Amine Substitution Research Articles

Homopolymerization of methacrylamide by anionic process under effect of Maghnite-Na+ (Algerian MMT)

The present study describes a new way for synthesis of methacrylamide (MAM) and it's homologue polymethacrylamide (PMAM) under effect of montmorillonite clay (Algerian MMT). The interlayer cation of montmorillonite clay was exchanged with Na + protons (anionic process). Monomer was successfully synthesized by the condensation of ammonia with methacrylic anhydride in bulk (without solvent) and the polymer with increasing anionic catalyst (Mag-Na+) in Tetrahydrofuran THF. Furthermore, the obtained monomer (MAM) and polymer (PMAM) were characterized and confirmed by Infrared Spectroscopy (FT-IR), 1H nuclear magnetic resonance (NMR) spectroscopy and Thermal properties by thermogravimetric analysis (TGA). The conversion and yield of monomer-polymer increased with the increase of the amount of catalyst “Maghnite-Na+”, the reactivity of the ammonia related to its basicity and the effect of amine substitution with methacrylic anhydride involved electron donor forces of the substitution group.

Photogeneration of hydroxyl radical in Fe(III)-citrate-oxalate system for the degradation of fluconazole: mechanism and products.

The photochemical role of Fe(III)-citrate complex is significant in natural waters due to its ubiquitous existence and excellent photoreactivity at near neutral pH. Although there are many reports on the photoinduced degradation of pollutants in the Fe(III)-citrate system, the optimum pH for its photoreactivity is yet not clearly understood. Here, for the first time, we demonstrated that the optimum pH was 5.5 for the photoproduction of •OH in the Fe(III)-citrate system via kinetics modeling based on the steady-state approximation. According to the experimental results, the •OH photoproduction increased with increasing pH until 5.5 and then decreased in Fe(III)-citrate solution, which agreed well with the prediction trend of kinetic modeling. The effect of the common ligand oxalate on the photoreactivity of Fe(III)-citrate system was also investigated. The addition of oxalate promoted the photoproduction of •OH in Fe(III)-citrate solutions, and the measured [•OH]ss increased with oxalate concentration under a fixed Fe(III)-to-citrate ratio. Little synergistic effect exists in Fe(III)-citrate-oxalate system at pH4.0-5.5. In contrast, an appreciable synergistic effect was observed at near neutral pH (6.0-8.0). Higher oxalate-to-citrate ratio facilitated the synergistic effect. Furthermore, antifungal drug fluconazole could be removed efficiently in the Fe(III)-citrate-oxalate system. The photodegradation kinetics also verified the optimum pH of Fe(III)-citrate system and synergistic effect of oxalate. By LC-ESI-MS/MS analyses, the photoproducts of fluconazole in the Fe(III)-citrate-oxalate system were identified and the reaction mechanism involving hydroxylation substitution and subsequent cleavage of heterocyclic amine was proposed. These findings suggest that Fe(III)-citrate exhibits best photoreactivity at pH5.5, and the coexistence of reactive ligands will enhance its photoreactivity at circumneutral pH, indicating potential application in wastewater treatment via addition of appropriate citrate and co-ligands.

Formation and Optical Properties of Brown Carbon from Small α-Dicarbonyls and Amines.

Brown Carbon (BrC) aerosols scatter and absorb solar radiation, directly affecting the Earth's radiative budget. However, considerable uncertainty exists concerning the chemical mechanism leading to BrC formation and their optical properties. In this work, BrC particles were prepared from mixtures of small α-dicarbonyls (glyoxal and methylglyoxal) and amines (methylamine, dimethylamine, and trimethylamine). The absorption and scattering of BrC particles were measured using a photoacoustic extinctometer (405 and 532 nm), and the chemical composition of the α-dicarbonyl-amine mixtures was analyzed using orbitrap-mass spectrometry and thermal desorption-ion drift-chemical ionization mass spectrometry. The single scattering albedo for methylglyoxal-amine mixtures is smaller than that of glyoxal-amine mixtures and increases with the methyl substitution of amines. The mass absorption cross-section for methylglyoxal-amine mixtures is two times higher at 405 nm wavelength than that at 532 nm wavelength. The derived refractive indexes at the 405 nm wavelength are 1.40-1.64 for the real part and 0.002-0.195 for the imaginary part. Composition analysis in the α-dicarbonyl-amine mixtures reveals N-heterocycles as the dominant products, which are formed via multiple steps involving nucleophilic attack, steric hindrance, and dipole-dipole interaction between α-dicarbonyls and amines. BrC aerosols, if formed from the particle-phase reaction of methylglyoxal with methylamine, likely contribute to atmospheric warming.

Monosaccharide inhibitors targeting carbohydrate esterase family 4 de-N-acetylases.

The Carbohydrate Esterase family 4 contains virulence factors which modify peptidoglycan and biofilm-related exopolysaccharides. Despite the importance of this family of enzymes, a potent mechanism-based inhibition strategy has yet to emerge. Based on the postulated tridentate binding mode of the tetrahedral de-N-acetylation intermediate, GlcNAc derivatives bearing metal chelating groups at the 2 and 3 positions were synthesized. These scaffolds include 2-C phosphonate, 2-C sulfonamide, 2-thionoacetamide warheads as well as derivatives bearing thiol, amine and azide substitutions at the 3-position. The inhibitors were assayed against a representative peptidoglycan deacetylase, Pgda from Streptococcus pneumonia, and a representative biofilm-related exopolysaccharide deacetylase, PgaB from Escherichia coli. Of the inhibitors evaluated, the 3-thio derivatives showed weak to moderate inhibition of Pgda. The strongest inhibitor was benzyl 2,3-dideoxy-2-thionoacetamide-3-thio-β-d-glucoside, whose inhibitory potency showed an unexpected dependence on metal concentration and was found to have a partial mixed inhibition mode (Ki = 2.9 ± 0.6 μM).

Synthesis and Biological Evaluation of Novel Alkyl Amine Substituted Icariside II Derivatives as Potential Anticancer Agents.

A series of novel alkyl amine-substituted icariside II (ICA II) derivatives were synthesized by Mannich reactions at the 6-C position (compounds 4a–d) and changing the carbon chain length at the 7-OH position (compounds 7a–h), and their in vitro antitumor activity towards human breast cancer lines (MCF-7 and MDA-MB-231) and human hepatoma cell lines (HepG2 and HCCLM3-LUC) were evaluated by the MTT assay. Compared with ICA II, most of the twelve derivatives showed good micromole level activity and a preliminary structure-activity relationship (SAR) for the anticancer activity was obtained. Compound 7g showed the most potent inhibitory activity for the four cancer cell lines (13.28 μM for HCCLM3-LUC, 3.96 μM for HepG2, 2.44 μM for MCF-7 and 4.21 μM for MDA-MB-231), which was 2.94, 5.54, 12.56 and 7.72-fold stronger than that of ICA II. The preliminary SAR showed that the introduction of a alkyl amine substituent at 6-C was not favorable for the anticancer activity, while most of the 7-O-alkylamino derivatives exhibited good antitumor activity and the anticancer activity 7-O-alkylamino derivatives were influenced by the alkyl chain length and the different terminal amine substituents. Furthermore, the effects of compound 7g on apoptosis and cell cycle of MCF-7 cells were further investigated, which showed that compound 7g triggered apoptosis and arrested the cell cycle at the G0/G1 phase in MCF-7 cells. Our findings indicate that compound 7g may be a promising anticancer drug candidate lead.

Impact of functional groups substitution on the molecular properties of magnesium and scandium phthalocyanines

This investigation reports the molecular properties of magnesium and scandium phthalocyanines, substituted with different functional groups such as methyl (CH3), hydroxyl (OH), amine (NH2), carboxyl (COOH) and aldehyde (CHO) using DFT method. The structure reveals that substituted Mg-Pc possess planar configuration in which the Mg atom lies along the Pc plane while the substituted Sc-Pc acquires shuttlecock structure where Sc protrudes out of the Pc plane. Substituted Mg-Pcs are more stable when compared to substituted Sc-Pcs and functionalization plays an important role in enhancing the molecular properties of M-Pcs. Substitution of amine, hydroxyl and methyl groups renders electron donating character while the carboxyl and aldehyde substitutions make M-Pcs electron acceptors, respectively. The HOMO-LUMO gap character in substituted M-Pcs implies their utilization in the area of organic solar cells and gas capturing applications.

The role of phenolic OH groups of flavonoid compounds with H-bond formation ability to suppress amyloid mature fibrils by destabilizing β-sheet conformation of monomeric Aβ17-42

Alzheimer’s disease (AD) is a kind of brain disease that arises due to the aggregation and fibrillation of amyloid β-peptides (Aβ). The peptide Aβ17–42 forms U-shape protofilaments of amyloid mature fibrils by cross-β strands, detected in brain cells of individuals with AD. Targeting the structure of Aβ17–42 and destabilizing its β-strands by natural compounds could be effective in the treatment of AD patients. Therefore, the interaction features of monomeric U-shape Aβ17–42 with natural flavonoids including myricetin, morin and flavone at different mole ratios were comprehensively studied to recognize the mechanism of Aβ monomer instability using molecular dynamics (MD) simulations. We found that all flavonoids have tendency to interact and destabilize Aβ peptide structure with mole ratio-dependent effects. The interaction free energies of myricetin (with 6 OHs) and morin (with 5 OHs) were more negative compared to flavone, although the total binding energies of all flavonoids are favorable and negative. Myricetin, morin and flavone penetrated into the core of the Aβ17–42 and formed self-clusters of Aβ17-42-flavonoid complexes. Analysis of Aβ17-42-flavonoids interactions identified that the hydrophobic interactions related to SASA-dependent energy are weak in all complexes. However, the intermolecular H-bonds are a main binding factor for shifting U-shape rod-like state of Aβ17–42 to globular-like disordered state. Myricetin and morin polyphenols form H-bonds with both peptide’s carbonyl and amine groups whereas flavone makes H-bonds only with amine substitution. As a result, polyphenols are more efficient in destabilizing β-sheet structures of peptide. Accordingly, the natural polyphenolic flavonoids are useful in forming stable Aβ17-42-flavonoid clusters to inhibit Aβ17–42 aggregation and these compounds could be an effective candidate for therapeutically targeting U-shape protofilaments’ monomer in amyloid mature fibrils.

Nitrite ion mitigates the formation of N-nitrosodimethylamine (NDMA) during chloramination of ranitidine

Ranitidine (RNT) has been an important tertiary amine precursor of N-nitrosodimethylamine (NDMA) in chlorine-based water treatment, due to reaction with monochloramine (NH2Cl) with exceptionally high molar yields up to 90%. This study examined the effects of nitrite ions (NO2−) on the kinetics of NDMA formation during the chloramination of RNT under variable concentrations of dissolved oxygen (DO, 0.7–7.5mg/L), RNT (5–30μM), NH2Cl (5–20mM), NO2− or NO3− (0–2mM) and pH (5.6–8.6). In the absence of the NO2−, the ultimate molar yield of NDMA after 6h of reaction was primarily influenced by [DO] and pH, while marginally affected by initial [RNT] and [NH2Cl]. A kinetic model, prepared in accordance with the reaction sequence of NDMA formation, suggested that the rate determining step was accelerated with increasing [NH2Cl]0, [DO], and pH. A Kinetic study together with ultra-performance liquid chromatography-quadrupole-time of flight mass spectrometer (UPLC-Q-TOF MS) and gas chromatography (GC)/TOF MS analyses in parallel demonstrated that the nitrite ion inhibited the nucleophilic substitution of the terminal amine on NH2Cl, and reduced the pseudo-steady state concentration of N-peroxyl radicals, significantly decreasing the ultimate yields of NDMA.

Excited-State Proton Transfer in Thiazolo-[4, 5-d]thiazo Heterocyclic Systems and the Geometry Alterations' Effect on Photophysical Characters: A Theoretical Study.

Thiazolo-[4,5- d]-thiazo-frame (tztz) compounds are important heteroaromatic organic systems, which recently became a subject of several studies in the field of organic electronics and organic photovoltaics. The most important physical nature of these systems is reported to be an equilibrium between enol and keto forms following excited-state proton transfer. This process originates from a flat trend of the S1 PE (potential energy) profile along the proton transfer coordinate. In the present work, we determined and interpreted the excited-state proton transfer and photophysical nature of these systems extensively by means of the MP2/CC2 and CASSCF theoretical approaches. Also, the effects of amine (-NH2) and cyano (-CN) substitutions were taken into account comprehensively by considering the transition energies and proton transfer pathways of the resulting tztz derivatives. It has been predicted that the physical nature of the excited-state intramolecular proton transfer, as the main character of these systems, is being affected significantly by substitutions. For all of the considered tztz derivatives, a conical intersection (CI) between ground and the S1 excited state was predicted. This CI makes the considered species capable to be responsible for photochromism and photoswitching as well.

The Interplay Between Hydrogen Bonding and Coulombic Forces in Determining the Structure of Sulfuric Acid-Amine Clusters.

Acid-base cluster chemistry drives atmospheric new particle formation (NPF), but the details of the growth mechanisms are difficult to experimentally probe. Clusters of ammonia, alkylamines, and sulfuric acid, species fundamental to NPF, are probed by infrared spectroscopy. These spectra show that substitution of amines for ammonia, which is linked to accelerated growth, induces profound structural rearrangement in clusters with initial compositions (NH4+) n+1(HSO4-) n (1 ≤ n ≤ 3). This rearrangement is driven by the loss of N-H hydrogen bond donors, yielding direct bisulfate-bisulfate hydrogen bonds, and its onset with respect to cluster composition indicates that more substituted amines induce rearrangement at smaller sizes. A simple model counting hydrogen bond donors and acceptors explains these observations. The presence of direct hydrogen bonds between formal anions shows that hydrogen bonding can compete with Coulombic forces in determining cluster structure. These results suggest that NPF mechanisms may be highly dependent on amine identity.

Synthesis of 2-(2, 6-Bis((E)-4-(dialkylamino)styryl)-4H-pyran-4 ylidene) Malononitrile (bis-DCM) from Nucleophilic Aromatic Substitution (SNAr) Reaction

Background: Functional organic dyes with donor-π-conjugation-acceptor (D-π-A) molecular structure and electron transfer in the excited state have attracted much attention because of their potential applications in optical, electronics, magnets materials, dye sensitized solar cells (DSSCs), organic light emitting diodes (OLED), sensors, solid state lasers and photovoltaic cells and thin film transistors. Methods: An efficient and convenient method for synthesis of 2,6-bis-[2-(4-dialkylaminophenyl) vinyl]- 4H-Pyran-4-one starting from reaction of 4-fluorobenzaldehyde with 2,6-dimethyl-4H-pyran-4- one in the presence of MeONa as base was described. In continuation, secondary amines were reacted with 2,6-bis((E)-4-fluorostyryl)-4H-pyran-4-one and 2,6-bis-[2-(4-dialkylaminophenyl)vinyl]-4HPyran- 4-one was obtained as the final product. 1H and 13C NMR, FT-IR spectroscopy supported the predicted structure of the products. The UV-Vis absorption spectra of synthesis compound were measured in diluted dichloromethane solution. Results: Knoevenagel reaction of 4-fluorobenzaldehyde and 2,6-dimethyl-4H-pyran-4-one to afford 2,6-bis((E)-4-fluorostyryl)-4H-pyran-4-one was performed in room temperature.To optimize the reaction conditions, a variety of solvents (EtOH, MeOH, t-BuOH) and bases (KOH, NaOH, EtONa, Me- ONa, t-BuONa) were tested; MeOH/MeONa system was selected as the best condition for this step. The best operative system for nucleophilic aromatic substitution of secondary amines with 2,6-bis((E)- 4-fluorostyryl)-4H-pyran-4-one was obtained when DMF was used as a solvent and K2CO3 was employed as the base and HDTMAB as ligands. In addition, malononitrile was reacted with 2,6-bis((E)-4- fluorostyryl)-4H-pyran-4-one and obtained compound was employed in SNAr reaction. The UV-Vis spectroscopy studies were carried out in diluted dichloromethane solution (5×10-5 M) on the synthesized bis-condensed DCM derivatives. Conclusion: In summary, this study focused on preparation of novel compounds with bis-DCM-type skeleton for application in organic light-emitting diodes, for this purpose, 2,6-bis-[2-(4-dialkylaminophenyl) vinyl]- 4H-Pyran-4-one derivatives were prepared from reaction of 4-fluorobenzaldehyde with 2,6-dimethyl- 4H-pyran-4-one in the presence of MeONa as base. In continuation, secondary amines were reacted with 2,6-bis((E)-4-fluorostyryl)-4H-pyran-4-one and 2,6-bis-[2-(4-dialkylaminophenyl) vinyl]-4HPyran- 4-one was obtained as the final product. Additionally, reaction of malononitrile as an active methylene group with 2,6-bis((E)-4-fluorostyryl)-4H-pyran-4-one before N-arylation reaction resulted in 2-(2,6-bis(4-(dialkylamino)styryl)-4H-pyran-4ylidene)malononitrile derivatives. Keywords: Bis-DCM, malononitrile, push-pull system, SNAr, organic light-emitting diodes (OLED), Knoevenagel condensation.

Solid-phase parallel synthesis of 1,3,4-oxadiazole based peptidomimetic library as a potential modulator of protein-protein interactions

Design and solid phase synthesis of the 1,3,4-oxadiazole based peptidomimetic library is presented. Library synthesis starts from the coupling of the thiosemicarbazide resin with Fmoc-protected amino acid following desulfurative cyclization to 1,3,4-oxadiazoles. Following substitution of the secondary amine with the 3-nitrobenzoyl functional group and its further reduction were performed. Thus, the functionalization with amino acids could be performed on both sides of the core skeleton. After diversification and cleavage from the resin using TFA: DCM cleavage cocktail, an enantiopure library of compounds was obtained. Further evaluation of physicochemical properties was performed.

Meditope-Fab interaction: threading the hole.

Meditope, a cyclic 12-residue peptide, binds to a unique binding side between the light and heavy chains of the cetuximab Fab. In an effort to improve the affinity of the interaction, it was sought to extend the side chain of Arg8 in the meditope, a residue that is accessible from the other side of the meditope binding site, in order to increase the number of interactions. These modifications included an n-butyl and n-octyl extension as well as hydroxyl, amine and carboxyl substitutions. The atomic structures of the complexes and the binding kinetics for each modified meditope indicated that each extension threaded through the Fab `hole' and that the carboxyethylarginine substitution makes a favorable interaction with the Fab, increasing the half-life of the complex by threefold compared with the unmodified meditope. Taken together, these studies provide a basis for the design of additional modifications to enhance the overall affinity of this unique interaction.

Kinetics and mechanism of ligand substitution reactions in [cis-M(CO)4(amine)(EPh3)] complexes (M = Mo, W; amine = pyridine, piperidine; E = As, Sb)

Group 6 metal carbonyls [cis-M(CO)4(amine)(EPh3)] (M = Mo, W; amine = piperidine (pip), pyridine (py); E = As, Sb) have been prepared and characterized. These complexes react thermally in chlorobenzene solutions with phosphine or phosphite ligands (= L) to give cis- and trans-M(CO)4(L)(EPh3) products. Kinetics of amine substitution by L in these complexes, under pseudo-first-order conditions, indicate that these reactions proceed by a rate law that is first-order in concentration of the metal complex. Rate constants and activation parameters for these reactions have been determined and are discussed. Competition studies for the [M(CO)4(EPh3)] intermediates show that these intermediates are highly reactive and react almost indiscriminately with various incoming nucleophiles with slight preference for more basic ones.

Selective and membrane-permeable small molecule inhibitors of nicotinamide N-methyltransferase reverse high fat diet-induced obesity in mice

There is a critical need for new mechanism-of-action drugs that reduce the burden of obesity and associated chronic metabolic comorbidities. A potentially novel target to treat obesity and type 2 diabetes is nicotinamide-N-methyltransferase (NNMT), a cytosolic enzyme with newly identified roles in cellular metabolism and energy homeostasis. To validate NNMT as an anti-obesity drug target, we investigated the permeability, selectivity, mechanistic, and physiological properties of a series of small molecule NNMT inhibitors. Membrane permeability of NNMT inhibitors was characterized using parallel artificial membrane permeability and Caco-2 cell assays. Selectivity was tested against structurally-related methyltransferases and nicotinamide adenine dinucleotide (NAD+) salvage pathway enzymes. Effects of NNMT inhibitors on lipogenesis and intracellular levels of metabolites, including NNMT reaction product 1-methylnicotianamide (1-MNA) were evaluated in cultured adipocytes. Effects of a potent NNMT inhibitor on obesity measures and plasma lipid were assessed in diet-induced obese mice fed a high-fat diet. Methylquinolinium scaffolds with primary amine substitutions displayed high permeability from passive and active transport across membranes. Importantly, methylquinolinium analogues displayed high selectivity, not inhibiting related SAM-dependent methyltransferases or enzymes in the NAD+ salvage pathway. NNMT inhibitors reduced intracellular 1-MNA, increased intracellular NAD+ and S-(5′-adenosyl)-l-methionine (SAM), and suppressed lipogenesis in adipocytes. Treatment of diet-induced obese mice systemically with a potent NNMT inhibitor significantly reduced body weight and white adipose mass, decreased adipocyte size, and lowered plasma total cholesterol levels. Notably, administration of NNMT inhibitors did not impact total food intake nor produce any observable adverse effects. These results support development of small molecule NNMT inhibitors as therapeutics to reverse diet-induced obesity and validate NNMT as a viable target to treat obesity and related metabolic conditions. Increased flux of key cellular energy regulators, including NAD+ and SAM, may potentially define the therapeutic mechanism-of-action of NNMT inhibitors.

Determination of the Absolute Configuration of Cyclic Amines with Bode’s Chiral Hydroxamic Esters Using the Competing Enantioselective Conversion Method

The competing enantioselective conversion (CEC) strategy has been extended to cyclic amines. The basis for the CEC approach is the use of two complementary, enantioselective reactions to determine the configuration of the enantiopure substrate. Bode's chiral acylated hydroxamic acids are very effective enantioselective acylating agents for a variety of amines. Pseudoenantiomers of these acyl-transfer reagents were prepared and demonstrated to react with enantiopure cyclic amines with modest to high selectivity. The products were analyzed by ESI-MS to determine selectivity, and the results were used to assign the configuration of the amine substrate. The method was applicable to a variety of cyclic amines as well as primary amines and acyclic secondary amines. The method is limited to amines that are unhindered enough to react with the reagents, and not all amine substitution patters lead to high selectivity.

Direct Formation of Carbon(sp3)-Heteroatom Bonds from RhIII To Produce Methyl Iodide, Thioethers, and Alkylamines.

Thermolysis of the RhIII-Me complex (DPEphos)RhMeI2 (1) results in reductive elimination of MeI. Mechanistic studies are consistent with SN2 attack by I- at the RhIII-Me group via two separate competing paths. Addition of sulfur and nitrogen nucleophiles allows effective competition and formation of C(sp3)-S and C(sp3)-N coupled products in high yields. C(sp3)-N bond formation is second-order in amine, consistent with amine substitution of iodide at the metal followed by nucleophilic attack at carbon by a second amine.

Structure-Function Analysis of Phenylpiperazine Derivatives as Intestinal Permeation Enhancers.

A major obstacle preventing oral administration of macromolecular therapeutics is poor absorption across the intestinal epithelium into the bloodstream. One strategy to improve transport across this barrier is the use of chemical permeation enhancers. Several molecular families with permeation enhancing potential have been identified previously, including piperazines. In particular, 1-phenylpiperazine has been shown to enhance transepithelial transport with minimal cytotoxicity compared to similarly effective molecules. To better understand how the chemistry of 1-phenylpiperazine affects its utility as an intestinal permeation enhancer, this study examined a small library of 13 derivatives of 1-phenylpiperazine. The efficacy and cytotoxicity of 13 phenylpiperazine compounds were assessed in a Caco-2 model of the intestinal epithelium. Efficacy was measured using the paracellular diffusion marker calcein as well as by immunostaining and confocal imaging of Caco-2 monolayers. Of the 13 derivatives, two enhanced the permeability of the fluorescent marker calcein over 100-fold. It was found that hydroxyl or primary amine substitutions on the phenyl ring significantly increased toxicity, while aliphatic substitutions resulted in efficacy and toxicity profiles comparable to 1-phenylpiperazine. Several potent derivatives, including 1-methyl-4-phenylpiperazine and 1-(4-methylphenyl)piperazine, displayed lower toxicity than 1-phenylpiperazine, suggesting promise in future applications.

Stereospecific Nucleophilic Substitution of Enantioenriched Tertiary Benzylic Amines via in Situ Activation with Benzyne.

A one-pot protocol has been developed for sequential benzyne activation and nucleophilic substitution of enantioenriched tertiary benzylic amines. In the presence of 2-(trimethylsilyl)phenyl triflate and CsF, a range of enantioenriched tertiary benzylic amines were substituted by various nucleophiles, delivering structurally diverse benzylic compounds in moderate to excellent yields with excellent retention of enantiopurity. Importantly, this operationally simple protocol permitted formation of various chiral C-S, C-Se, C-C, and C-N bonds with excellent enantiopurity under metal-free conditions.

Thiolated chitosan micelles: Highly mucoadhesive drug carriers

Current study was aimed to generate thiolated chitosan micelles based on amphiphilic chitosan-stearic acid conjugate (CSA) and to evaluate adhesive properties on mucosal membranes. Chitosan-stearic acid-thioglycolic acid (CSA-TGA) conjugate was synthesized via stearic acid linkage to chitosan and later, thioglycolic acid was covalently attached to CSA. CSA-TGA and CSA were characterized by degree of amine substitution, thiol group determination, ATR-FTIR and cytotoxicity analysis. Micelle size was 13.40±9.38 and 26.30±26.86nm and zeta potential −0.01 and 0.03mV for CSA and CSA-TGA, respectively. In porcine mucus CSA-TGA micelles exhibited 1.80-, 2.12- and 1.72-fold increase in dynamic viscosity, elastic modulus and viscous modulus, respectively. Compared to CSA micelles CSA-TGA micelles remained up to 56.1- fold and 28.6- fold higher degree attached on intestinal and vaginal mucosa, respectively. Taking possibility to incorporate both lipophilic and hydrophilic drugs into these micelles into account, thiol functionalized micelles could be promising carriers for mucosal drug delivery.