The metallocyclic ring in mononuclear iminoisoindoline-based palladacycle [(κ2-iminoisoidoline)PdCl(PCy3)] (3) can be ring opened by coordination of phosphine to form the trans bis(phosphine) iminoisoindoline-based palladium(II) complex [(η1-iminoisoidoline)PdCl(PCy3)2] (4) where the η1-iminoisoindoline is coordinated only by an Ar–Pd bond. The ring-opened analogue showed significantly higher coupling activity in Suzuki-Miyaura reactions with aryl chlorides than any iminoisoindoline-based palladacycle studied to date. These results are compared to existing mononuclear palladacycles and reported acyclic analogues.

Crystals of the dimethyl sulfoxide (DMSO) solvate of [1-9-NαC]-linusorb B3 (Cyclo-linopeptide A; CLP-A; C57H84N9O9·C2H6OS), a cyclic polypeptide were obtained following peptide extraction and purification from flaxseed oil. There are four intramolecular N-H⋯O hydrogen bonds. In the crystal, the mol-ecules are linked in chains along the a axis by N-H⋯O hydrogen bonds. Each DMSO O atom accepts a hydrogen bond from an NH group at the Phe6 location in the CLP-A mol-ecule.

A study has been carried out in detail to measure the effects of the removal of nitrogen compounds on the hydrotreatment of light gas oil (LGO) using a synthesized polymer consisting of a polymer support, copolymer of glycidyl methacrylate and ethylene glycol dimethacrylate (PGMA-co-EDGMA), a pi-acceptor moiety (2,4,5,7-tetranitrofluorenone, TENF), and a three-carbon linker (diaminopropane, DAP (3)). The primary focus of this paper is first to study the effects of selectively removing nitrogen compounds on the hydrotreatment of LGOs. Removal of these catalyst inhibiting and poisoning compounds prior to hydrotreatment will help in improving the hydroprocessing efficiency as well as in reducing the chemical fouling, thus improving the catalyst life. Second, the effectiveness on the reusability of bulk polymer after regeneration was studied. To achieve this, nitrogen compounds from LGO were adsorbed on the synthesized polymer by mixing polymer and LGO. The polymer was regenerated by washing with toluene in a Soxhlet apparatus. Hydrotreating experiments were performed in a pilot scale trickle-bed reactor. To create a baseline for monitoring the hydrotreatment activity, untreated LGO (without polymer adsorption) was hydrotreated with a commercial NiMo/gamma-Al2O3 catalyst and analyzed for nitrogen, sulfur, and aromatics content. The pretreated feed (with polymer adsorption) was also hydrotreated, and the results were compared. The results show that prior selective removal of nitrogen compounds improved overall hydrotreatment activity and resulted in additional decrease of 18.7%, 8.3%, and 9.4% in total nitrogen, sulfur, and aromatics content, respectively.

The unique molecular structure confers the diquaternary ammonium gemini surfactants with enhanced nucleic acid complexation ability, bottom-up design flexibility, and relatively low cytotoxicity. To capitalize on their potential as gene delivery vectors, novel structural modifications should be explored. In this work, 22 novel peptide-modified gemini surfactants with various alkyl tails and peptide spacer modifications were evaluated. This work represents the first report of dendrimer-like gemini surfactants and first evaluation of the impact of incorporating a hydrocarbon linker into the peptide chain. Our aim was to establish a structure activity relationship of the peptide-modified gemini surfactants and to identify the fundamental architectural requirements needed for the ultimate gene delivery systems. In vitro assessment revealed that the highest transfection efficiency and lowest cytotoxicity were associated with the glycyl-lysine modified gemini surfactants having the hexadecyl tail, 16-7N(G-K)-16. In fact, it showed an 8-fold increase in secreted protein with 20% increase in cell viability relative to the first-generation unsubstituted gemini surfactants. Further increase in the size of the attached peptides resulted in a decrease in the transfection efficiency and cell viability. Whereas the incorporation of a hydrocarbon linker into the peptide chain decreased the transfection efficiency of compounds with dipeptides, it increased the transfection efficiency of compounds with larger peptide chains. Such an increase was more prominent with the incorporation of a longer hydrocarbon linker. We conclude that a balance between the hydrophilic and hydrophobic characteristics of the compound is necessary since it results in physicochemical parameters conducive to the gene delivery process.

Diquaternary ammonium gemini surfactants are a class of non-viral gene delivery vectors, primarily studied for their dermal applications. However, their biological fate has rarely been investigated. In this work, we developed simple flow injection analysis tandem mass spectrometric methods, (FIA)-MS/MS, to understand the fate and biodistribution of topically applied gemini surfactant-based therapeutics in an ex-vivo skin model. Three peptide-modified gemini surfactants with varied structures and transfection efficiencies were evaluated. For each compound, two methods were developed to quantify their presence in skin tissue and in phosphate buffered saline (PBS). The methods were developed using single-point calibration mode. Skin penetration was assessed on CD1 mice dorsal skin tissue mounted in a Franz diffusion cell after extraction. Amongst the five evaluated liquid-liquid extraction protocols, the Folch method provides the highest extraction efficiency for all compounds. Weak cationic exchange solid phase extraction was also used to further isolate gemini surfactants from endogenous skin lipids. FIA-MS/MS analysis of the skin revealed that all compounds were detected in the skin with minimal partition into the PBS compartment, which represents circulation. Interestingly, the detected amounts of gemini lipids in the skin were correlated with their transfection efficiencies. (C) 2018 Elsevier B.V. All rights reserved.

PURPOSE:We have developed and evaluated novel peptide-targeted gemini surfactant-based lipoplexes designed for melanoma gene therapy.METHODS:Integrin receptor targeting peptide, cyclic-arginylglycylaspartic acid (cRGD), was either chemically coupled to a gemini surfactant backbone or physically co-formulated with lipoplexes. Several formulations and transfection techniques were developed. Transfection efficiency and cellular toxicity of the lipoplexes were evaluated in an in vitro human melanoma model. Physicochemical properties were examined using dynamic light scattering, zeta-potential, and small-angle X-ray scattering measurements.RESULTS:RGD-modified gemini surfactant based lipoplexes showed significant enhancement in gene transfection activity in A375 cell lines compared to the standard non-targeted formulation, especially when RGD was chemically conjugated to the gemini surfactant (RGD-G). The RGD had no effect on the cell toxicity profile of the lipoplex systems. Targeting specificity was confirmed by using an excess of free RGD and negative control peptide (RAD) and was demonstrated by using normal human epidermal keratinocytes. Physicochemical characterization showed that all nanoparticles were in the optimal size range for cellular uptake and there were no significant differences between RGD-modified and standard lipoplexes.CONCLUSIONS:These findings indicate the potential of RGD-modified gemini surfactant-based lipoplexes for use in melanoma gene therapy as an alternative to conventional chemotherapy.

The aim of this work was to elucidate the structure-activity relationship of new peptide-modified gemini surfactant-based carriers. Glycyl-lysine modified gemini surfactants that differ in the length and degree of unsaturation of their alkyl tail were used to engineer DNA nano-assemblies. To probe the optimal nitrogen to phosphate (N/P) ratio in the presence of helper lipid, in vitro gene expression and cell toxicity measurements were carried out. Characterization of the nano-assemblies was accomplished by measuring the particle size and surface charge. Morphological characteristics and lipid organization were studied by small angle X-ray scattering technique. Lipid monolayers were studied using a Langmuir-Blodgett trough. The highest activity of glycyl-lysine modified gemini surfactants was observed with the 16-carbon tail compound at 2.5 N/P ratio, showing a 5- to 10-fold increase in the level of reporter protein compared to the 12 and 18:1 carbon tail compounds. This ratio is significantly lower compared to the previously studied gemini surfactants with alkyl or amino- spacers. In addition, the 16-carbon tail compound exhibited the highest cell viability (85%). This high efficiency is attributed to the lowest critical micelle concentration of the 16-tail gemini surfactant and a balanced packing of the nanoparticles by mixing a saturated and unsaturated lipid together. At the optimal N/P ratio, all nanoparticles exhibited an inverted hexagonal lipid assembly. The results show that the length and nature of the tail of the gemini surfactants play an important role in determining the transgene efficiency of the delivery system. We demonstrated here that the interplay between the headgroup and the nature of tail is specific to each series, thus in the process of rational design, the contribution of the latter should be assessed in the appropriate context.

The title compound, C 57 H 85 N 9 O 9 ·2C 2 H 3 N [systematic name: cyclo -(prolyl-prolyl-phenylalanyl-phenylalanyl-leucyl-isoleucyl-isoleucylleucyl-valyl) acetonitrile disolvate; synonym: cyclolinopeptide acetonitrile disolvate], is a polypeptide with nine amino acids, viz. NαC-(Pro 1 –Pro 2 –Phe 3 –Phe 4 –Leu 5 –Ile 6 –Ile 7 –Leu 8 –Val 9 ). It was extracted from flaxseed oil and crystallized from acetonitrile as a disolvate. In the title molecule, there are four intramolecular N—H...O hydrogen bonds. One of the two acetonitrile molecules is hydrogen bonded to Phe 3 via an N—H...N hydrogen bond, while the second acetonitrile molecule is located at the other side of the peptide ring and is linked to the title molecule by a C—H...N hydrogen bond. In the crystal, molecules are linked by N—H...O hydrogen bonds, forming chains along the a -axis direction. The chains are linked by C—H...O hydrogen bonds, forming undulating layers parallel to the ac plane.

This work investigated the effect of cross-linking agents on the efficiency and selectivity of functionalized polymers toward the removal of nitrogen- and sulfur-containing compounds from gas-oil. The following polymeric supports with increasing particles size were synthesized: poly(glycidyl methacrylate) [PGMA], poly(glycidyl methacrylate-co-ethylene glycol dimethacrylate) [PGMA-co-EGDMA] and poly(glycidyl methacrylate-co-trimethylolpropane trimethacrylate)[PGMA-co-TMPTMA]. Diaminopropane (DAP) and tetra-nitro-9-fluorenone (TENF) were utilized as a linker and a π-acceptor moiety, respectively. Particles were fully characterized using different methods including Fourier transform infrared spectroscopy (FTIR), Brunauer–Emmett–Teller (BET), thermogravimetric analysis/differential thermal analysis (TGA/DTA), etc. Results showed that the particles with the larger spherical beads [PGMA-co-TMPTMA-DAP(3)-TENF] gave the highest nitrogen and sulfur adsorption.

The utility of novel functionalized nanodiamonds (NDs) as matrices for matrix-assisted laser desorption ionization-mass spectrometry (MALDI-MS) is described herein. MALDI-MS analysis of small organic compounds (<1000 Da) is typically complex because of interferences from numerous cluster ions formed when using conventional matrices. To expand the use of MALDI for the analysis of small molecules, novel matrices were designed by covalently linking conventional matrices (or a lysine moiety) to detonated NDs. Four new functionalized NDs were evaluated for their ionization capabilities using five pharmaceuticals with varying molecular structures. Two ND matrices were able to ionize all tested pharmaceuticals in the negative ion mode, producing the deprotonated ions [M - H](-). Ion intensity for target analytes was generally strong with enhanced signal-to-noise ratios compared with conventional matrices. The negative ion mode is of great importance for biological samples as interference from endogenous compounds is inherently minimized in the negative ion mode. Since the molecular structures of the tested pharmaceuticals did not suggest that negative ion mode would be preferable, this result magnifies the importance of these findings. On the other hand, conventional matrices primarily facilitated the ionization as expected in the positive ion mode, producing either the protonated molecules [M + H](+) or cationic adducts (typically producing complex spectra with numerous adduct peaks). The data presented in this study suggests that these matrices may offer advantages for the analysis of low molecular weight pharmaceuticals/metabolites. Graphical Abstract ᅟ.

A major challenge in achieving deep hydrodesulfurization with the conventional hydrotreating technology is the inhibition and deactivation of the catalyst caused by heterocyclic nitrogen compounds. In this research, novel polymeric adsorbents were introduced for the selective removal of nitrogen compounds from bitumen-derived light gas oil. Synthesis of polymers with high internal phase emulsion (polyHIPEs) was carried out using a monomeric mixture of unsaturated polyester resin, glycidyl methacrylate and divinylbenzene. To facilitate the selective removal of nitrogen compounds, reactive epoxy groups present in glycidyl methacrylate were used to functionalize the polyHIPEs with a fluorenone based π-acceptor, 2,4,5,7-tetranitro-9-fluorenone (TENF). Successful application of the synthesized polymers was found in the batch adsorption experiments at ambient temperature. Functionalized polyHIPEs were capable of selectively adsorbing nitrogen species from light gas oil. The optimum ratio of monomers was found to be one of the key factors in determining the polymer performance. Particles with high glycidyl methacrylate content with toluene as the porogenic solvent were capable of removing 14.6% of nitrogen compounds. Reusability studies were performed successfully by regenerating the used polymers with toluene; which aids the separation of complexing agent and the adsorbed nitrogen species.

Functionalized polymers were synthesized and applied in removing nitrogen and sulfur compounds from gas oils. In this work, the polyglycidyl methacrylate-co-ethylene glycol dimethacrylate polymer incorporated with tetranitrofluorenone, PGMA-DAP-TENF, was synthesized with and without alumina support. Different techniques were used to characterize the synthesized polymers including Fourier transform infrared spectroscopy, Brunauer-Emmett-Teller method, dynamic light scattering, thermogravimetry/differenial thermal analyzer, carbon hydrogen nitrogen sulfur elemental analysis, and field emission scanning electron microscopy. The performance of the polymer with alumina, Al-PGMA-DAP-TENF, was compared to that without alumina using light gas oil. In addition, heavy gas oil feed was used to confirm the adsorption behavior of both polymers in a higher nitrogen and sulfur environment. The effect of adsorption time and temperature was tested using a 1:5, by weight, polymer to feed ratio. Results have shown that alumina particles enhanced the nitrogen removal efficiency of PGMA-DAP-TENF polymer while sulfur removal efficiency was not affected. The nitrogen removal efficiency of Al-PGMA-DAP-TENF polymer was more than twice that of PGMA-DAP-TENF polymer in LGO feed, and twice that in HGO feed. This was due to the higher surface area of Al-PGMA-DAP-TENF polymer, 202 m(2)/g, compared to that of PGMA-DAP-TENF polymer, 27 m(2)/g. In addition, Al-PGMA-DAP-TENF polymer removed more basic nitrogen compounds than PGMA-DAP-TENF polymer. This was attributed to the acidic nature of alumina particles that enhance the adsorption of basic nitrogen compounds present in gas oil feeds.

Novel drug delivery systems are developed to improve the biological behavior of poorly soluble drugs and to improve therapeutic outcomes. In melanoma therapy, the goal is efficient drug delivery and mitigation of drug resistance. Melphalan (Mel), a currently used therapeutic agent for melanoma, requires solvent system for solubilization, leading to poor chemical stability. Moreover, drug resistance often renders the drug inefficient in clinical setting. A novel β-cyclodextrin-modified gemini surfactant (CDgemini) delivery system was developed to incorporate Mel in order to improve its physicochemical and biological behavior. Melphalan nanoparticles (Mel-NP) showed optimal particle size in the 200-250 nm range for endocytosis and induced significantly higher cell death compared with Mel (50% of inhibitory concentration [IC50] of 36 µM for the complexes vs 82 µM for Mel). The CDgemini delivery system did not alter the pathway of the cellular death triggered by Mel and caused no intrinsic toxicity to the cells. The Mel-NP complexes induced significant cell death in melanoma cells that were rendered resistant to Mel. These findings demonstrate in principle the applicability of the CDgemini delivery system as safe and efficient alternative to the current melanoma therapy, especially in chemoresistant cases.

PURPOSE:Nanodiamonds (NDs) are emerging as an attractive tool for gene therapeutics. To reach their full potential for biological application, NDs should maintain their colloidal stability in biological milieu. This study describes the behavior of lysine-functionalized ND (lys-ND) in various dispersion media, with an aim to limit aggregation and improve the colloidal stability of ND-gene complexes called diamoplexes. Furthermore, cellular and macromolecular interactions of lys-NDs are also analyzed in vitro to establish the understanding of ND-mediated gene transfer in cells.METHODS:lys-NDs were synthesized earlier through covalent conjugation of lysine amino acid to carboxylated NDs surface generated through re-oxidation in strong oxidizing acids. In this study, dispersions of lys-NDs were prepared in various media, and the degree of sedimentation was monitored for 72 hours. Particle size distributions and zeta potential measurements were performed for a period of 25 days to characterize the physicochemical stability of lys-NDs in the medium. The interaction profile of lys-NDs with fetal bovine serum showed formation of a protein corona, which was evaluated by size and charge distribution measurements. Uptake of lys-NDs in cervical cancer cells was analyzed by scanning transmission X-ray microscopy, flow cytometry, and confocal microscopy. Cellular uptake of diamoplexes (complex of lys-NDs with small interfering RNA) was also analyzed using flow cytometry.RESULTS:Aqueous dispersion of lys-NDs showed minimum sedimentation and remained stable over a period of 25 days. Size distributions showed good stability, remaining under 100 nm throughout the testing period. A positive zeta potential of >+20 mV indicated a preservation of surface charges. Size distribution and zeta potential changed for lys-NDs after incubation with blood serum, suggesting an interaction with biomolecules, mainly proteins, and a possible formation of a protein corona. Cellular internalization of lys-NDs was confirmed by various techniques such as confocal microscopy, soft X-ray spectroscopy, and flow cytometry.CONCLUSION:This study establishes that dispersion of lys-NDs in aqueous medium maintains long-term stability and also provides evidence that lysine functionalization enables NDs to interact effectively with the biological system to be used for RNAi therapeutics.

Aim: Recently, we synthesized amino acid- and peptide-substituted gemini surfactants, biolipids' that exhibited high transfection efficiency in vitro. In this study, we developed these plasmid DNA and gemini surfactant lipid particles for noninvasive administration in vaginal cavity. Material & methods: Novel formulations of these gene delivery systems were prepared with poloxamer 407 to induce in situ gelling of the formulation and diethylene glycol monoethyl ether to improve their penetration across mucosal tissue. Results: Poloxamer at 16% w/v concentration in diethylene glycol monoethyl ether aqueous solution produced dispersions that gelled near body temperature and had a high yield value, preventing leakage of the formulation from the vaginal cavity. Intravaginal administration in rabbits showed that the glycyl-lysine-substituted gemini surfactant led to a higher gene expression compared with the parent unsubstituted gemini surfactant. Conclusion: This provides a proof-of-concept that amino acid substituted gemini surfactants can be used as noninvasive mucosal (vaginal) gene delivery systems to treat diseases associated with mucosal epithelia.

Background Curcumin analogs, including the novel compound NC 2067, are potent cytotoxic agents that suffer from poor solubility, and hence, low bioavailability. Cyclodextrin-based carriers can be used to encapsulate such agents. In order to understand the interaction between the two molecules, the physicochemical properties of the host–guest complexes of NC 2067 with β-cyclodextrin (CD) or β-cyclodextrin–gemini surfactant (CDgemini surfactant) were investigated for the first time. Moreover, possible supramolecular structures were examined in order to aid the development of new drug delivery systems. Furthermore, the in vitro anticancer activity of the complex of NC 2067 with CDgemini surfactant nanoparticles was demonstrated in the A375 melanoma cell line. Methods Physicochemical properties of the complexes formed of NC 2067 with CD or CDgemini surfactant were investigated by synchrotron-based powder X-ray diffraction, Fourier-transform infrared spectroscopy, and thermogravimetric analysis. Synchrotron-based small- and wide-angle X-ray scattering and size measurements were employed to assess the supramolecular morphology of the complex formed by NC 2067 with CDgemini surfactant. Lastly, the in vitro cell toxicity of the formulations toward A375 melanoma cells at various drug-to-carrier mole ratios were measured by cell viability assay. Results Physical mixtures of NC 2067 and CD or CDgemini surfactant showed characteristics of the individual components, whereas the complex of NC 2067 and CD or CDgemini surfactant presented new structural features, supporting the formation of the host–guest complexes. Complexes of NC 2067 with CDgemini surfactants formed nanoparticles having sizes of 100–200 nm. NC 2067 retained its anticancer activity in the complex with CDgemini surfactant for different drug-to-carrier mole ratios, with an IC50 (half-maximal inhibitory concentration) value comparable to that for NC 2067 without the carrier. Conclusion The formation of host–guest complexes of NC 2067 with CD or CDgemini surfactant has been confirmed and hence the CDgemini surfactant shows good potential to be used as a delivery system for anticancer agents.

Background: Curcumin analogs, including the novel compound NC 2067, are potent cytotoxic agents that suffer from poor solubility, and hence, low bioavailability. Cyclodextrin-based carriers can be used to encapsulate such agents. In order to understand the interaction between the two molecules, the physicochemical properties of the host-guest complexes of NC 2067 with beta-cyclodextrin (CD) or beta-cyclodextrin-gemini surfactant (CDgemini surfactant) were investigated for the first time. Moreover, possible supramolecular structures were examined in order to aid the development of new drug delivery systems. Furthermore, the in vitro anticancer activity of the complex of NC 2067 with CDgemini surfactant nanoparticles was demonstrated in the A375 melanoma cell line.Methods: Physicochemical properties of the complexes formed of NC 2067 with CD or CDgemini surfactant were investigated by synchrotron-based powder X-ray diffraction, Fourier-transform infrared spectroscopy, and thermogravimetric analysis. Synchrotron-based small- and wide-angle X-ray scattering and size measurements were employed to assess the supramolecular morphology of the complex formed by NC 2067 with CDgemini surfactant. Lastly, the in vitro cell toxicity of the formulations toward A375 melanoma cells at various drug-to-carrier mole ratios were measured by cell viability assay.Results: Physical mixtures of NC 2067 and CD or CDgemini surfactant showed characteristics of the individual components, whereas the complex of NC 2067 and CD or CDgemini surfactant presented new structural features, supporting the formation of the host-guest complexes. Complexes of NC 2067 with CDgemini surfactants formed nanoparticles having sizes of 100-200 nm. NC 2067 retained its anticancer activity in the complex with CDgemini surfactant for different drug-to-carrier mole ratios, with an IC50 (half-maximal inhibitory concentration) value comparable to that for NC 2067 without the carrier.Conclusion: The formation of host-guest complexes of NC 2067 with CD or CDgemini surfactant has been confirmed and hence the CDgemini surfactant shows good potential to be used as a delivery system for anticancer agents.

In this work, four poly(glycidyl methacrylate-co-ethylene glycol methacrylate) [PGMA-co-EDGMA] functionalized particles were synthesized and characterized, and tested in gas oil adsorption. Particles consisted of identical polymer support (PGMA-co-EDGMA, henceforth referred to as PGMA) and pi-acceptor moiety (2,4,5,7-tetranitroflorenone, TENF), while the linkers (linear diamines) were varied from a two- (diaminoethane, DAE (2)), a three- (diaminopropane, DAP(3)) to a four-carbon (diaminobutane, DAB(4)) containing compounds. The particles notation takes the form: PGMA-DAE(2)-TENF, PGMA-DAP(3)-TENF, PGMA-DAB(4)-TENF and PGMA-DAB(4)5-TENF, where 5 denotes the synthesis in 5% (vol./vol.) linker and 95% (vol./vol.) toluene solution, while for other three, 100% (vol./vol.) linker was used. Particles were characterized by, among others, Fourier transform infrared spectroscopy (FT-IR), thermogravimetric analysis (TGA), elemental carbon, hydrogen, nitrogen and sulfur analysis (CHNS) and scanning electron microscopy (SEM). The change in linker length did not result in a significant effect on loading as similar amounts of TENF were immobilized on the polymeric particles regardless of the linker length. From the adsorption studies of light gas oil (LGO), results showed that diaminopropane (PGMA-DAP(3)-TENF) substituted particles gave the highest % adsorption of nitrogen compounds, followed by the diaminobutane (PGMA-DAB(4)-TENF)-based particles, while no significant differences between the particles with diaminoethane (PGMA-DAE(2)-TENF) and PGMA-DAB(4)5-TENF were observed. The results further showed that all the four types of particles selectively adsorbed nitrogen compounds, while the sulfur concentration in LGO remained unchanged under the following adsorption process conditions: ambient temperature (24 degrees C), time (24 h), particles to oil loading ratio (1:4 wt./wt.) and stirring speed (400 rpm). Generally, steric hindrance around the TENF molecules, on the surface of the particles, had a major role to play in the adsorption process than the length of the linker.