Spacer Moiety Research Articles

Synthesis, characterization, in vitro and in vivo evaluation of PEGylated oridonin conjugates

Oridonin (ORI), a diterpenoid compound with promising antitumor activity, was proved to possess potent antileukemia efficacies in vitro and in vivo recently. However, the development and application of ORI was limited by its poor solubility and rapid plasma clearance. The purpose of this study was to solve these problems. PEGylated oridonin linked with succinic acid (SA) as spacer moiety (PEG-SA-ORI conjugate) was synthesized. mPEG amines with four specifications of molecular weight (MW) were utilized. All polymeric conjugates showed satisfactory aqueous solubility and in vitro studies implied that the drug solubility and release features of conjugates were relevant to PEGs. The drug solubility increased more when the MW of PEG was lower, while more significant sustained-release effect was shown with higher PEG MW. Moreover, the release behaviors of conjugates showed a pH-sensitive property. In vivo pharmacokinetic studies demonstrated that the elimination half-life was prolonged in comparison with ORI solution. PEGylation could be a promising method to obtain better efficacy in the field of drug delivery system.

Synthesis and Surface Activity of Bisphosphate Gemini Surfactants

AbstractAnionic bisphosphodiester gemini surfactants with two different spacer moieties and varying alkyl chain lengths were synthesized and investigated for their surface active properties. The equilibrium and dynamic surface tension studies were carried out using the Wilhelmy plate technique and maximum bubble pressure method respectively. It was found that these gemini surfactants possess lower critical micellar concentration values, and reduce the surface tension to a greater extent in comparison with the conventional analogues. The efficiency of the synthesized gemini surfactants was also evaluated. The results of surface activities obtained were correlated with the structures of gemini surfactants. The dynamic surface tension measurements showed that the geminis with long chains adsorb very slowly at the air/water interface within the time span of measurements. These gemini surfactants showed low foamability.

ChemInform Abstract: Organic Mixed‐Valence Compounds: A Playground for Electrons and Holes

AbstractReview: 326 refs.

Synthesis and Photophysical Properties of Aryl-Substituted 2-Borylbenzaldimines and Their Extended π-Conjugated Congeners

Novel N-aryl-substituted 2-borylbenzaldimines 6 and related systems with extended π-framework 7 based on two borylbenzaldimine units linked by a spacer moiety were synthesized by condensation reactions of 2-(dimesitylboryl)benzaldehyde 3 with various amines 4 and diamines 5. All compounds were completely characterized including X-ray diffraction, especially in view of Lewis acid-base B-O and B-N interactions. The electronic as well as the photophysical properties of bisimines 7 were determined using cyclic voltammetry, UV/vis, and fluorescence spectroscopy and quantum chemistry. These compounds feature large Stokes shifts and reversible reduction waves. Interestingly, UV irradiation experiments unfold enhanced photostability for compounds 7 with an extended π-skeleton. By use of 1,8-diaminonaphthalene we observed the formation of a hitherto unknown BN-heterocyclic compound 9 fused with a perimidine skeleton. Structural and energetic aspects were evaluated by high level quantum chemical methods (DFT and SCS-MP2-calculations).

Synthesis, structure, EPR, and DFT calculation on dinuclear paddle wheel Cu(II) complexes with bis-chelate rings

A series of diester-dicarboxylic acids, L1H2, L2H2, L3H2, L4H2, and L5H2 and their dinuclear Cu2 complexes [Cu(L1)CH3CN]2 (1), [Cu(L2)H2O]2 (2), [Cu(L3)CH3CN]2 (3), [Cu(L4)EtOH]2 (4), and [Cu(L5)CH3CN]2 (5), were synthesized. The crystal structures obtained for 1, 2, and 4 and the density functional theory optimized structures for 2, 3, and 5 illustrated the formation of tetracarboxylate “paddle wheel” complexes. The phthalyl and diphenyl head groups and the spacer moieties were appropriately altered and the size of the chelate ring expanded from 15-membered in 1 to 21-membered in 5. The dinuclear units have strong Cu–Cu interaction with EPR spectra exploring spin coupled features.

Synthesis of novel porphyrin and chlorin phosphonic acids and their immobilization on metal oxides

In this study an easy and flexible access to porphyrin and chlorin phosphonic acids is presented. Novel types of phosphonic acid terminated porphyrins and chlorins were synthesized starting from commercially available red blood pigment hemin chloride. Phosphonic acid groups were linked to the porphyrinoids by amide coupling via appropriate spacer moieties. Self-assembled monolayers of the synthesized phosphonates on mesoporous TiO2 electrodes of approximately 3 μm thickness were formed. Surface concentrations in a range of 1 to 4 × 10-8 mol.cm-2 could be determined by UV-vis spectroscopy.

Synthesis and characterization of low-molecular-weight azo-acetoxystyrene and azo-naphthalene oligomers via stable free radical polymerization (SFRP)

As an approach toward controlled molecular architecture through stable free radical polymerization (SFRP), we have prepared a series of oligomers of controlled molecular weights (Mn) and low polydispersities (structures 2 and 3, with n values ranging from 2 to 52). Definitive evidence of structure was obtained through MALDI/MS (inter-peak interval of 162 m/z in azo-acetoxystyrene oligomers 2 and 260 m/z in azo-naphthalene oligomers 3, which correspond to the acetoxystyrene (AS) and naphthalenic (Np) repeating units, with corroborative evidence from NMR and GPC. Two synthetic pathways were explored. Pathway 1 yields azo-acetoxystyrene oligomer 2 via SFR addition of a TEMPO-capped unimer 1 to acetoxystyrene. Subsequent reactions would convert 2 into 3. In an alternative pathway 2, SFR addition of 1 to 4-(1-methoxynaphthyl)styrene gives azo-naphthalene oligomer 3 directly. Thus, the present reported methodology for controlled architecture has achieved synthesis of oligomers from low Mn (chlorobenzene, PhCl, solvent) to relatively high Mn (bulk), with incorporation of naphthyl (donor) and azobenzene (acceptor) moieties, as well as spacer moieties, in a controlled manner.

Trypsin immobilization on three monolithic disks for on-line protein digestion

The preparation and characterization of three trypsin-based monolithic immobilized enzyme reactors (IMERs) developed to perform rapid on-line protein digestion and peptide mass fingerprinting (PMF) are described. Trypsin (EC 3.4.21.4) was covalently immobilized on epoxy, carbonyldiimidazole (CDI) and ethylenediamine (EDA) Convective Interaction Media ® (CIM) monolithic disks. The amount of immobilized enzyme, determined by spectrophotometric measurements at 280 nm, was comprised between 0.9 and 1.5 mg per disk. Apparent kinetic parameters K m * and V max * , as well as apparent immobilized trypsin BAEE-units, were estimated in flow-through conditions using N-α-benzoyl- l-arginine ethyl ester (BAEE) as a low molecular mass substrate. The on-line digestion of five proteins (cytochrome c, myoglobin, α 1-acid glycoprotein, ovalbumin and albumin) was evaluated by inserting the IMERs into a liquid chromatography system coupled to an electrospray ionization ion-trap mass spectrometer (LC-ESI–MS/MS) through a switching valve. Results were compared to the in-solution digestion in terms of obtained scores, number of matched queries and sequence coverages. The most efficient IMER was obtained by immobilizing trypsin on a CIM ® EDA disk previously derivatized with glutaraldehyde, as a spacer moiety. The proteins were recognized by the database with satisfactory sequence coverage using a digestion time of only 5 min. The repeatability of the digestion (R.S.D. of 5.4% on consecutive injections of myoglobin 12 μM) and the long-term stability of this IMER were satisfactory since no loss of activity was observed after 250 injections.

X-Ray crystal structure determination of a series of 1-aryl- 2-[3-(3-[2-aryl-1-diazenyl]-1,3-diazepan-1-ylmethyl)-1, 3-diazepan-1-yl]-1-diazenes obtained from the reaction of diazonium salts with mixtures of formaldehyde and 1,4-diaminobutane

A new series of bis-triazenes, the 1-aryl-2-[3-(3-[2-aryl-1-diazenyl]-1,3-diazepan-1-ylmethyl)-1,3-diazepan-1-yl]-1-diazenes has been synthesized from the reaction of diazonium salts with a mixture of 1,4-diaminobutane and formaldehyde. The structures of 1-(p-bromophenyl)-2-[3-{3-[2-(p-bromophenyl)-1-diazenyl]-1,3-diazepan-1-ylmethyl}-1,3-diazepan-1-yl]-1-diazene(1), 1-(p-cyanophenyl)-2-[3-{3-[2-(p-cyanophenyl)-1-diazenyl]-1,3-di azepan-1-ylmethyl}-1,3-diazepan-1-yl]-1-diazene(2), and 1-(p-methoxyphenyl)-2-[3-{3-[2-(p-methoxy-phenyl)-1-diazenyl]-1,3-diazepan-1-ylmethyl}-1,3-diazepan-1-yl]-1 diazene(3) have been unequivocally determined by X-ray crystallography. The new bis-triazenes are important since the structure contains the novel saturated heterocycle, 1,3-diazepane. The general conclusion of this study is that alkanediamines with 3 or 4 carbon atoms in the spacer link between the nitrogen atoms give rise to the linear bicyclic molecules of type 5, in contrast to the case of ethylenediamine (spacer link 2 carbon atoms), which affords molecules of type 6, which exemplify the general cage structure of type 4. The crystal structures of 1, 2 and 3 are compared with the previously reported structure of the hexahydropyrimidine analogue 8a(X=CN); compounds 2 and 8a(X=CN) are homologous with respect to the alkane spacer moiety. The structures of 2 and 8a(X=CN) are very different in one respect; in 2 the aryldiazenyl-1,3-diazepanyl groups are in the s-trans orientation around the central methylene group whereas in 8a(X=CN) the arrangement of the aryldiazenyl-hexahydropyrimidinyl groups is the s-cis orientation. Crystal data: 1 C23H30N8Br2, triclinic, space group P-1, a=8.3979(2), b=10.7828(3), c=14.4692(5) A, α=83.670(1), β=78.662(1), γ=78.758(1)°, V=1256.48(6) A3, for Z=2. 2 C25H30N10, monoclinic, space group P2 1 /n, a=13.4046(6), b=9.4482(4), c=10.6913(4)A, β=103.239(2)°, V=2490.5(2) A3, for Z=4. 3 C25H36N8O2, triclinic, space group P-1, a=8.5223(3), b=10.6913(4), c=14.4034(7)A, α=85.657(2), β=78.731(2), γ=80.153(1)°, V=1266.88(9) A3, for Z=2.

Multivalent glycomimetics: synthesis of nonavalent mannoside clusters with variation of spacer properties

Oligosaccharide mimetics are important tools in the glycosciences. In this work, we have employed spaced glycodendrons for the synthesis of oligomannoside mimetics. Starting from a number of trivalent, branched molecular wedges, the preparation of nonavalent cluster mannosides was accomplished, which were varied with regard to the chemical characteristics of their spacer moieties and spacer lengths. For ligation of the various trivalent dendrons to the nonavalent target molecules peptide coupling was employed.

N,N′-Bis[1-(4-pyridyl)ethylidene]-p-phenylenediamine

The title compound, C20H18N4, is a 4,4′-bipyridyl-type ligand with a long spacer moiety between the two pyridyl functions. Its low-temperature single-crystal analysis reveals that it lies on an inversion center, which is at the center of the 1,4-disubstituted benzene ring.

Molecular dynamics simulations of glycoclusters and glycodendrimers

Protein–carbohydrate recognition plays a crucial role in a wide range of biological processes, required both for normal physiological functions and the onset of disease. Nature uses multivalency in carbohydrate–protein interactions as a strategy to overcome the low affinity found for singular binding of an individual saccharide epitope to a single carbohydrate recognition domain of a lectin. To mimic the complex multi-branched oligosaccharides found in glycoconjugates, which form the structural basis of multivalent carbohydrate–protein interactions, so-called glycoclusters and glycodendrimers have been designed to serve as high-affinity ligands of the respective receptor proteins. To allow a rational design of glycodendrimer-type molecules with regard to the receptor structures involved in carbohydrate recognition, a deeper knowledge of the dynamics of such molecules is desirable. Most glycodendrimers have to be considered highly flexible molecules with their conformational preferences most difficult to elucidate by experimental methods. Longtime molecular dynamics (MD) simulations with inclusion of explicit solvent molecules are suited to explore the conformational space accessible to glycodendrimers. Here, a detailed geometric and conformational analysis of 15 glycodendrimers and glycoclusters has been accomplished, which differ with regard to their core moieties, spacer characteristics and the type of terminal carbohydrate units. It is shown that the accessible conformational space depends strongly on the structural features of the core and spacer moieties and even on the type of terminating sugars. The obtained knowledge about possible spatial distributions of the sugar epitopes exposed on the investigated hyperbranched neoglycoconjugates is detailed for all examples and forms important information for the interpretation and prediction of affinity data, which can be deduced from biological testing of these multivalent neoglycoconjugates.

Immobilization of Bis(imino)pyridyliron(II) Complexes on Silica

The well-known catalyst precursor 2,6-bis[1-((2,6-diisopropylphenyl)imino)ethyl]pyridine (1) is functionalized by various alkenyl groups to yield the corresponding alkenyl-functionalized 2,6-bis[1-((2,6-diisopropylphenyl)imino)ethyl]pyridine ligand. Reaction of these novel functionalized bis(imino)pyridyl ligands with iron(II) chloride results in the formation of precatalysts 5−7, which possess different spacer moieties. The possibility of self-immobilization has been investigated with respect to the chain length of the alkenyl moiety. Additionally, experiments to heterogenize these functionalized iron(II) complexes on modified silica via hydrosilation are presented (8−10). The immobilization has been studied by IR, and the resulting polymers have been characterized by GPC and static light scattering.

ChemInform Abstract: Controlled Drug Release: New Water‐Soluble Prodrugs of an HIV Protease Inhibitor.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Controlled drug release: new water-soluble prodrugs of an HIV protease inhibitor

We designed and synthesized a series of highly water-soluble prodrugs of an HIV protease inhibitor, KNI-727 ( 1), containing tandem-linked two auxiliary units, a solubilizing moiety and a self-cleavable spacer. Prodrugs with an ionized amino group at the solubilizing moiety exhibited a remarkable increase of water-solubility (>10 4 fold) compared to the parent drug 1. These prodrugs released 1 not enzymatically, but chemically via an intramolecular cyclization-elimination reaction through an imide formation in physiological conditions. Diversified rates of parent drug release were observed when the chemical structure of both the solubilizing and the spacer moieties were modified. This new approach for water-soluble prodrugs will enable to control chemically the release of parent drug as well as to maintain high water-solubility.

Orally active cephalosporins. Part 2: Synthesis, structure–activity relationships and oral absorption of cephalosporins having a C-3 pyridyl side chain

A series of 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]cephalosporins having a pyridine ring connected through various spacer moieties at the C-3 position was designed and synthesized and evaluated for antibacterial activity and oral absorption in rats. All compounds showed potent antibacterial activity against Staphylococcus aureus, whereas antibacterial activity against Gram-negative bacteria was markedly influenced by the spacer moiety between the pyridine and cephem nucleus. Oral absorption was influenced by the position of the pyridine nitrogen as well as by the spacer moiety. Among these compounds, FR86830 (14 ), having a 4-pyridylmethylthio moiety at the C-3 position, showed the most well balanced activity and moderate oral absorption.

Synthesis and transfection properties of novel non-toxic monocationic lipids. variation of lipid anchor, spacer and head group structure

This report describes the synthesis and the transfection properties of novel monocationic non-toxic lipids. We have carried out structural variations in all three units of the transfection lipid, the lipid anchor, the spacer moiety and the positively charged head group. Our results lead to the conclusion that systematic modification of structural subunits is a promising way to enhance the transfection efficiency.

Specificity of Pyridinium Inhibitors of the Ubiquinone Reduction Sites in Mitochondrial Complex I

Dual binding sites for pyridinium-type inhibitors in bovine heart mitochondrial complex I have been proposed (Gluck, M. R., Krueger, M. J., Ramsay, R. R., Sablin, S. O., Singer, T. P., and Nicklas, W. J. (1994) J. Biol. Chem. 269, 3167-3174). The marked biphasic nature of the dose-response curve for inhibition of the enzyme by MP-6(N-methyl-4-[2-(p-tert-butylbenzyl)propyl]pyridinium) makes this compound the first selective inhibitor of the two sites (Miyoshi, H., Inoue, M., Okamoto, S., Ohshima, M., Sakamoto, K., and Iwamura, H. (1997) J. Biol. Chem. 272, 16176-16183). Modifications of the structure of MP-6 show that a tert-butyl group on the benzene ring, a methyl group attached to the pyridine nitrogen atom, para-substitution pattern in the pyridine ring, and the presence of a branched structure in the spacer moiety are important for the selective inhibition. On the basis of the structural specificity, we synthesized a selective inhibitor, MP-24 (N-methyl-4-[2-methyl-2-(p-tert-butylbenzyl)propyl]pyridinium), which elicits greater selectivity. Characterization of the inhibitory behavior of MP-24 provided further strong evidence for the dual binding sites model.

Inhibition of Human Cytomegalovirus Proteinase by Salcomine Derivatives

Salcomine, N,N'-bis(salicylidene)ethylene diamino-cobalt (II), and its derivatives were evaluated for their ability to inhibit selectively human cytomegalovirus (HCMV) proteinase activity. The 50% inhibitory concentration (IC50) of salcomine was 1.4 microM for HCMV proteinase, but > 200 microM for three other serine proteinases (trypsin, > 250 microM; chymotrypsin, 206 microM; and elastase, > 250 microM). Two salcomine derivatives also inhibited HCMV proteinase with IC50 values under 2 microM. Studies of the structure-activity relationship of salcomine-related compounds showed that the phenyl moiety and the spacer moiety (distance between the two amines) were instrumental in the inhibition of HCMV proteinase. Moreover, salcomine inhibited the growth of laboratory strain AD169 and three clinical isolates at a 50% effective concentration (EC50) range of 1.92-2.89 microM. These results show that salcomine derivatives are potent and selective inhibitors of HCMV proteinase and HCMV replication in cell culture. Salcomine derivatives appear to be worth pursuing as candidate drugs for the chemotherapy of HCMV infection.

Cyclisation of meta-phenylene-bis-alanine derivatives

The cyclisation of a meta-phenylene-bis-alanine derivative with several different spacer moieties was investigated. A large difference in the ease of cyclisation was observed depending on which path of cyclisation was chosen. NMR studies indicate that the closed-loop molecules adopt folded conformations with the loop directly above the aromatic ring plane.