Pendant Primary Amine Research Articles

Toward 68Ga and 64Cu Positron Emission Tomography Probes: Is H2dedpa-N,N'-pram the Missing Link for dedpa Conjugation?

H2dedpa-N,N'-pram (H2L1), a new chelator derived from the hexadentate ligand 1,2-bis[[(6-carboxypyridin-2-yl)methyl]amino]ethane (H2dedpa), which incorporates 3-propylamine chains anchored to the secondary amines of the ethylenediamine core of the latter, has emerged as a very promising scaffold for preparing 68Ga- and 64Cu-based positron emission tomography probes. This new platform is cost-effective and easy to prepare, and the two pendant primary amines make it versatile for the preparation of bifunctional chelators by conjugation and/or click chemistry. Reported herein, we have also included the related H2dedpa-N,N'-prpta (H2L2) platform as a simple structural model for its conjugated systems. X-ray crystallography confirmed that the N4O2 coordination sphere provided by the dedpa2- core is maintained at both Ga(III) and Cu(II). The complex formation equilibria were deeply investigated by a thorough multitechnique approach with potentiometric, NMR spectrometric, and UV-vis spectrophotometric titrations, revealing effective chelation. The thermodynamic stability of the Ga(III) complexes at physiological relevant conditions is slightly higher than that of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), the common and clinically approved chelator used in the clinic [pGa = 19.5 (dedpa-N,N'-pram) and 20.8 (dedpa-N,N'-prpta) versus 18.5 (DOTA) at identical conditions], and significantly higher for the Cu(II) complexes [pCu = 21.96 (dedpa-N,N'-pram) and 22.8 (dedpa-N,N'-prpta) versus 16.2 (DOTA)], which are even more stable than that of the parent ligand dedpa2- (pCu = 18.5) and that of 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) (pCu = 18.5). This high stability found for Cu(II) complexes is related to the conversion of the secondary amines of the ethylenediamine core of dedpa2- into tertiary amines, whereby the architecture of the new H2L1 chelator is doubly optimal in the case of this metal ion: high accessibility of the primary amine groups and their incorporation via the secondary amines, which contributes to a significant increase in the stability of the metal complex. Quantitative labeling of both chelators with both radionuclides ([68Ga]Ga3+ and [64Cu]Cu2+) was observed within 15 min at room temperature with concentrations as low as 10-5 M. Furthermore, serum stability studies confirmed a high radiochemical in vitro stability of all systems and therefore confirmed H2L1 as a promising and versatile chelator for further radiopharmaceutical in vivo studies.

NIPAm-Based Modification of Poly(L-lysine): A pH-Dependent LCST-Type Thermo-Responsive Biodegradable Polymer.

Polylysine is a biocompatible, biodegradable, water soluble polypeptide. Thanks to the pendant primary amines it bears, it is susceptible to modification reactions. In this work Poly(L-lysine) (PLL) was partially modified via the effortless free-catalysed aza-Michael addition reaction at room temperature by grafting N-isopropylacrylamide (NIPAm) moieties onto the amines. The resulting PLL-g-NIPAm exhibited LCST-type thermosensitivity. The LCST can be tuned by the NIPAm content incorporated in the macromolecules. Importantly, depending on the NIPAm content, LCST is highly dependent on pH and ionic strength due to ionization capability of the remaining free lysine residues. PLL-g-NIPAm constitutes a novel biodegradable LCST polymer that could be used as “smart” block in block copolymers and/or terpolymers, of any macromolecular architecture, to design pH/Temperature-responsive self-assemblies (nanocarriers and/or networks) for potential bio-applications.

Influence of Intermolecular Hydrogen Bonding Interactions on the Electrocatalytic Reduction of CO2 to CO by 6,6′‐Amine Substituted Rhenium Bipyridine Complexes

AbstractThe introduction of biologically inspired motifs into electrocatalysts is an attractive strategy for efficiently transforming harmful fossil fuel combustion products such as carbon dioxide into useful chemical fuels. Herein, we present a series of Re(bpy)(CO)3Cl electrocatalysts with pendant primary, secondary, and tertiary amines with the aim of determining the effect of available pendant protons on the reduction of CO2 to CO. Cyclic voltammetry studies indicate that the availability of pendant protons leads to intermolecular hydrogen bonding interactions, altering the electrochemical behavior of the complexes. Further, controlled potential electrolysis studies show a clear trend in the catalytic activity of these complexes based on the availability of pendant protons. For the NMe2‐substituted complex with no pendant protons, the Faradaic efficiency (FE) remains quite stable with changing potential (41–65 % FECO), but for the NH2‐substituted complex with maximum available pendant protons, the FECO increases with more negative potentials, peaking at 83 % FECO. Together with the formation of H2 by the NH2‐substituted Re(bpy)(CO)3Cl complex, this suggests a change in electrocatalytic behavior due to the intermolecular hydrogen bonding interactions that occur with additional pendant protons.

Two-step synthesis of polystyrene sulfonate based copolymers bearing pendant primary amines

Polyelectrolytes are macromolecular building blocks which find numerous applications in the design of colloids, interfaces, gels and membranes. Herein, new functional polyelectrolytes copolymers bearing pendant primary amines have been synthesized through the free radical copolymerization of sodium p-styrene sulfonate (SS) and acrylamide (AAm) or chloromethylstyrene (CMS) followed by a post-polymerization modification. The first strategy relies on the use of the Hofmann reaction to convert polystyrene sulfonate-polyacrylamide (P(SS-co-AAm)) copolymers into polystyrene sulfonate-polyvinylamine (P(SS-co-VA)) copolymers. The second route includes the N-alkylation of polystyrene sulfonate-polychloromethylstyrene (P(SS-co-CMS)) copolymers with 1,8-diamino-3,6-dioxaoctane (DADO). It was observed that the chemical modification of P(SS-co-AAm) copolymers of different composition through the Hofmann reaction was effective but lead to some side reactions. In addition, P(SS-co-CMS) copolymers of several composition were prepared in anhydrous DMSO to prevent the early hydrolysis of the CMS units, and were quantitatively post-modified at RT with an excess of DADO. The resulting copolymers were soluble in both water and DMSO, and preliminary experiments on their properties evidenced both the reactivity of their amino group toward reductive amination (either performed with propanal or onto an oxidized nanocellulose), and their polyampholyte behavior at pH below the amine pKa.

Synthesis, Characterization, and Antimicrobial Evaluation of Random Poly(ester-Carbonate)s Bearing Pendant Primary Amine in the Main Chain.

Starting from primary amine bearing cyclic carbonate tert-butyl-(2-oxo-1,3-dioxan-5-yl) carbamate (TBODC) and caprolactone (CL), amphiphilic poly(caprolactone-ran-amino trimethyl carbonate)s (P(CL-ran-ATC)s) random copolymers with controlled molecular weight and composition were synthesized via ring opening polymerization (ROP) and deprotection, using stannous octoate (Sn(Oct)2) as catalyst and benzyl alcohol (BnOH) as initiator. Therefore, hydrophilic/lipophilic ratio (HLR) of the P(CL-ran-ATC)s copolymers can be finely adjusted by the feed ratio of TBODC and CL. The antimicrobial activity against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) of P(CL-ran-ATC)s were proportional to HLR, and P(CL-ran-ATC)s presented more vigorous bactericidal activity towards S. aureus. The minimum inhibitory concentration (MIC) values of P(CL-ran-ATC 50.9%) are 2000 μg mL−1 and 3000 μg mL−1 for S. aureus and E. coli. While P(CL-ran-ATC 50.9%) exhibited deficient hemolytic activity as 1.41%. In addition, the P(CL-ran-ATC)s showed extremely low cytotoxicity towards fibroblast L929 cells.

Hybrid Injectable Sol-Gel Systems Based on Thermo-Sensitive Polyurethane Hydrogels Carrying pH-Sensitive Mesoporous Silica Nanoparticles for the Controlled and Triggered Release of Therapeutic Agents.

Injectable therapeutic formulations locally releasing their cargo with tunable kinetics in response to external biochemical/physical cues are gaining interest in the scientific community, with the aim to overcome the cons of traditional administration routes. In this work, we proposed an alternative solution to this challenging goal by combining thermo-sensitive hydrogels based on custom-made amphiphilic poly(ether urethane)s (PEUs) and mesoporous silica nanoparticles coated with a self-immolative polymer sensitive to acid pH (MSN-CS-SIP). By exploiting PEU chemical versatility, Boc-protected amino groups were introduced as PEU building block (PEU-Boc), which were then subjected to a deprotection reaction to expose pendant primary amines along the polymer backbone (PEU-NH2, 3E18 -NH2/gPEU–NH2) with the aim to accelerate system response to external acid pH environment. Then, thermo-sensitive hydrogels were designed (15% w/v) showing fast gelation in physiological conditions (approximately 5 min), while no significant changes in gelation temperature and kinetics were induced by the Boc-deprotection. Conversely, free amines in PEU-NH2 effectively enhanced and accelerated acid pH transfer (pH 5) through hydrogel thickness (PEU-Boc and PEU-NH2 gels covered approximately 42 and 52% of the pH delta between their initial pH and the pH of the surrounding buffer within 30 min incubation, respectively). MSN-CS-SIP carrying a fluorescent cargo as model drug (MSN-CS-SIP-Ru) were then encapsulated within the hydrogels with no significant effects on their thermo-sensitivity. Injectability and in situ gelation at 37°C were demonstrated ex vivo through sub-cutaneous injection in rodents. Moreover, MSN-CS-SIP-Ru-loaded gels turned out to be detectable through the skin by IVIS imaging. Cargo acid pH-triggered delivery from PEU-Boc and PEU-NH2 gels was finally demonstrated through drug release tests in neutral and acid pH environments (in acid pH environment approximately 2-fold higher cargo release). Additionally, acid-triggered payload release from PEU-NH2 gels was significantly higher compared to PEU-Boc systems at 3 and 4 days incubation. The herein designed hybrid injectable formulations could thus represent a significant step forward in the development of multi-stimuli sensitive drug carriers. Indeed, being able to adapt their behavior in response to biochemical cues from the surrounding physio-pathological environment, these formulations can effectively trigger the release of their payload according to therapeutic needs.

Synthesis and Self‐assembly of a Helical Polymer Grafted from a Foldable Polyurethane Scaffold

Herein a polyurethane graft poly-l-glutamate amphiphilic copolymer was synthesized from a polyurethane (PU)-based macro-initiator (containing pendant primary amine groups) through the ring opening polymerization of N-carboxy anhydride of γ-benzyl-l-glutamate (BLG-NCA). On average, twenty two l-glutamic acids were grafted from each amino group which was pendant on the polyurethane chain with 10 repeating units. The grafted polymer (PU-PP-1) exhibits self-assembly to produce a hydrogel in a wide pH window ranging from pH 5.0 to 8.0 with a critical gelation concentration (CGC) of 5.0 wt % (w/v) at pH 7.4. Furthermore, circular dichroism study revealed the transition of the α-helix to a random coil upon increasing the pH. Due to the protonation of side chains at pH 4.0, PU-PP-1 adopted an α-helical conformation whereas at pH >8.0 the side-chain carboxylic acid groups of the PLGAs were ionized, leading to the formation of an extended random coil conformation as a result of charge repulsion. Conformational switching was also supported by FTIR spectroscopy.

Synthesis of polyaniline (PANI) and functionalized polyaniline (F-PANI) nanoparticles with controlled size by solvent displacement method. Application in fluorescence detection and bacteria killing by photothermal effect

Polyaniline nanoparticles (PANI-NPs) were easily obtained applying the solvent displacement method by using N-methylpyrrolidone (NMP) as good solvent and water as poor solvent. Different polymers such as polyvinylpyrrolidone (PVP), chondroitin sulfate (ChS), polyvinyl alcohol (PVA), and polyacrylic acid (PAA) were used as stabilizers. Dynamic light scattering and scanning electron microscopy corroborated the size and morphology of the formed NPs. It was demonstrated that the size of nanoparticles could be controlled by setting the concentration of PANI in NMP, the NMP to water ratio, and the stabilizer’s nature. The functionalization and fluorescence of NPs were checked by spectroscopic techniques. Since polyaniline show only weak intrinsic luminescence, fluorescent groups were linked to the polyaniline chains prior to the nanoparticle formation using a linker. Polyaniline chains were functionalized by nucleophilic addition of cysteamine trough the thiol group thereby incorporating pendant primary aliphatic amine groups to the polyaniline backbone. Then, dansyl chloride (DNS-Cl), which could act as an extrinsic chromophore, was conjugated to the amine pendant groups. Later, the functionalized polyaniline was used to produce nanoparticles by solvent displacement. The optical and functional properties of fluorescent nanoparticles (F-PANI-NPs) were determined. F-PANI-NPs in the conductive state (pH < 4) are able to absorb near infrared radiation (NIR) creating a photothermal effect in an aqueous medium. Thus, multifunctional nanoparticles are obtained. The application of NIR on a F-PANI-NPs dispersion in contact with Pseudomonas aeruginosa causes bacterial death. Therefore, the F-PANI-NPs could be tracked and applied to inhibit different diseases caused by pathogenic microorganisms and resistant to antibiotics as well as a new disinfection method to surgical materials.

Reactive compatibilization of poly(methyl acrylate‐ran‐acrylonitrile)/poly(ethylene) blends through amine–anhydride coupling

ABSTRACTMethyl acrylate/acrylonitrile copolymers (MA/AN) were reactively compatibilized as the dispersed phase into poly(ethylene) (PE) for potential hydrocarbon barrier materials. The MA/AN was made reactive by including p‐aminostyrene (PAS), yielding terpolymers (MA/AN/PAS) with pendant primary amine functionality (number average molecular weight = 65–133 kg mol−1, dispersity (Đ)=1.83–2.53, molar composition of PAS in copolymer FPAS = 0.03–0.14, molar composition of AN = FAN = 0.27–0.52). The non‐functional MA/AN and amino functional MA/AN/PAS were each melt blended into PE that was grafted with maleic anhydride (PE‐g‐MAnn) at 200 °C at 70:30 wt % PE‐g‐MAnn:co/terpolymer. After extrusion, the dispersed phase particle size (volume to surface area diameter, ) was coarse (12.6 μm) for the non‐reactive blend whereas it was much lower for the reactive blend ( = 1.2 μm). Coarsening after annealing at 150 °C was slow, but the domain sizes increased only slightly for both cases. The reactive blend was deemed sufficiently stable and thus was suitable as a candidate barrier material for further testing against olefins. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016, 133, 44177.

Controlled Synthesis of Poly(vinylamine)-Based Copolymers by Organometallic-Mediated Radical Polymerization

Living/controlled polymerization methods have enabled the synthesis of numerous (co)polymers with defined compositions and architectures. However, the precision design of poly(vinylamine)-based copolymers remains challenging despite their extensive use in various fields of applications and the clear benefits to finely tune their properties. Here, we report on a two-step strategy for the synthesis of tailor-made poly(vinylamine) derivatives through the organometallic-mediated radical (co)polymerization (OMRP) of N-vinylacetamide and/or N-methylvinylacetamide followed by acid hydrolysis of the acetamide groups. A series of well-defined homopolymers as well as statistical and block copolymers with pendant primary and/or secondary amines having controlled molar masses, compositions, and low dispersities were produced accordingly. The reactivity ratios of the comonomers as well as the composition drift along the chain were determined in order to have a precise idea of the polymer structures. These advances rep...

Exploring amino acid‐tethered polymethacrylates as CO2‐sensitive macromolecules: A concealed property

ABSTRACTCarbon dioxide (CO2)‐responsive polymers have been gaining considerable interest because of their reactions with CO2, giving rise to gas‐switchable properties, which can easily be reversed by mild heating or purging with inert gases. Herein, the synthesis of a series of side‐chain amino acids (alanine, leucine, isoleucine, phenylalanine, tryptophan) appending poly(meth)acrylates carrying primary amine (NH2) groups via reversible addition‐fragmentation chain transfer (RAFT) polymerization method was reported. It was found that alanine, leucine, isoleucine containing polymers displayed solubility–insolubility transition behavior and their associated property changes (solution transmittance, electrical conductivity, pH, zeta potential, and hydrodynamic diameter) in water upon alternate bubbling of CO2/N2 at room temperature. Among the three CO2‐sensitive polymers only leucine based macromolecule was further chain extended with a thermoresponsive motif, di(ethylene glycol) methyl ether methacrylate (DEGMMA), via RAFT polymerization. CO2‐tunable lower critical solution temperature and self‐assembling behavior of the diblock copolymer was carefully examined by UV–vis, 1H NMR spectroscopy, dynamic light scattering (DLS), and field emission‐scanning electron microscopy (FE‐SEM) to establish dual thermo and gas‐tunable flip–flop micellizaion from the as‐synthesized block copolymer. Formation of polyammonium methacrylate bearing bicarbonate as counter anion is responsible for pendant primary amine containing polymer induced CO2‐responsiveness. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016, 54, 2794–2803

Dynamic covalent cross-linked polymer gels through the reaction between side-chain β-keto ester and primary amine groups

A dynamic covalent gel network was constructed via the coupling reaction between the pendant primary amine groups of poly(l-leucine methacryloyloxyethyl ester) (P(H2N-Leu-EMA)) and the side-chain β-keto ester functionalities of poly(2-(acetoacetoxy)ethyl methacrylate) (PAEMA) by varying the molar ratios of P(H2N-Leu-EMA)/PAEMA and the concentration of polymers in different solvents at room temperature. Fourier transform infrared (FT-IR) spectroscopy and solid-state 13C nuclear magnetic resonance (NMR) study confirmed the newly formed enamine bonds in the polymeric gel. Rheological studies showed that the mechanical strength of gels increased with increasing weight percentage (wt.%) of polymers in solution. Furthermore, polymer gels can be transferred to the mixture of starting polymer solutions by regulating the pH of the system, which can be further transformed into the gel state by adding an external base.

Protein covalent immobilization via its scarce thiol versus abundant amine groups: Effect on orientation, cell binding domain exposure and conformational lability

Quantity, orientation, conformation and covalent linkage of naturally cell adhesive proteins adsorbed or covalently linked to a surface, are known to influence the preservation of their subsequent long term cell adhesion properties and bioactivity. In the present work, we explore two different strategies for the covalent linking of plasma fibronectin (pFN) – used as a cell adhesive model protein, onto a polystyrene (PS) surface. One is aimed at tethering the protein to the surface in a semi-oriented fashion (via one of the 4 free thiol reactive groups on the protein) with a heterofunctional coupling agent (SSMPB method). The other aims to immobilize the protein in a more random fashion by reaction between the abundant pendant primary amine bearing amino acids of the pFN and activated carboxylic surface functions obtained after glutaric anhydride surface treatment (GA method). The overall goal will be to verify the hypothesis of a correlation between covalent immobilization of a model cell adhesive protein to a PS surface in a semi-oriented configuration (versus randomly oriented) with promotion of enhanced exposure of the protein's cell binding domain. This in turn would lead to enhanced cell adhesion. Ideally the goal is to elaborate substrates exhibiting a long term stable protein monolayer with preserved cell adhesive properties and bioactivity for biomaterial and/or cell adhesion commercial plate applications. However, the initial restrictive objective of this paper is to first quantitatively and qualitatively investigate the reversibly (merely adsorbed) versus covalently irreversibly bound protein to the surface after the immobilization procedure.Although immobilized surface amounts were similar (close to the monolayer range) for all immobilization approaches, covalent grafting showed improved retention and stronger “tethering” of the pFN protein to the surface (roughly 40%) after SDS rinsing compared to that for mere adsorption (0%) suggesting an added value to the covalent grafting immobilization methods. However no differences in exposure of the cell binding domains were observed (ELISA results) before SDS rinsing, suggesting that pFN protein grafting to the surface is initially kinetically driven be a stochastic random adsorption phenomenon. Covalent grafting acts in the final stage as a process that simply tethers and stabilizes (or freezes) the initial conformation/orientation of the adsorbed protein on the surface. In addition covalent linkage via the SSMPB approach is likely favored by surface-induce exposure of one of the normally hidden free thiol group pair, thus optimizing covalent linkage to the surface.However after SDS rinsing, this “tethering”/”freezing” effect was significantly more prominent for the GA grafting approach (due to greater number of potential covalent links between the protein and the surface) compared to that for the SSMPB approach. This hypothesis was buttressed by the improved resistance to denaturation (smaller conformational lability) for the GA compared to the SMPB approach and improved exposure of the cell binding domain for the former (>50%) even after SDS rinsing.These results are promising in that they suggest covalent tethering of fibronectin to PS substrate in a monolayer range, with significantly improved irreversible protein surface bonding via both approaches (compared to that for mere adsorption). The latter are likely applicable to a wide range of proteins.

Probing the structure-relaxivity relationship of bis-hydrated Gd(DOTAla) derivatives.

Two structural isomers of the heptadentate chelator DO3Ala were synthesized, with carboxymethyl groups at either the 1,4- or 1,7-positions of the cyclen macrocycle. To interrogate the relaxivity under different rotatational dynamics regimes, the pendant primary amine was coupled to ibuprofen to enable binding to serum albumin. These chelators 6a and 6b form bis(aqua) ternary complexes with Gd(III) or Tb(III) as estimated from relaxivity measurements or luminescence lifetime measurements in water. The relaxivity of [Gd(6a)(H2O)2] and [Gd(6b)(H2O)2] was measured in the presence and absence of coordinating anions prevalent in vivo such as phosphate, lactate, and bicarbonate and compared with data attained for the q = 2 complex [Gd(DO3A)(H2O)2]. We found that relaxivity was reduced through formation of ternary complexes with lactate and bicarbonate, albeit to a lesser degree then the relaxivity of Gd(DO3A). In the presence of 100-fold excess phosphate, relaxivity was slightly increased and typical for q = 2 complexes of this size (8.3 mM(-1) s(-1) and 9.5 mM(-1) s(-1), respectively, at 37 °C, 60 MHz). Relaxivity for the complexes in the presence of HSA corresponded well to relaxivity obtained for complexes with reduced access for inner-sphere water (13.5 and 12.7 mM(-1) s(-1) at 37 °C, 60 MHz). Mean water residency time at 37 °C was determined using temperature-dependent (17)O-T2 measurements at 11.7 T and calculated to be (310)τM = 23 ± 1 ns for both structural isomers. Kinetic inertness under forcing conditions (pH 3, competing DTPA ligand) was found to be comparable to [Gd(DO3A)(H2O)]. Overall, we found that the replacement of one of the acetate arms of DO3A with an amino-propionate arm does not significantly alter the relaxometric and kinetic inertness properties of the corresponding Gd complexes; however, it does provide access to easily functionalizable q = 2 derivatives.

Use of the interior cavity of the P22 capsid for site-specific initiation of atom-transfer radical polymerization with high-density cargo loading

Virus-like particles (VLPs) have emerged as important and versatile architectures for chemical manipulation in the development of functional hybrid nanostructures. Here we demonstrate a successful site-selective initiation of atom-transfer radical polymerization reactions to form an addressable polymer constrained within the interior cavity of a VLP. Potentially, this protein-polymer hybrid of P22 and cross-linked poly(2-aminoethyl methacrylate) could be useful as a new high-density delivery vehicle for the encapsulation and delivery of small-molecule cargos. In particular, the encapsulated polymer can act as a scaffold for the attachment of small functional molecules, such as fluorescein dye or the magnetic resonance imaging (MRI) contrast agent Gd-diethylenetriaminepentacetate, through reactions with its pendant primary amine groups. Using this approach, a significant increase in the labelling density of the VLP, compared to that of previous modifications of VLPs, can be achieved. These results highlight the use of multimeric protein-polymer conjugates for their potential utility in the development of VLP-based MRI contrast agents with the possibility of loading other cargos.

Poly(amidoamine)s with pendant primary amines and flexible backbone for enhanced nonviral gene delivery: Transfection and intracellular trafficking

We synthesized poly(amidoamine)s with pendant primary amines and flexible backbone (polymers 1-3) by Michael polyaddition of N-tert-butyloxycarbonyl (N-Boc) protected diamine to 1,6-Bis(acrylamido)hexane, followed by the deprotection of N-Boc under acidic conditions. The physicochemical properties of polymers 1-3, including buffer capacity, DNA-binding capacity, cytotoxicity, particle sizes, and zeta potentials of polycation/DNA complexes, were explored. All the three polymers possess high buffer capacity and excellent DNA-binding capacity. In vitro MTT assay revealed that these synthesized poly(amidoamine)s were less cytotoxic than commercial branched PEI (25 kDa). These poly(amidoamine)s with pendant primary amines and flexible backbone were evaluated as in vitro nonviral gene delivery vectors for 293T and COS-7 cells. All the three polymers exhibited high transfection efficiencies, which were even higher than branched PEI (25 kDa) at optimized conditions. Further evidences from confocal laser scanning microscope (CLSM) demonstrated that the high transfection efficiencies of polymers 1-3 were due to the efficient uptake and intracellular trafficking of plasmid DNA in the cells during the transfection.

Diastereodivergent Asymmetric Sulfa-Michael Additions of α-Branched Enones using a Single Chiral Organic Catalyst

A significant limitation of modern asymmetric catalysis is that, when applied to processes that generate chiral molecules with multiple stereogenic centers in a single step, researchers cannot selectively access the full matrix of all possible stereoisomeric products. Mirror image products can be discretely provided by the enantiomeric pair of a chiral catalyst. But modulating the enforced sense of diastereoselectivity using a single catalyst is a largely unmet challenge. We document here the possibility of switching the catalytic functions of a chiral organic small molecule (a quinuclidine derivative with a pendant primary amine) by applying an external chemical stimulus, in order to induce diastereodivergent pathways. The strategy can fully control the stereochemistry of the asymmetric conjugate addition of alkyl thiols to α-substituted α,β-unsaturated ketones, a class of carbonyls that has never before succumbed to a catalytic approach. The judicious choice of acidic additives and reaction media switches the sense of the catalyst's diastereoselection, thereby affording either the syn or anti product with high enantioselectivity.

ChemInform Abstract: Isolation and Complexation of the cis Isomer of the Pendant Arm Macrocycle 6,13-Dimethyl-1,4,8,11-tetraazacyclotetradecane-6,13- diamine.

The cis isomer of the pendant arm macrocyclic hexaamine 6,13-dimethyl-1,4,8,11-tetraazacyclotetradecane-6,13-diamine (L2) has been isolated for the first time. The ligand has been complexed with cadmium(II) and characterised structurally. The complex [CdL2][ClO4]2 crystallises in the monoclinic space group P21/n, a= 10.238(1), b= 16.445(2), c= 13.106(2)A, β= 103.33(1)°, and Z= 4. The Cd–N bond lengths are not unusual by comparison with those exhibited by typical CdN62+ complexes, compared with the generally short M–N bond lengths that have been observed in sexidentate co-ordinated complexes of the trans isomer L1. Reaction of L1 with cadmium(II) does not yield a hexaamine complex, instead the pendant primary amines are not co-ordinated and the four secondary amines encircle the metal centre.

ChemInform Abstract: Crystallographic and Molecular Mechanics Study of a Cobalt(III) Complex of a Structurally Reinforced Macrocycle.

The complex [CoL6(Cl)][CoCl4]·H2O, where L6 is the reinforced macrocycle 7-amino-7-methyl-1,5,9,13-tetraazabicyclo[11.2.2]heptadecane, has been prepared and its crystal structure determined. The green-black crystals are monoclinic, space group P21/c, with a= 8.778(2), b= 13.344(4), c= 19.380(8)A, β= 98.48(2)°, Z= 4, and a final conventional R= 0.0736. The cobalt is co-ordinated in a planar fashion in the cavity of the macrocycle, with one axial co-ordination site occupied by the pendant primary amine group, and the other by a chloride. The Co–N bond lengths to the tertiary nitrogens of the piperazine bridge of the macrocycle are 2.01(1) and 2.02(1)A, distinctly longer than those [1.97(1)A] to the secondary amines in the cavity of the macrocycle. The Co–N distance to the pendant primary amine is 2.01(1)A, and Co–Cl to the axially co-ordinated chloride trans to the pendant amine group is 2.26(1)A. Molecular mechanics calculations are used to analyse the highly distorted co-ordination sphere around the CoIII, where the N–Co–N angle involving the nitrogens of the piperazine bridge of the macrocycle is only 73.5(4)°. The calculations reproduce the co-ordination geometry around the CoIII well, including the variation in Co–N bond length and the highly distorted N–Co–N angles.

Novel Poly(amidoamine)s with Pendant Primary Amines as Highly Efficient Gene Delivery Vectors

Three poly(amidoamine)s with pendant primary amines were synthesized by Michael polyaddition of a diamine to N,N-methylenebis(acrylamide). The poly(amidoamine)s with primary and tertiary amines possess a high buffer capacity between pH = 5 and 7, which facilitates the escape of polymer/DNA complexes from endosomes according to the 'proton sponge hypothesis'. In vitro cytotoxicity of poly(amidoamine)s depends on the side-chain structure of the polymer. Polymers 1a-1c can condense plasmid DNA by electrostatic interactions to form nanosized polyelectrolyte complexes with a positive surface charge. In vitro transfection results indicate that the transfection efficiency of polymer 1b under optimized conditions is comparable to that of commercial branched PEI 25,000.