N-alkyl Groups Research Articles

Delivering bioactive cyclic peptides that target Hsp90 as prodrugs

The most challenging issue facing peptide drug development is producing a molecule with optimal physical properties while maintaining target binding affinity. Masking peptides with protecting groups that can be removed inside the cell, produces a cell-permeable peptide, which theoretically can maintain its biological activity. Described are series of prodrugs masked using: (a) O-alkyl, (b) N-alkyl, and (c) acetyl groups, and their binding affinity for Hsp90. Alkyl moieties increased compound permeability, Papp, from 3.3 to 5.6, however alkyls could not be removed by liver microsomes or in-vivo and their presence decreased target binding affinity (IC50 of ≥10 µM). Thus, unlike small molecules, peptide masking groups cannot be predictably removed; their removal is related to the 3-D conformation. O-acetyl groups were cleaved but are labile, increasing challenges during synthesis. Utilising acetyl groups coupled with mono-methylated amines may decrease the polarity of a peptide, while maintaining binding affinity.

The Mechanisms of Action of Triindolylmethane Derivatives on Lipid Membranes.

The effects of new synthetic antibacterial agents – tris(1-pentyl-1H-indol-3-yl)methylium chloride (LCTA-1975) and (1-(4-(dimethylamino)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)-1H-indol-3-yl)bis(1-propyl- 1H-indol-3-yl)methylium chloride (LCTA-2701 – on model lipid membranes were studied. The ability of the tested agents to form ion-conductive transmembrane pores, influence the electrical stability of lipid bilayers and the phase transition of membrane lipids, and cause the deformation and fusion of lipid vesicles was investigated. It was established that both compounds exert a strong detergent effect on model membranes. The results of differential scanning microcalorimetry and measuring of the threshold transmembrane voltage that caused membrane breakdown before and after adsorption of LCTA-1975 and LCTA-2701 indicated that both agents cause disordering of membrane lipids. Synergism of the uncoupling action of antibiotics and the alkaloid capsaicin on model lipid membranes was shown. The threshold concentration of the antibiotic that caused an increase in the ion permeability of the lipid bilayer depended on the membrane lipid composition. It was lower by an order of magnitude in the case of negatively charged lipid bilayers than for the uncharged membranes. This can be explained by the positive charge of the tested agents. At the same time, LCTA-2701 was characterized by greater efficiency than LCTA-1975. In addition to its detergent action, LCTA-2701 can induce ion-permeable transmembrane pores: step-like current fluctuations corresponding to the opening and closing of individual ion channels were observed. The difference in the mechanisms of action might be related to the structural features of the antibiotic molecules: in the LCTA-1975 molecule, all three substituents at the nitrogen atoms of the indole rings are identical and represent n-alkyl (pentyl) groups, while LCTA-2701 contains a maleimide group, along with two alkyl substituents (n-propyl). The obtained results might be relevant to our understanding of the mechanism of action of new antibacterial agents, explaining the difference in the selectivity of action of the tested agents on the target microorganisms and their toxicity to human cells. Model lipid membranes should be used in further studies of the trends in the modification and improvement of the structures of new antibacterial agents.

Poly( N-isopropylacrylamide)-Based Polymer-Inducing Isothermal Hydrophilic-to-Hydrophobic Phase Transition via Detachment of Hydrophilic Acid-Labile Moiety.

The polymerization of N-isopropylacrylamide (NIPAAm) with ionizable monomers results in pH-responsive lower critical solution temperature (LCST) polymer which works in an ionization-dependent manner. However, gradual ionization of the comonomer occurs at a broad pH range due to the electrostatic field generated by the polymers, limiting the extent of LCST shift in response to pH change. Furthermore, excess introduction of comonomer may dull phase transition behavior. Here, we report the development of an ionization-independent LCST polymer that exerts a sharp isothermal hydrophilic-to-hydrophobic phase transition in response to slight pH change. Our polymer has a poly(NIPAAm/2-aminoisoprpylacrylamide (AIPAAm)) (P(NIPAAm/AIPAAm)) backbone that retains the continuous structural similarity of N-alkyl groups for preserving phase transition sensitivity, and primary amine for forming hydrophilic acid-labile 2-propionic-3-methylmaleic (PMM) amide linkage. The PMM moiety improves the polymer's hydrophilicity and drastically increases the LCST. Detachment of the PMM moiety in response to mild acidic condition (pH < 6.8) lowers the LCST to that of original P(NIPAAm/AIPAAm), permitting isothermal pH-responsive phase transition. Utilizing this mechanism, P(NIPAAm/AIPAAm) modified with PMM amide linkage exhibits a sharp hydrophilic-to-hydrophobic transition at a physiological temperature (37 °C) and, strikingly, facilitates interaction with cultured cells. Most importantly, our polymer showed significantly higher accumulation within a solid tumor after systemic injection compared to conventional PNIPAAm, which may be due to its phase transition responding to slightly acidic tumor microenvironment. Thus, this study provides a novel polymer that offers delicate control of LCST and pH-responsiveness suitable for use in even fuzzy biological environments.

Anchoring Fullerene onto Perovskite Film via Grafting Pyridine toward Enhanced Electron Transport in High-Efficiency Solar Cells.

Fullerene derivatives have been popularly applied as electron transport layers (ETLs) of inverted (p-i-n) planar heterojunction perovskite solar cells (iPSCs) due to their strong electron-accepting abilities, and so far, [6,6]-phenyl-C61-butyric acid methyl ester (PCBM) has been the most commonly used ETL, which suffers, however, from high cost due to the complicated synthetic route. Herein, novel pyridine-functionalized fullerene derivatives (abbreviated as C60-Py) were synthesized facilely via a one-step 1,3-dipolar cycloaddition reaction and applied as ETLs superior to PCBM in iPSC devices. Three pyridine-functionalized fullerene derivatives with different alkyl groups, including methyl, n-butyl, and n-hexyl, grafted onto the pyrrolidine moiety (abbreviated as C60-MPy, C60-BPy, and C60-HPy, respectively) were synthesized. According to cyclic voltammogram study, the chain length of the N-alkyl group has negligible influence on the molecular energy level of C60-Py. However, the ETL performance of C60-Py is sensitively dependent on the chain length of the N-alkyl group, with C60-BPy exhibiting the highest power conversion efficiency (PCE) of 16.83%, which surpasses that based on PCBM ETL (15.87%). The PCE enhancement of C60-BPy device is attributed to the coordination interactions between the pyridine moiety with the Pb2+ ion of CH3NH3PbI3 perovskite, which anchor C60-BPy onto perovskite film and reinforce the passivation of the trap state within the CH3NH3PbI3 perovskite film and suppress the nonradiative electron-hole recombinations, leading to enhanced electron transport reflected by the increase of short-circuit current density ( Jsc). The ambient stability of C60-HPy-based device is much better than that based on PCBM ETL since its long N-alkyl group can function as a superior encapsulating layer protecting the CH3NH3PbI3 layer from contact with the ambient moisture.

Oxidative removal of brilliant green by UV/S2O82‒, UV/HSO5‒ and UV/H2O2 processes in aqueous media: A comparative study

The removal of brilliant green (BG), a toxic organic and cationic dye, has been examined by UV/S2O82− (PS), UV/HSO5− (PMS) and UV/H2O2 processes. BG showed insignificant direct photolysis at 254 nm (i.e., 8.6% after 30 min). However, enhanced BG degradation was observed in UV/PS, UV/PMS and UV/H2O2 systems as revealed from 63.1, 47.0 and 34.8% BG degradation, respectively, at 30 min of reaction time, using 0.05 mM BG and 1.0 mM oxidant initial concentration. The bimolecular rate constants of OH and SO4− with BG were determined to be 2.35 × 109 and 2.21 × 109 M−1 s−1, respectively. Electrical energy per order (EE/O) values for UV/PS, UV/PMS and UV/H2O2 processes were calculated to be 5.4, 6.8, and 7.8 KWh/m3/order, respectively. The addition of humic acid (HA) and inorganic anions inhibited the degradation of BG by UV/PS in the order of NO2− > HA > HCO3− > Cl− > NO3− ≈ SO42−. The results of frontier electron densities (FEDs) showed that C-atom holding the three rings (C7), and C-atoms at para positions to N-alkyl groups of the two rings (C4 and C14) are the predominant sites for radical addition. Furthermore, nine degradation products (DPs) of BG were detected experimentally using LC/MS/MS.

Synthesis and photophysical properties of blue-emitting fluorescence dyes derived from naphthalimide derivatives containing a diacetylene linkage group

Four naphthalimide-based dyes with a diacetylene linkage at the 3- or 4-position were synthesized to improve the thermal stability of the fluorescence dye as well as the efficiency of fluorescent emission at blue region. The absorption and fluorescence properties of the synthesized dyes were also investigated. The geometries and molecular orbitals of the dyes prepared were simulated using by density functional theory and time-dependent density functional theory using Gaussian 09. Furthermore, the suitability of the dyes for application in light-conversion films was examined. N-Phenyl groups were found to have a greater effect on the fluorescence of naphthalimide-based dyes than analogue containing an N-alkyl group. In addition, investigation of the effect of diacetylene linkages at the 3- or 4-positions of naphthalimide-based dyes showed that the fluorescence was influenced by the electron-donating effect of the diacetylene linkage which could afford more conjugation of π orbitals of the dyes. Four blue fluorescence dyes derived from 1,8-naphthalimide containing a diacetylene linkage were synthesized and then coated in PE film. The photophysical properties were analyzed using density functional theory (DFT) calculations, and excitations from the highest occupied molecular orbitals (HOMOs) to the lowest unoccupied molecular orbitals (LUMOs) of the dyes were simulated at the B3LYP/6-31G level of theory via the Gaussian 09 suite of programs. Using these methods, the influences of the position of the ethynyl linkages, alkyl groups, and phenyl groups on the electronic and fluorescence properties of the dyes were also clarified.

Effect of the alkyl group in the piperazine N-substitution on the therapeutic action of rifamycins: A drug-membrane interaction study

In this work, we studied the effects of the N-alkyl group (methyl, cyclopentyl) in the piperazine ring of, respectively, rifampicin (RIF) and rifapentine (RPT) to correlate this substitution with their differential pharmacokinetic properties and overall clinical performance. Since this group is their only structural change, and given that they share the same pharmacological target, differences in their therapeutic behavior may respond to this asset, particularly in their interaction with lipid membranes across the organism. In this study, surface pressure-area isotherms, as well as spectroscopic and microscopic techniques of characterization of phospholipid monolayers at the air/water interface were used to gain insight into drug-membrane interactions. Differences in the affinity for lipid membranes for both drugs, given by the vibration frequency of characteristic chemical groups in the lipid, as well as by reflectivity and mean molecular area of the monolayer, seem to be due to the N-alkyl substituent and can contribute to provide a molecular explanation as why they pose different choices in the chemotherapy against the deadliest infectious disease, tuberculosis.

Self-Assembly of Cis-Configured Squaraine Dyes at the TiO2-Dye Interface: Far-Red Active Dyes for Dye-Sensitized Solar Cells.

To synergize both steric and electronic factors in designing the dyes for dye-sensitized solar cells, a series of cis-configured unsymmetrical squaraine dyes P11-P15 with suitably functionalized alkyl groups and squaric acid units containing the electron-withdrawing groups were synthesized, respectively. These dyes capture the importance of (i) the effect and position of branched alkyl groups, (ii) mono- and di-anchoring groups containing dyes, and (iii) further appending the alkyl groups through the cyanoester vinyl unit on the central squaric acid units of D-A-D-based cis-configured squaraine dyes. All the above factors govern the controlled self-assembly of the dyes on the TiO2 surface which helps to broaden the absorption profile of the dyes with an increased energy-harvesting process. With respect to the position of the branched alkyl groups, dye P11 with the sp3-C and N-alkyl groups away from the TiO2 surface showed a better device efficiency of 5.98% ( Jsc of 14.46 mA cm-2, Voc of 0.576 V, and ff of 71.8%) than its positional isomer P12 with 3.45% ( Jsc of 8.78 mA cm-2, Voc of 0.554 V, and ff of 70.9%). However, with respect to the dyes containing mono- and di-anchoring groups, P13 with two anchoring units exhibited a superior device performance of 7.58% ( Jsc of 17.12 mA cm-2, Voc of 0.618 V, and ff of 71.7%) in the presence of optically transparent co-adsorbent CDCA (3α,7α-dihydroxy-5β-cholanic acid) than dyes P11 and P12.

Synthesis of 3-(3-hydroxyphenyl)pyrrolidine dopamine D3 receptor ligands with extended functionality for probing the secondary binding pocket

A series of 3-(3-hydroxyphenyl)pyrrolidine analogues which incorporate N-alkyl groups and N-butylamide-linked benzamide functionality have been synthesized and their in vitro binding affinities at human dopamine receptors have been evaluated. Our ligand design strategy was to take the 3-(3-hydroxyphenyl)pyrrolidine scaffold and extend functionality from the orthosteric binding site to the secondary binding pocket for enhancing affinity and selectivity for the D3 receptor. The N-alkyl analogues constitute a homologous series from N-pentyl to N-decyl to probe the length/bulk tolerance of the secondary binding pocket of the D3 receptor. Enantiomeric 3-(3-hydroxyphenyl)pyrrolidine analogues were also prepared in order to test the chirality preference of the orthosteric binding site for this scaffold. Benzamide analogues were prepared to enhance affinity and/or selectivity based upon the results of the homologous series.

SYNTHESIS OF N-ALKYL AMINO LACTAM DERIVATIVES

Bengamides are sponge-derived natural products of mixed biosynthesis (polyketides andamino acids), the first two members, isolated from Jaspidae sponges in coral surrounding Fijiislands, were reported in 1986. The main structural variation is located on the 3-aminocaprolactam moiety, and displays a wide range of biological activities, includingantitumor, antibiotic, and anthelmintic properties. These interesting biological activities havemade bengamides popular targets for synthesis and biological studies. There have been somereports on diverse modifications of the caprolactame unit, and indication that N-substitution oncaprolactam greatly influences the antitumor activity. In this paper, we reported the method forsynthesis of 6 amino lactams containing an additional N-alkyl group (4a-4c) and (8a-8c) forfurther synthesis of new bengamide analogues. Their structures were established by MS andNMR spectroscopies.

Development of a scalable synthetic route towards a 2,2,6-trisubstituted chiral morpholine via stereoselective hydroalkoxylation

A scalable synthetic route towards a chiral 2,2,6-trisubstituted chiral morpholine, which is a known opioid antagonist, was developed. The synthetic route involves incorporating an aryl group via Suzuki-Miyaura coupling and stereoselective hydroalkoxylation catalyzed by trifluoromethanesulfonic acid. Late stage incorporation of both the aryl and N-alkyl groups make this route suitable for further SAR studies on this molecule.

Bicyclo((aryl)methyl)benzamides as inhibitors of GlyT1

A series of isoquinuclidine benzamides as glycine uptake inhibitors for the treatment of schizophrenia are described. Potency, lipophilicity, and intrinsic human microsomal clearance were parameters for optimization. Potency correlated with the nature of the ortho substituents of the benzamide ring, and reductions in lipophilicity could be achieved through heteroatom incorporation in the benzamide and pendant phenyl moieties. Improvements in human CLint were achieved through changes in ring size and the N-alkyl group of the isoquinuclidine itself, with des-alkyl derivatives (40–41, 44) demonstrating the most robust microsomal stability. Dimethylbenzamide 9 was tested in a mouse MK801 LMA assay and had a statistically significant attenuation of locomotor activity at 3 and 10 μmol/kg compared to control.

Recycling of wastes from fish beneficiation by composting: chemical characteristics of the compost and efficiency of their humic acids in stimulating the growth of lettuce.

Waste from the beneficiation of fish was composted with crushed grass aiming to characterize their chemical composition and investigate the possibility of the use of the final compost as source of humic acids (HA) able to stimulate the growth of lettuce. Compost presented pH value, C/N ratio, and electrical conductivity that allow its use as an organic fertilizer. The element content was present in the following order of abundance in the compost: P > Ca > N > Mg > K > Fe > Zn > Mn > Mo > Cu, and the humus composition was similar to that observed in others kind of organic residues composted. The high content of oxygen pointed out a high level of oxidation of HA, in line with the predominance of phenolic acidity in the functional groups. The 13C-NMR spectra showed marked resonances due to the presence of lipids and other materials resistant to degradation as methoxy substituent and N-alkyl groups. A concentration of 20mgL-1 HA increased significantly both dry and wet root matter in lettuce but the CO2 assimilation, stomatal conductance, and number of lateral roots of the plants were not affected. However, increases of 64% in the water-use efficiency was observed due to the HA addition, probably related to the root morphology alteration which resulted in 1.6-fold increase of lateral root average length and due to the higher H+ extrusion activity. Reuse of residues from the fish beneficiation activity by composting may represent a safe tool to increase the value of recycled organic residues and generate HA with potential use as plant growth stimulants.

Insignificant influence of the matrix on the melting of ice confined in decorated mesoporous silica

For a critical examination of matrix effect on the melting of confined ice, mesoporous silica (SBA-15) are synthesised and decorated with n-Alkyl and aminopropyl groups to tune the surface hydrophobicity. Water contact angle to these decorated surfaces are estimated to be about 100° and 60°, respectively. By examining the melting of ice confined in these decorated samples, we find that the influence of the matrix is indeed not significant. The reported apparent matrix effect is more likely method effect in the determination of pore diameters as was demonstrated in our previous studies (Philos. Mag. 93 (2013), p. 1827).

Expanding the Family of Hoveyda–Grubbs Catalysts Containing Unsymmetrical NHC Ligands

A series of Hoveyda–Grubbs second-generation catalysts containing N-alkyl/N′-aryl N-heterocyclic carbene (NHC) ligands were synthesized and investigated in representative olefin metathesis reactions. Steric perturbations of unsymmetrical NHCs were achieved through modulation of the hindrance of alkyl (neopentyl, neophyl, cyclohexyl) and aryl (2-isopropylphenyl, mesityl) substituents at the nitrogen atoms in combination with different backbone configurations (syn and anti). The NHC substitution patterns strongly influence the stability and reactivity of the corresponding complexes. In general, complexes bearing an anti NHC backbone are more stable and more active than their corresponding syn isomers. In both the series, the presence of bulky, highly branched N-alkyl groups tends to give reduced catalytic differences between syn and anti isomers, whereas the nature of the N′-aryl substituent (2-isopropylphenyl or mesityl) gives rise to different activity and/or selectivity. Of note, an N′-mesityl catalyst w...

Rapid and Clean Covalent Attachment of Methylsiloxane Polymers and Oligomers to Silica Using B(C6F5)3 Catalysis.

The rapid, room-temperature covalent attachment of alkylhydridosilanes (R3Si-H) to silicon oxide surfaces to form monolayers using tris(pentafluorophenyl)borane (B(C6F5)3, BCF) catalysis has recently been described. This method, unlike alternative routes to monolayers, produces only unreactive H2 gas as a byproduct and reaches completion within minutes. We report the use of this selective reaction between surface silanols and hydridosilanes to prepare surface-grafted poly(dimethylsiloxane)s (PDMSs) with various graft architectures that are controlled by the placement of hydridosilane functionality at one end, both ends, or along the chain of PDMS samples of controlled molecular weight. We also report studies of model methylsiloxane monolayers prepared from pentamethyldisiloxane, heptamethyltrisiloxane (two isomers), heptamethylcyclotetrasiloxane, and tris(trimethylsiloxy)silane. These modified silica surfaces with structurally defined methylsiloxane groups are not accessible by conventional silane surface chemistry and proved to be useful in exploring the steric limitations of the reaction. Linear monohydride- and dihydride-terminated PDMS-grafted surfaces exhibit increasing thickness and decreasing contact angle hysteresis with increasing molecular weight up to a particular molecular weight value. Above this value, the hysteresis increases with increasing molecular weight of end-grafted polymers. Poly(hydridomethyl-co-dimethylsiloxane)s with varied hydride content (3-100 mol %) exhibit decreasing thickness, decreasing contact angle, and increasing contact angle hysteresis with increasing hydride content. These observations illustrate the importance of molecular mobility in three-phase contact line dynamics on low-hysteresis surfaces. To calibrate our preparative procedure against both monolayers prepared by conventional approaches as well as the recent reports, a series of trialkylsilane (mostly, n-alkyldimethylsilane) monolayers was prepared to determine the reaction time required to achieve the maximum bonding density using dynamic contact angle analysis. Monolayers prepared from hydridosilanes with BCF catalysis have lower bonding densities than those derived from chlorosilanes, and the reactions are more sensitive to alkyl group sterics. This lower bonding density renders greater flexibility to the n-alkyl groups in monolayers and can decrease the contact angle hysteresis.

Melt Miscibility in Diblock Copolymers Containing Polyethylene and Substituted Hydrogenated Polynorbornenes

The thermodynamic interaction strengths between linear polyethylene (PE) and members of a family of hydrogenated polynorbornenes prepared by ring-opening metathesis polymerization can be tuned across a wide range via the choice of substituent appended to the polynorbornene backbone at the 5-position. Isopropyl and certain n-alkyl groups yield polynorbornenes that are highly miscible with PE, capable of producing symmetric diblock copolymers with homogeneous melts at molecular weights in excess of 100 kg/mol. In contrast, phenyl-substituted polynorbornenes are quite immiscible with PE, exhibiting microphase separation in the melt at diblock molecular weights as low as 10 kg/mol. Interaction strengths within this series of polymers do not quantitatively obey regular mixing; entropic contributions to the mixing energy arising from mismatches in free volume and chain stiffness cannot account for the observed deviations. Instead, the interactions can be satisfactorily described by an empirical mixing rule of t...

The Viologen Cation Radical Pimer: A Case of Dispersion-Driven Bonding.

The π bonds between organic radicals have generated excitement as an orthogonal interaction for designing self-assembling architectures in water. A systematic investigation of the effect of the viologen cation radical structure on the strength and nature of the pimer bond is provided. A striking and unexpected feature of this π bond is that the bond strength is unchanged by substitution with electron-donating groups or withdrawing groups or with increased conjugation. Furthermore, the interaction is undiminished by sterically bulky N-alkyl groups. Theoretical modeling indicates that strong dispersion forces dominate the interaction between the radicals, rationalizing the insensitivity of the bonding interaction to substituents: The stacking of polarizable π radicals leads to attractive dispersion forces in excess of typical dispersion interactions of small molecules and helps overcome the Coulombic repulsion of bringing two cationic species into contact.

Synthesis of High Molecular Weight Poly(p-benzamide)s

The polymerization of aromatic para-amino acid ester derivatives was studied using model compounds. Mechanistic and kinetic experiments led to the discovery of some side reactions. Finally, high molecular weight poly(p-benzamide)s were synthesized and characterized. The use of highly reactive pentafluorophenol ester lead to polymers up to molecular weights of around 50 000 Da. Poly(benzamides) carrying both N-alkyl or N-benzyl groups on the amine could be polymerized to high molecular weight.

Precise synthesis of a series of poly(4-n-alkylstyrene)s and their glass transition temperatures

Poly(4-n-alkylstyrene)s with six kinds of n-alkyl groups such as methyl, ethyl, propyl, butyl, hexyl, and octyl groups covering wide molecular weight range from around 5 k to over 100 k were precisely synthesized by living anionic polymerizations. It was confirmed that all the polymers obtained have narrow molecular weight distribution, that is, Mw/Mn is all less than 1.1, by SEC. Tgs of all the polymers were estimated by DSC measurements and it turned out to be clear that their molecular weight dependence was well described by the Fox–Flory equations. Furthermore, it is evident that Tg monotonically decreases as a number of carbon atoms of n-alkyl group is increased, though Tg values are all 20 K or more higher than those reported previously for the same polymer series. This is because backbone mobility increases by introducing longer n-alkyl side groups with high mobility, while Tg difference in between this work and the previous one may due to the experimental conditions and also to the molecular weight range adopted. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2017, 55, 757–763