Jørn B. Christensen

Dendrimers in Medicine: Therapeutic Concepts and Pharmaceutical Challenges

Dendrimers are three-dimensional macromolecular structures originating from a central core molecule and surrounded by successive addition of branching layers (generation). These structures exhibit a high degree of molecular uniformity, narrow molecular weight distribution, tunable size and shape characteristics, as well as multivalency. Collectively, these physicochemical characteristics together with advancements in design of biodegradable backbones have conferred many applications to dendrimers in formulation science and nanopharmaceutical developments. These have included the use of dendrimers as pro-drugs and vehicles for solubilization, encapsulation, complexation, delivery, and site-specific targeting of small-molecule drugs, biopharmaceuticals, and contrast agents. We briefly review these advances, paying particular attention to attributes that make dendrimers versatile for drug formulation as well as challenging issues surrounding the future development of dendrimer-based medicines.

In situ scanning tunnelling spectroscopy of inorganic transition metal complexes

Redox molecules with equilibrium potentials suitable for electrochemical control offer perspectives in nanoscale and single-molecule electronics. This applies to molecular but also towards higher sophistication such as transistor or diode function. Most recent nanoscale or single-molecule functional systems are, however, fraught with operational limitations such as cryogenic temperatures and ultra-high vacuum, or lack of electrochemical potential control. We report here cyclic voltammetry (CV) using single-crystal Au(111)- and Pt(111)-electrodes and electrochemical in situ scanning tunnelling microscopy (STM) of a class of Os(II)/(III)- and Co(II)/(III)-complexes, the former novel molecular electronics. The complexes are robust, with ligand groups suitable for linking the complexes to the Au(111)- and Pt(111)-surfaces via N- and S-donor atoms. The data reflect monolayer behaviour. Interfacial ET of the Os-complexes is fast, kET(0) > or = 10(6) s(-1), while the Co-complex reacts much more slowly, kET(0) approximately (1-3) x 10(3) s(-1). In STM of the Os-complexes shows a maximum in the tunnelling current/overpotential relation at constant bias voltage with up to 50-fold current rise. The peak position systematically the bias voltage and equilibrium potential, in keeping with theoretical frames for two-step electron transfer (ET) of in situ STM of redox molecules. The molecular conductivity behaves broadly similarly. The Co-complex also shows a tunnelling spectroscopic feature but much weaker than the Os-complexes. This can be ascribed much smaller interfacial ET rate constant, again caused by large intramolecular nuclear reorganization and weak electronic coupling to the substrate electrode. Overall the has mapped the properties of target molecules needed for stable electronic switching, possible importance in molecular electronics towards the single-molecule level, in room temperature condensed matter environment.

Organic Light‐Emitting Diodes from Symmetrical and Unsymmetrical π‐Extended Tetraoxa[8]circulenes

The understanding and development of molecular electronics depends on the discovery and exploitation of new pextended organic materials. One area of interest is the design of small molecules that are suitable as the fluorescent component in blue organic light-emitting diodes (OLEDs). OLEDs based on small organic molecules or conjugated polymers have been explored for applications in full-colour flat-panel displays, since the seminal work by the group at Kodak. Some classes of low-mass blue-emitting materials have been exploited, such as spirobifluorenes, oligofluorenes, siloles and distyrylarylenes, but the introduction of completely new structural motifs remain scarce. To this end, we report the acid-mediated condensation of a 2,3-diACHTUNGTRENNUNGalkyl-1,4-benzoquinone with 1,4-naphthoquinone to produce a series of highly soluble p-extended tetraoxa[8]circulenes (Figure 1) as well as the application of these materials in blue OLEDs. Tetraoxa[8]circulene (4 B) is a planar heteroaromatic compound formed in trace amounts by treating 1,4-benzoquinone with strong acids. The structure of the tetraoxa[8]circulene framework was deduced by means of mass spectrometry of the all-naphthalene tetraoxa[8]circulene (4 N) by Erdtman and Hçgberg, and was later confirmed by single-crystal X-ray crystallography. It became clear that when one side of the 1,4-benzoquinone was substituted, either by using 1,4-naphthoquinone or a 2,3-disubstituted1,4-benzoquinone, the tetraoxa[8]circulene was a major product upon acid treatment. More recently a series of liquid-crystalline tetraoxa[8]circulenes were synthesised by attachment of linear alkyl chains to the tetraoxa[8]circulene framework. That work also introduced a relatively mild method for the cyclisation reaction: treatment of the quinone with BF3·OEt2 in boiling CH2Cl2. The tetraoxa[8]circulene has been suggested as an intercalator for DNA. Rathore and co-workers used this synthetic protocol to prepare new stable radical cation salts based on tetraoxa[8]circulenes. From a synthetic and a materials point of view, the exploration of p-extended tetraoxa[8]circulenes is of interest. As the processing ability of large aromatic materials and polymers relies on solubility in organic solvents, the development of tetraoxa[8]circulenes based on 2,3-dialkyl-1,4-ben[a] Dr. C. B. Nielsen, T. Brock-Nannestad, Dr. T. K. Reenberg, Dr. P. Hammershøj, Dr. J. B. Christensen, Dr. M. Pittelkow Department of Chemistry, University of Copenhagen Universitetsparken 5, 2100 Copenhagen Ø (Denmark) E-mail : pittel@kiku.dk [b] Dr. J. W. Stouwdam Laboratory of Macromolecular and Organic Chemistry Eindhoven University of Technology, P. O. Box 513 5600 MB Eindhoven (The Netherlands) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201002261. Figure 1. Structure of symmetrical and unsymmetrical p-extended tetraACHTUNGTRENNUNGoxa[8]circulenes.

Surface modification of PAMAM dendrimer improves its biocompatibility

Modification of dendrimer surface groups is one of the methods available to obtain compounds characterized by reduced toxicity. This article reports results of preliminary biocompatibility studies of a modified polyamidoamine dendrimer of the fourth generation. Reaction with dimethyl itaconate resulted in transformation of surface amine groups into pyrrolidone derivatives. Interaction of the modified dendrimer with human serum albumin (HSA) was analyzed. The influence of the dendrimer on mouse neuroblastoma cell line viability and its hemolytic properties were also investigated. The binding constant between analyzed dendrimer and HSA was found to be equal to 1.2 × 10(5) ± 0.2 × 10(5) M(-1). Small changes in HSA secondary structure were observed. The analyzed dendrimer revealed minor toxic activity, as diminishment in cell viability was observed only for dendrimer concentrations higher than 2 mg/mL. Moreover, under the applied experimental conditions, no hemolytic activity was observed. Those observations point to the potential of the analyzed compound for further studies toward its applicability in nanomedicine.

NMR in commensurate and incommensurate spin density waves

We present 13C NMR lineshapes and spin lattice relaxation measurements of (TMTTF)2Br and (TMTSF)2PF6 in the spin density wave (SDW) state. We confirm that (TMTSF)2PF6 has an incommensurate SDW and show that the phason mode is dominant in the relaxation. We prove that (TMTTF)2Br is commensurate and estimate the SDW amplitude. No phason contribution to the relaxation is observed in this compound. The implications for theory are discussed.

Modified PAMAM dendrimer with 4-carbomethoxypyrrolidone surface groups reveals negligible toxicity against three rodent cell-lines

UNLABELLED Modification of the surface groups of dendrimers is one of the methods to improve their biocompatibility. This article presents results of experiments related to the toxicity of a modified polyamidoamine (PAMAM) dendrimer of the fourth generation with 4-carbomethoxypyrrolidone surface groups (PAMAM-pyrrolidone dendrimer). The cytotoxic activity of the dendrimer was tested on Chinese hamster fibroblasts (B14), embryonic mouse hippocampal cells (mHippoE-18) and rat liver derived cells (BRL-3A). The same cell lines were used to investigate the influence of pyrrolidone dendrimer on the mitochondrial membrane potential, intracellular ROS level and its ability to induce apoptosis or necrosis. The analyzed dendrimer showed only minor toxicity and no ability to induce apoptosis. The most important finding is the lack of influence of the PAMAM-pyrrolidone dendrimer on intracellular ROS level and mitochondrial membrane potential. FROM THE CLINICAL EDITOR The authors demonstrate that pyrrolidone-functionalized PAMAM dendrimers have very low toxicity in the tested cell lines, as evidenced by no alteration of mitochondrial membrane potential and no increase of ROS production.

Slow alkyl, alkene, and alkenyl loss from primary alkylamines: Isomerization of the low-energy molecular ions prior to fragmentation in the μsec timeframe

Abstract Isomerization of the molecular ion precedes alkyl radical elimination from many primary aliphatic amines. Rearrangement of the carbon skeleton is initiated by 1,5-hydrogen abstraction by the -NH 2 +· and converts primary-alkyl amines to sec - and tert -alkyl amines; fragmentation is then by α-cleavage of the rearranged molecular ions. Isomerization is also encountered for amines branched at the α-carbon atom. The elimination of propene from n -pentylamine and of a butenyl radical from neo -pentylamine is discussed. Remote (δ or e) cleavage does not contribute to the low-energy reactions.

Tetramethyl Fluoro Formamidinium Hexafluorophoshate – An Improved Synthesis and Some New Uses.

Abstract A non-phosgene, cheap synthesis of Tetramethyl Fluoro Formamidinium Hexafluorophosphate (TFFH) has been developed, and TFFH has been shown to be an useful reagent for preparation of isothiocyanates and hydrazides.

Thioridazine protects the mouse from a virulent infection by Salmonella enterica serovar Typhimurium 74

When administered to mice at doses of 100microg/mouse and 200microg/mouse, thioridazine (TDZ) significantly protected animals from the lethality produced by a virulent strain of Salmonella enterica serovar Typhimurium and reduced the number of bacteria retrieved from the spleen, liver and heart blood. The protection conferred by TDZ against a virulent Salmonella infection is hypothesised to be due to a reduction in the 55kDa virulence protein of the outer membrane of the organism, as this protein is almost totally absent when the organism is exposed to the phenothiazine. It is further hypothesised that the reduction in the 55kDa virulence factor renders the organism susceptible to the action of hydrolytic enzymes of the neutrophil phagolysosome, whereas in the absence of exposure to TDZ intracellular ingestion and localisation of the phagocytosed bacterium does not result in killing owing to rapid induction of the two-step PmrA/B regulon that results in the eventual synthesis and insertion of lipid A into the nascent lipopolysaccharide layer of the outer membrane.

Copper(II) complexes with 4-carbomethoxypyrrolidone functionalized PAMAM-dendrimers: an EPR study.

The internal flexibility and interacting ability of PAMAM-dendrimers having 4-carbomethoxypyrrolidone-groups as surface groups (termed Gn-Pyr), which may be useful for biomedical purposes, and ion traps were investigated by analyzing the EPR spectra of their copper(II) complexes. Increasing amounts (with respect to the Pyr groups) of copper(II) gave rise to different signals constituting the EPR spectra at room and low temperature corresponding to different coordinations of Cu(2+) inside and outside the dendrimers. At low Cu(2+) concentrations, CuN4 coordination involving the DAB core is preferential for G3- and G5-Pyr, while G4-Pyr shows a CuN3O coordination. CuN2O2 coordination into the external dendrimer layer was also contributing to G3- and G4-Pyr spectra. The structures of the proposed copper-dendrimer complexes were also shown. G4-Pyr displays unusual binding ability toward Cu(II) ions. Mainly the remarkably low toxicity shown by G4-Pyr and its peculiar binding ability leads to a potential use in biomedical fields.