICG, indicative of their promising utility as the NIR-emissive dyes.

Cyclic Aliphatic Hydrocarbons as Linkers in Metal-Organic Frameworks: New Frontiers for Ligand Design.

In this Minireview we outline the development of cyclic aliphatic moieties as ligands in metal-organic frameworks (MOFs), with a focus on the relationship between ligand design and synthesis and the properties of the subsequent materials. Aliphatic ligands have received considerably less attention than aromatic analogues in MOF chemistry but offer advantages in their unique combinations of geometric and electronic properties which are unattainable from conventional ligands. Here, we focus on rigid and semi-rigid backbone moieties derived from monocyclic and fused polycyclic aliphatic backbones, including cyclohexane and adamantane, cubane and bicyclo[2.2.2]octane, and discuss the synthetic chemistry of these species along with their potential importance as the next generation of building blocks for microporous materials.

Polyguanamine Derivative-Based Supramolecular Assemblies with Multiple Hydrogen Bonding and Their Metal-Scavenging Abilities.

Polyguanamine derivatives having cyclic moieties constituted by two phenyl and two triazine rings have been synthesized, and a supramolecular organization based on their multiple hydrogen-bonding ability was investigated. The obtained polyguanamine derivatives with cyclic moieties were transparent and amorphous in the bulk state and showed excellent mechanical strength emanating from multiple hydrogen bonds, owing to the abundant amino groups present in the structure. These polyguanamine derivatives formed stable monolayers at the air/water interface. The multilayers were transferred using the Langmuir-Blodgett method, and they formed highly periodic layered structures. To evaluate the metal scavenging ability of the cyclic moieties, the metal ions, Cd2+, Nd3+, and Pd2+, were introduced in the subphase. As a result, the cyclic moieties in the polyguanamine derivatives efficiently captured Cd2+, Nd3+, and Pd2+ metal ions. After the metal was captured, the layered structure of each organized film showed higher periodicity because of rearrangement. Moreover, the annular part had a cup-like structure, and the steric size effect of the ring influenced the metal scavenging.

Lignosulfonate-based polyurethane materials via cyclic carbonates: preparation and characterization

AbstractUsage of lignin and its derivatives as chemical and carbon source, i.e. in processes other than burning, is one of the most active fields in renewable resource chemistry today. In this study, the synthesis of lignosulfonate (LS)-based polyurethane (PU) materials from non-toxic reagents and through environmentally friendly processes is presented. LS, modified with bio-based (glycerin-derived) cyclic carbonate moieties, was reacted with 1,6-hexamethylenediamine (HMDA) to form characteristic PU material. For mechanistic studies and reaction optimization, cyclic carbonates and 1,2-diol derivatives of vanillyl alcohol (VA), as a simplifying lignin model compound, were employed. An LS-bound cyclic carbonate can be formed in one pot without a transesterification step, which simplifies the route toward non-isocyanate lignin-based PU materials. Attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectra showed typical linkages of cyclic carbonates and 1,2-diols on LS. Further analytical characterization, in both the model compound and the LS polymer case, was provided by liquid-state nuclear magnetic resonance (NMR) spectroscopy [one-dimensional (1D), two-dimensional (2D) and 31P] and 13C solid-state (ss) NMR. The production of PU materials from sulfonated lignin and glycerol carbonate, synthesized through a non-isocyanate reaction pathway, confirms the good potential of LS utilization in the development of PU composites based on renewable resources.

Combined Effects from Solvation and Nuclear Quantum Fluctuations on Autoionization Mechanisms in Aqueous Clusters.

Using path-integral molecular dynamics simulations, we examine isomerization paths involving collective proton transfers in [H2O]5 and [H2O]8 clusters under cryogenic conditions. We focused attention on combined effects derived from solvation and nuclear quantum fluctuations on the characteristics of free energy barriers and relative stabilities of reactants and products. In particular, we analyzed two different processes: the first one involves the exchange of donor-acceptor hydrogen bond roles along cyclic moieties, whereas the second one corresponds to charge separation leading to stable [H3O]+[OH]- ion pairs. In the first case, the explicit incorporation of quantum tunneling introduces important modifications in the classical free energy profile. The resulting quantum profile presents two main contributions, one corresponding to compressions of O-O distances and a second one ascribed to nuclear tunneling of the light protons. Solvation effects promote a moderate polarization of the cyclic structures and a partial loss of concertedness in the collective modes, most notably, at the onset of tunneling. Still, the latter effects are also sufficiently strong to promote the stabilization of ion pairs along the classical trajectories. In contrast, the explicit incorporation of nuclear quantum fluctuations leads to charge separated configurations that are marginally stable. As such, the latter states could also be regarded as short-lived intermediate states along the reactive exchange path.

CD13-specific ligand facilitates Xanthatin nanomedicine targeting dendritic cells for therapy of refractory allergic rhinitis.

Relapse in Allergic Rhinitis (AR) is triggered by various unclear mechanisms. Xanthium strumarium L. as a traditional folk medicine can inhibit inflammatory responses through multiple mechanisms. Xanthatin (XT) is a bioactive compound derived from Xanthium strumarium L, and we developed a polymeric micelle (PM) that is dendritic cells (DCs)-specific targeting delivery system loading XT (NGR-XT-PM) based on a cyclic peptide moiety (NGR) to render DCs maturation-resistant for therapy of refractory AR. A murine model of AR was employed to investigate the in vivo therapeutic efficiency and relapse rate compared with the commercial product Budesonide. The results showed intranasal administration of NGR-XT-PM presented significant anti-allergy effect with no recurrence, in contrast, all mice treatment with Budesonide relapsed. NGR-XT-PM could effectively reverse the Th1/Th2 imbalance by depleting the serum inflammatory levels (IgE, histamine and IL-4) and DCs surface costimulatory molecules (CD80, CD86 and I-A/I-E), and promote immune tolerance by upregulating the level of Treg cells and reducing the levels of Th2, Th9 and Th17 cells. Furthermore, we appealed to virtual screening of inflammatory targets and found XT blocking the COX-2/PGE2 signaling pathway, which is a key effector in immune responses. These indicated CD13-specific NGR could facilitate XT selectively targeting DCs for efficiently ameliorating refractory rhinitis, and NGR-XT-PM should be a potential anti-AR drug.

Methods to Access 2-aminobenzimidazoles of Medicinal Importance

:Benzimidazole (BI) and derivatives are interesting because several of these compounds have been found to have a diversity of biological activities with clinical applications. In view of their importance, the synthesis of BI and its derivatives is still considered as a challenge for synthetic chemists. Examples of compounds used in medicinal chemistry containing BI, as important nucleus, are Astemizole (antihistaminic), Omeprazole (antiulcerative) and Rabendazole (fungicide), some of these compounds have the 2- aminobenzimidazole (2ABI) as base nucleus. The structure of 2ABI derivatives contains a cyclic guanidine moiety, which is interesting because of its free lone pairs, labile hydrogen atoms and planar delocalized structure. The delocalized 10-π electron system and the extension of the electron conjugation with the exocyclic amino group, in 2ABI, making these heterocycles to have amphoteric character. The 2ABI has been used as building blocks for the synthesis of several BI derivatives as medicinally important molecules. On these bases, herein, we present a bibliographic review concerning the recent methodologies used in the synthesis of 2ABIs, including the substituted ones.

Silver ion-induced chiral enhancement by argentivorous molecules.

Optically active tetra-armed cyclens with an asymmetric chiral centre in the cyclen moiety were synthesized and were shown to enhance chirality and control of enantiomers on complexation with Ag+. Binding studies of the Ag+ complex demonstrated that Ag+ preferentially interacts with electron-rich substituents over other aromatic substituents.