Saccharide-branched Cyclodextrins as Targeting Drug Carriers

A synthetic series of heptakis-galactose-branched cyclodextrins (termed CDs) having a longer spacer arm using two amino-caproic acids as an enlarging unit were prepared. Starting with heptakis-amino-β-CD or heptakis-amino-caproic-amide-β-CD, treated with galactosyl-glucono-amide-caproic acid, the new compounds heptakis (Gal-cap1)-CD (4) or heptakis (Gal-cap2)-CD (5) were obtained. The longer galactose spacer arm extremely favors the PNA association. The effect of branch length on K with PNA was enhanced up to 138-fold 3 as well as with DXR enhanced up to 81-fold. Hexakis (Gal-cap2)-CD (6) was prepared and the association constants with rat liver cells were observed to be 2.5 × 10¹⁰ M⁻¹. A multi-high mannose type oligosaccharide branched CD (7) showed a large association constant with DXR up to 1.1 × 10⁹ M⁻¹. The two-dimensional map for the association constants of newly synthesized oligosaccharide-branched CDs toward lectin or liver cells versus the association constants toward a drug (doxorubicin) suggested a method of finding a better targeting drug carrier. The structural effect of the oligosaccharide-CDs showed that the number and length of the branch were dominant factors in designing for enhanced dual recognition.     

Novel titanocene anti-cancer drugs derived from fulvenes and titanium dichloride

Starting from 6-(p−N,N-dimethylanilinyl)fulvene (1a) or 6-(pentamethylphenyl)fulvene (1b) [1,2-di(cyclopentadienyl)-1,2-di(p−N,N-dimethylaminophenyl)ethanediyl] titanium dichloride (2a) and [1,2-di(cyclopentadienyl)-1,2-bis(pentamethylphenyl)ethanediyl] titanium dichloride (2b) and their corresponding dithiocyanato complexes (3a, 3b) were synthesized. Titanocene 2b did not show a cytotoxic effect, but when 2a was tested against pig kidney carcinoma cells (LLC-PK) or human ovarian carcinoma cells (A2780/cp70) inhibitory concentrations (IC₅₀) of 2.7 × 10⁻⁴ and 1.9 ×  10⁻⁴ M, respectively, were observed.     

Inverse Perovskites (Eu3O)E with E = Sn,In – Preparation,Crystal Structures and Physical Properties

The cubic inverse Perovskites (Eu₃O)In and (Eu₃O)Sn were prepared from the metals and Eu₂O₃ or SnO₂, respectively. For (Eu₃O)In the crystal structure analysis was performed on single crystal X‐ray diffraction data (space group , a = 512.79(3) pm, Z = 1, R_gt(F) = 0.022, wR(F²) = 0.044). The data indicated full occupancy on all sites and a fully ordered structure. According to magnetic susceptibility measurements and X‐ray absorption spectroscopic data at the Eu L_III edge both compounds contain europium in the 4f⁷ (Eu²⁺) electronic state. (Eu₃O)In orders ferromagnetically at 185(5) K, (Eu₃O)Sn shows antiferromagnetic order at 31.4(2) K. Both compounds behave as metallic conductors in electrical resistivity measurements. However, (Eu₃O)In may be classified a metal, while (Eu₃O)Sn is more likely a heavily doped degenerated semiconductor or semimetal according to the absolute values of the resistivity.     

Dithiol proteins as guardians of the intracellular redox milieu in parasites: old and new drug targets in trypanosomes and malaria-causing plasmodia

Parasitic diseases such as sleeping sickness, Chagas' heart disease, and malaria are major health problems in poverty-stricken areas. Antiparasitic drugs that are not only active but also affordable and readily available are urgently required. One approach to finding new drugs and rediscovering old ones is based on enzyme inhibitors that paralyze antioxidant systems in the pathogens. These antioxidant ensembles are essential to the parasites as they are attacked in the human host by strong oxidants such as peroxynitrite, hypochlorite, and H2O2. The pathogen-protecting system consists of some 20 thiol and dithiol proteins, which buffer the intraparasitic redox milieu at a potential of -250 mV. In trypanosomes and leishmania the network is centered around the unique dithiol trypanothione (N1,N8-bis(glutathionyl)spermidine). In contrast, malaria parasites have a more conservative dual antioxidative system based on glutathione and thioredoxin. Inhibitors of antioxidant enzymes such as trypanothione reductase are, indeed, parasiticidal but they can also delay or prevent resistance against a number of other antiparasitic drugs.     

Design criteria for molecular mimics of fragments of the β-turn. 1. Cα atom analysis

Peptides represent an extensive class of biologically active molecules. They may be used as leads in the development of novel therapeutic agents provided the pharmacophoric information present within them can be translated into non-peptide analogs that lack the peptide backbone and are stable to proteolysis. This is the rationale for peptidomimetic drug design. Frequently, the -turn has been implicated as a conformation important for biological recognition of peptides. Empirical evidence from known peptidomimetics, coupled with a theoretical model of peptide binding and the observation that glycine and proline residues are common within the -turn, has suggested the design of molecules to mimic placement of between two and four of the side-chains. The moderate number of different -turn conformations, combined with the combinatoric nature of side-chain selection complicates the procedure. In this paper, cluster analysis has been used to classify the arrangement of C_{_} atoms about the various fragments of the -turn. Recombination of the observed patterns provides a general model for the -turn which may be used as an effective screen for potential peptidomimetic scaffolds in chemical databases.     

Cyanidverbrückte Koordinationspolymere aus cis‐ oder trans‐[Ru(tBuNC)4(CN)2] und MnCl2: Zum Einfluß unterschiedlicher Topologien auf die magnetischen Eigenschaften von Materialien

Cyanide Bridged Coordination Polymers from cis‐ or trans‐[Ru(^tBuNC)₄(CN)₂] and MnCl₂: About the Influence of Different Topologies on the Magnetic Properties of Materials The reaction of cis‐ or trans‐[Ru(^tBuNC)₄(CN)₂] with MnCl₂ as an additional transition metal fragment yields the one dimensional coordination polymers {cis‐[Ru(CN)₂(^tBuNC)₄] MnCl₂}_n, ( 1 ), and {trans‐[Ru(CN)₂(^tBuNC)₄]MnCl₂}_n, ( 2 ), with a different arrangement of the metal centers caused by the different stereochemistry of the starting compounds. The variation of the Ru‐C‐N‐Mn geometry nevertheless leads to significant differences in the magnetic properties of 1 and 2 . The coordination polymer derived from trans‐[Ru(^tBuNC)₄(CN)₂] shows a more efficient antiferromagnetic intrachain interaction between the manganese centers compared to the cis‐derivative.     

Factor Xa: Simulation studies with an eye to inhibitor design

Factor Xa is a serine protease which activates thrombin and plays a key regulatory role in the blood-coagulation cascade. Factor Xa is at the crossroads of the extrinsic and intrinsic pathways of coagulation and, hence, has become an important target for the design of anti-thrombotics (inhibitors). It is not known to be involved in other processes than hemostasis and its binding site is different to that of other serine proteases, thus facilitating selective inhibition. The design of high-affinity selective inhibitors of factor Xa requires knowledge of the structural and dynamical characteristics of its active site. The three-dimensional structure of factor Xa was resolved by X-ray crystallography and refined at 2.2 Å resolution by Padmanabhan and collaborators. In this article we present results from molecular dynamics simulations of the catalytic domain of factor Xa in aqueous solution. The simulations were performed to characterise the mobility and flexibility of the residues delimiting the unoccupied binding site of the enzyme, and to determine hydrogen bonding propensities (with protein and with solvent atoms) of those residues in the active site that could interact with a substrate or a potential inhibitor. The simulation data is aimed at facilitating the design of high-affinity selective inhibitors of factor Xa.     

One-dimensional α-MnO2: Trapping chemistry of tunnel structures, structural stability, and magnetic transitions

Highly crystalline one-dimensional (1D) α-MnO₂ nanostructures were synthesized by a hydrothermal method. All samples were characterized by X-ray diffraction, transmission electron microscope, thermogravimetric and differential scanning calorimeter, and infrared spectroscopy. During the formation reactions, the tunnel structure of 1D α-MnO₂ was simultaneously modified by NH₄⁺ species and water molecules. The amount of NH₄⁺ species that were trapped in the tunnels is almost independent on the reaction temperature, while the total water content increased with the reaction temperature. The average diameter of α-MnO₂ nanorods increased from 9.2 to 16.5 nm when the reaction temperature increased from 140 to 220 °C. 1D α-MnO₂ was destabilized by a subsequent high-temperature treatment in air, which is accompanied by a structural transformation to 1D Mn₂O₃ of a cubic structure. At low temperatures, all 1D α-MnO₂ nanorods showed two magnetic transitions that were characterized by a decreased Néel temperature with rod diameter reduction. According to the effective magnetic moments experimentally measured, Mn ions presented in the nanorods were determined to be in a mixed valency of high spin state Mn⁴⁺/Mn³⁺.     

Synthesis, crystal structure and magnetic property of a new nickel selenite chloride: Ni5(SeO3)4Cl2

The new nickel selenite chloride, Ni₅(SeO₃)₄Cl₂, was obtained by high-temperature solid state reaction of NiCl₂, Ni₂O₃ and SeO₂ in a 1:2:4 molar ratio at 700 °C in an evacuated quartz tube. Its structure was established by single-crystal X-ray diffraction. Ni₅(SeO₃)₄Cl₂ crystallizes in the triclinic system, space group P-1 (No. 2) with cell parameters of a=8.076(2), b=9.288(2), c=9.376(2) Å, α=101.97(3), β=105.60(3), γ=91.83(3)° and Z=2. All nickel(II) ions in Ni₅(SeO₃)₄Cl₂ are octahedrally coordinated by selenite oxygens or/and chloride anions (([Ni(1)O₅Cl], [Ni(2)O₄Cl₂], [Ni(3)O₅Cl], [Ni(4)O₆] and [Ni(5)O₄Cl]). The structure of the title compound features a condensed three-dimensional (3D) network built by Ni(II) ions interconnected by SeO₃²⁻ anions as well as Cl⁻ anions. Magnetic property measurements show strong antiferromagnetic interaction between nickel(II) ions.     

Characterization by X-ray diffraction, magnetic susceptibility and Mössbauer spectroscopy of a new alluaudite-like phosphate:: Na4CaFe4(PO4)6

A single crystal of a new sodium calcium iron (III) phosphate, Na₄CaFe₄(PO₄)₆, has been synthesized by a flux method and characterized by X-ray diffraction, Mössbauer spectroscopy and magnetic susceptibility measurements. The compound crystallizes in the monoclinic space group C2/c(a=12.099(5) Å, b=12.480(5) Å, c=6.404(2) Å, β=113.77(3)°, Z=2, R₁=0.022, R_w2=0.066). The crystal structure belongs to the alluaudite type, characterized by the X(2)X(1)M(1)M(2)₂(PO₄)₃ general formula. The open framework results from Fe₂O₁₀ units of edge-sharing FeO₆ octahedra, which alternate with M(1)O₆ octahedra (M(1)=Na+Ca) that form infinite chains. These chains are linked together through the common corners of PO₄ tetrahedra yielding two distinct tunnels of sodium cation occupation. This compound is antiferromagnetic with a Néel temperature of 35 K. Mössbauer parameters are consistent with the structural results.