Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Cyclamates”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 829 records · Page 46Linked to original sources
PubMedDate not supplied

Fast water-exchange Gd3+-(DO3A-like) complex functionalized with aza-15-crown-5 showing prolonged residence lifetime in vivo.

A bis-hydrated Gd3+ complex based on tris acetic acid-1,4,7,10-tetraazacyclododecane (DO3A) that was functionalized with aza-15-crown-5 demonstrated a nearly optimal water-exchanging rate (k(ex) = 3.1 x 10(7) s(-1)) and low acute cytotoxicity. Efficient magnetic resonance signal intensity enhancements and prolonged residence lifetime induced by this small molecular complex in vivo were demonstrated even with one-fifth of the standard dosage used in the clinic.

Animals↗
PubMed2005

Lewis acid properties of zinc(II) in Its cyclen complex. The structure of [Zn(cyclen)(S=C(NH2)2](ClO4)2 and the bonding of thiourea to metal ions. Some implications for zinc metalloenzymes.

The structure of the complex [Zn(cyclen)Tu](NO(3))(2) (1) is reported (cyclen = 1,4,7,10-tetraazacyclododecane; Tu = thiourea): orthorhombic, space group P2(1)2(1)2(1), a = 11.4170(11) A, b = 12.1995(11) A, c = 12.5299(12) A, Z = 4, R = 0.0504. The coordination of the cyclen is the same as that found for other similar Zn(II) complexes, with square pyramidal coordination around the Zn(II) and mean Zn-N bond lengths of 2.16 A. The coordinated Tu occupies the axial coordination site, with Zn-S = 2.31 A. The Zn-S-C-N torsion angle, involving the coordinated Tu, of 75.4 degrees is unusually large, because such torsion angles involving coordinated Tu are normally closer to 0 degrees. The bonding between Zn and S is discussed in terms of overlap with the p orbitals on S, which favors the eclipsed (Zn-S-C-N torsion = 0 degrees) mode of coordination of Tu. The energies of eclipsed and staggered modes (Zn-S-C-N = 90 degrees) of coordination of Tu to metal ions are examined by means of ab initio calculations, using the STO-3G basis set. It is concluded that the rather low formation constant for the Tu complex with Zn(II)/cyclen reported in this work was due to steric effects in 1, which prevent the adoption of the lower energy eclipsed conformation. These steric effects, because of clashes that would occur between Tu in the eclipsed conformation and the cyclen ring, cause the coordination of Tu with a higher energy conformation, with Zn-S-C-N = 75.4 degrees. The latter approaches the high energy staggered conformation that has Zn-S-C-N = 90 degrees. log K(1) values for Cl(-), Br(-), I(-), and CN(-) are reported and shown to be consistent with the binding site on the Zn(II) in the Zn(II)/cyclen complex being softer in the hard and soft acids and bases (HSAB, Pearson 1997) sense than the Zn(II) aqua ion, but not as soft as Zn(II) in triaza macrocycles that promote tetrahedral coordination. The change in HSAB character from intermediate in the Zn(II) aqua ion to softer in the cyclen complex, and softer still in tridentate N-donor ligands in model complexes, and in the Zn(II) active site of carbonic anhydrase as representative of Zn(II) metalloenzymes in general, is discussed in terms of the role of such effects in the functioning of metalloenzymes.

Binding Sites↗
PubMed2006

Sensitized near-infrared lanthanide luminescence from Nd(III)- and Yb(III)-based cyclen-ruthenium coordination conjugates.

The development of novel mixed lanthanide-transition-metal (f-d) based supramolecular self-assemblies made from neodymium- and ytterbium-based tetraamide-functionalized cyclen complexes bearing a single 1,10-phenanthroline moiety coordinating to a RuII(bipy)2 (bipy = bipyridine) unit is described. Excitation of the Ru(II) metal-to-ligand charge-transfer band in water gave rise to long-wavelength sensitized emission from the Yb(III) or Nd(III) centers, observed in the near-infrared.

2,2'-Dipyridyl↗
PubMed2002

NADH model systems functionalized with Zn(II)-cyclen as flavin binding site-structure dependence of the redox reaction within reversible aggregates.

The relative positions and conformations of the prosthetic group FAD and the cofactor NADH have been remarkably conserved within the structurally diverse group of flavin enzymes. To provide a chemical rational for such an obviously optimal relative disposition of the redox partners for efficient reaction we have synthesized NADH models with Zn(II)-cyclen substituents for reversible flavin binding in water. Altogether, four of these model systems with systematically varying spacer length between the recognition site and the redox active dihydronicotinamide were prepared. The binding of these model systems to riboflavin tetraacetate was confirmed by potentiometric pH titration in water and their reaction with flavin was followed by UV-vis spectroscopy in aqueous media under physiological conditions. The measurements reveal a significant rate enhancement of up to 175 times that of an intermolecular reaction. Moreover, a strong dependence of the reaction rate on the spacer length was observed, which clearly shows that within the dynamic reversible assembly only the optimal relative disposition of the redox partners ensures an efficient redox reaction.

Binding Sites↗
PubMed2004

Synthetic creatinine receptor: imprinting of a Lewis acidic zinc(II)cyclen binding site to shape its molecular recognition selectivity.

Molecularly imprinted polymers (MIPs) from polymerizable Lewis acidic zinc(II)cyclen complexes and ethylene glycol dimethyl acrylate have been prepared. For the imprinting process the template molecule creatinine is reversibly coordinated to the zinc atom. The high strength of this interaction allows analyte binding to the MIP from aqueous solution with high affinity. Its pH dependence is used for controlled guest release with nearly quantitative analyte recovery rate. The binding capacity and selectivity profile of the MIP remains constant through several pH controlled binding and release cycles. MIPs missing a suitable metal binding site showed no significant affinity for thymine or creatinine. Flavin adsorbs nonspecifically to all polymers. The imprinting process reverses the binding selectivity of zinc(II)cyclen for creatinine and thymine from 1:34 in homogeneous solution to 3.5:1 in the MIP. Scatchard plot analysis of creatinine binding isotherms reveals uniform binding of the imprint, with fits indicating a one-site model; however, similar analysis for thymine indicate high and low affinity sites. This corresponds to unrestricted coordination sites freely accessible for thymine, e.g., at the polymer surface, and misshaped imprinted sites, which still can accommodate thymine. More than 50% of all binding sites exclusively bind creatinine and are not accessible to thymine. The binding properties of a copolymer of polymerizable zinc(II)cyclen and ethylene glycol dimethyl acrylate missing the creatinine template, which match the binding selectivity of the complex in solution, confirm that the origin of altered selectivities is the imprinting process. With binding ability at physiological pH, the MIPs are applicable for tasks in medicinal diagnostics or biotechnology. Imprinted zinc(II)cyclen complexes provide, like a metalloenzyme binding motif, high binding affinity by reversible coordination while the surrounding macromolecule determines binding selectivity.

Cations, Divalent↗
PubMed2005

Artificial metalloprotease with active site comprising aldehyde group and Cu(II)cyclen complex.

To design artificial proteases that cleave peptide backbones of a wide range of proteins at selected sites, artificial active sites comprising the Cu(II) complex of cyclen (Cu(II)Cyc) and aldehyde group were synthesized on a cross-linked polystyrene. The aldehyde group was employed as the binding site in view of its ability of reversible formation of imine bonds with epsilon-amino groups of Lys residues exposed on the surface of proteins and Cu(II)Cyc as the catalytic group for peptide hydrolysis. The two polymeric artificial metalloproteases synthesized in the present study cleaved all of the protein substrates examined (myoglobin, gamma-globulin, bovine serum albumin, human serum albumin, lysozyme, and ovalbumin), manifesting saturation kinetic behavior. At 50 degrees C and pH 9.0 or 9.5, K(m) was (1.3-22) x 10(-)(4) M, comparable to those of natural proteases, and k(cat) was (6.0-25) x 10(-)(4) s(-)(1), corresponding to half-lives of 4.6-19 min. Intermediacy of the imine complexes formed between the aldehyde group of the catalyst and the epsilon-amino groups of Lys residues of the substrates was confirmed by the trapping experiment with NaB(OAc)(3)H. MALDI-TOF MS of the proteolytic reaction mixtures revealed formation of various cleavage products. Structures of some of the cleavage products were determined by using carboxypeptidase A and trypsin. Among various cleavage sites thus identified, Gln(91)-Ser(92) and Ala(94)-Thr(95) were the major initial cleavage sites in the degradation of myoglobin by the two catalysts. The selective cleavage of Gln(91)-Ser(92) and Ala(94)-Thr(95) was attributed to general acid assistance in peptide cleavage by Tyr(146) located in proximity to the two peptide bonds. Broad substrate selectivity, high cleavage-site selectivity, and high proteolytic rate are achieved, therefore, by positioning the aldehyde group in proximity to Cu(II)Cyc attached to a cross-linked polystyrene.

Aldehydes↗
PubMed2005

Receptor for anionic pyrene derivatives provides the basis for new biomembrane assays.

This study describes a new receptor cyclen 1 capable of strong selective binding of pyrene-based anionic dyes under near-physiological conditions. This receptor comprises four naphthylthiourea groups tethered to a cyclen core via an ester linkage. The complexation behavior of cyclen 1 receptor is characterized by a series of (1)H NMR, microcalorimetry, UV-vis, and fluorometry experiments. The relevance of structural features of this receptor to its recognition function is assessed using control compounds that lack some of the groups found in cyclen 1. The specificity of cyclen 1 toward pyrene-based dyes is assessed through experiments using dyes with different molecular organization. The most important finding was the ability of cyclen 1 to bind efficiently to a pH-sensitive dye pyranine, a dye that is commonly used in various biomembrane assays. The high affinity of cyclen 1 to pyranine, its impermeability to the lipid bilayer membrane, fast kinetics of binding, and ability to quench the pyranine's fluorescence were used as a basis for a new membrane leakage assay. This membrane leakage assay is fully compatible with the commonly applied pH-stat transport assay, and therefore it allows for differentiation of the ion transport and nonselective leakage mechanisms within a single set of experiments. The ability of cyclen 1 to quench the fluorescence of pyranine also finds limited applicability to the detection of endovesiculation.

Anions↗
PubMed2006

A europium complex that selectively stains nucleoli of cells.

A europium complex selectively staining the nucleolus of NIH 3T3, HeLa, and HDF cells is reported. This complex possesses not only the advantage of the long lifetime of europium emission (0.3 ms), but also a chromophore that allows excitation at a relatively long wavelength (lambda(max) = 384 nm) and gives rise to an acceptable quantum yield (9%). The complex can be used both in live cell and fixed cell imaging, giving an average intracellular concentration on the order of 0.5 microM. Strong binding to serum albumin has been demonstrated by examination of the analogous gadolinium complex, studying relaxivity changes with increasing protein concentration. The intracellular speciation of the complex has been examined by circularly polarized emission spectroscopy and is consistent with the presence of more than one europium species, possibly protein bound.

Animals↗
PubMed2006

Structure-taste relationships for disubstituted phenylsulfamate tastants using classification and regression tree (CART) analysis.

Forty-two new disubstituted phenylsulfamates have been synthesized, and 30 of these have been combined with 40 already available from earlier work to create a training database of 70 compounds. On the basis of panel taste data these were divided into three categories, N (nonsweet), N/S (nonsweet/sweet), and (S) sweet, and a "sweetness value" or weighting was also calculated for each compound. Using these 70 compounds as a training set and a series of nine predictors derived from Corey-Pauling-Koltun (CPK) models, calculated from the PC SPARTAN PRO program and Hammett sigma values taken from the literature, a classification and regression tree analysis (CART) was carried out leading to a regression tree that correctly classified 62 of the 70 compounds (89% overall correct classification). The tree's predictive ability varies for the different taste categories, and for nonsweet compounds it is virtually 100%; for nonsweet/sweet compounds it is 66%, and for sweet compounds it is approximately 75%. This tree correctly predicted taste categories for 10 compounds from a test set of 12 randomly selected from among the 42 new compounds (83% correct classification). Therefore, it can be used with a good degree of confidence to predict the tastes of disubstituted phenylsulfamates. For the design of new sweeteners, appropriate values or ranges of the descriptors are derived.

Cyclamates↗
PubMed2004

Comparative in vivo behavior studies of cyclen-based copper-64 complexes: regioselective synthesis, X-ray structure, radiochemistry, log P, and biodistribution.

The in vivo behavior of copper(II)-cyclen complexes was modified via substitution of the parent ligand with two different substituents, 4-tert-butylbenzyl and acetate. This was achieved by using same synthetic strategy (regioselective protection/first alkylation/deprotection/second alkylation) to give nine cyclen derivatives. The X-ray structure of [Cu(2c)Cl]+ (2c = 1-(4-tert-butylbenzyl)-1,4,7,10-tetraazacyclododecane) showed that the chlorine ion from the reaction mixture occupied the remaining apical position of a square pyramidal coordination environment of these Cu-cyclen complexes. Eight out of nine compounds were labeled with 64Cu in high radiochemical purity. log P measurements showed that the lipophilicities of the copper complexes were increased dramatically by attaching hydrophobic substituents on the nitrogen atoms of cyclen. Conversely, as the number of acetate groups increased, the lipophilicity was decreased. The biodistribution of Cu-cyclen complexes was found to be influenced mostly by the overall charge of the complexes rather than their lipophilicity. Positively charged (+2) complexes showed high blood retention at early time points with sluggish clearance from liver by 24 h. The attachment of even one acetate group onto cyclen accelerated blood and liver clearance dramatically compared to +2 charged Cu(II) complexes. Neutral trans-substituted Cu-4 showed the best clearance and lowest retention of doses from all organs most time, followed by -1 charged complex Cu-2. Trans-substituted complexes structure isomers Cu-3 and Cu-4 showed better clearance and lower retention from all organs than their cis-counterparts Cu-5 and Cu-6.

Animals↗
PubMed1999

New bicyclam-AZT conjugates: design, synthesis, anti-HIV evaluation, and their interaction with CXCR-4 coreceptor.

We report the synthesis of mono- and bis-tetraazamacrocycle-AZT conjugates. All new compounds were screened for their ability to inhibit HIV-1 replication in MT4 cell line and were compared to AZT alone. It appears that N-protected covalent prodrugs are equipotent to AZT as inhibitor of HIV replication, while N-deprotected analogues exhibit both higher activity and selectivity against HIV-infected cells. The most active antiviral compounds 27, 28, 34, and 35 were then tested for their binding capability to CXCR-4 receptor. N-Boc analogues 27 and 34 were only weakly effective; in contrast, N-deprotected conjugates 28 and 35 were antagonists to 12G5 mAb binding until 0.05 and 5 microg/mL, respectively. The stability of compound 28 in human plasma was evaluated, and half-life was found to be approximately 8 h in the described conditions. All these results seem to demonstrate the confidence of our prodrug approach, with analogue 28 emerging as the best candidate as lead compound in HIV-1 polytherapy perspective.

Anti-HIV Agents↗
PubMed1999

Synthesis and structure-activity relationships of phenylenebis(methylene)-linked bis-azamacrocycles that inhibit HIV-1 and HIV-2 replication by antagonism of the chemokine receptor CXCR4.

Bis-tetraazamacrocycles such as the bicyclam AMD3100 are a class of potent and selective anti-HIV-1 and HIV-2 agents that inhibit virus replication by binding to the chemokine receptor CXCR4, the co-receptor for entry of X4 viruses. With the aim of optimizing the anti-HIV-1 and HIV-2 activity of bis-azamacrocycles, a series of analogues were synthesized which contain neutral heteroatom (oxygen, sulfur) or heteroaromatic (of lower pK(a) than a secondary amine) replacements for the amino groups of AMD3100. The introduction of one or more heteroatoms such as oxygen or sulfur into the macrocyclic ring of p-phenylenebis(methylene)-linked dimers (to give N(3)X or N(2)X(2) bis-macrocycles) gave analogues with substantially reduced anti-HIV-1 (III(B)) and anti-HIV-2 (ROD) potency. In addition, the bis-sulfur analogue was also markedly more cytotoxic to MT-4 cells. However, bis-tetraazamacrocycles featuring a single pyridine group incorporated within the macrocyclic framework exhibited anti-HIV-1 and HIV-2 potency comparable to that of their saturated, aliphatic counterparts. The p-phenylenebis(methylene)-linked dimer of the py[14]aneN(4) macrocycle inhibited HIV-1 replication at a 50% effective concentration (EC(50)) of 0.5 microM while remaining nontoxic to MT-4 cells at concentrations approaching 200 microM. A series of analogues containing macrocyclic heteroaromatic groups of varying pK(a) were also synthesized, and their ability to inhibit HIV replication was evaluated. Replacing the pyridine moiety of the py[14]aneN(4) macrocyclic ring with pyrazine or pyridine groups substituted in the 4-position (with electron-withdrawing or -donating groups) either reduced antiviral potency or increased cytotoxicity to MT-4 cells. Finally, we synthesized a series of analogues in which the ring size of the bis-pyridyl macrocycles was varied between 12 and 16 members per ring including the py[iso-14]aneN(4) ring system, an isomer of the py[14]aneN(4) macrocycle. The p-phenylenebis(methylene)-linked dimer of the py[iso-14]aneN(4) (AMD3329) displayed the highest antiviral activity of the bis-azamacrocyclic analogues reported to date, exhibiting EC(50)'s against the cytopathic effects of HIV-1 and HIV-2 replication of 0.8 and 1.6 nM, respectively, that is, about 3-5-fold lower than the EC(50) of AMD3100. AMD3329 also inhibited the binding of a specific CXCR4 mAb and the Ca(2+) flux induced by SDF-1alpha, the natural ligand for CXCR4, more potently than AMD3100. Furthermore, AMD3329 also interfered with virus-induced syncytium formation at an EC(50) of 12 nM.

Anti-HIV Agents↗
PubMed2005

Cholesterol-armed cyclens for helical metal complexes offering chiral self-aggregation and sensing of amino acid anions in aqueous solutions.

Cholesterol-armed cyclens worked as octadentate receptors for Na+, Ca2+, and Y3+ complexes in which four chiral cholesterol-functionalized sidearms were bundled and asymmetrically twisted above cyclen-metal complex platforms. Since the resulting helical metal complexes included chiral, hydrophobic cholesterol residues and charged, hydrophilic metal sites as well as asymmetric coordination geometries, they exhibited unique amphiphilic properties and provided chiral self-aggregates in aqueous solutions. Light scattering, fluorescence, and TEM characterizations demonstrated that Na+ complex with cholesterol-armed cyclen gave a particularly stable self-aggregate in aqueous solution and offered supramolecular environments effective for sensing and detection of amino acid anions. Various dansylamino acid derivatives (dansyl = 5-(dimethylamino)-1-naphthalenesulfonyl) were nicely accommodated in the helicate aggregates to give highly enhanced fluorescence signals, which could be detected by the naked eye at 10(-7) mol/L level. Their inclusion behaviors were analyzed by a Langmuir-type equation, indicating that enantiomer-selective inclusion occurred. MM/MD calculations and circular dichroism (CD) studies further suggested that cholesterol-armed cyclen helicates have chiral and hydrophobic cavities upon self-aggregation, in which the dansylamino acid anions were specifically accommodated. Since these helicates exhibited nonselective binding abilities in solvent extraction experiments of dansylamino acid anions, uncommon chiral recognition and sensing functions were generated by supramolecular alignments of the chiral metal helicates in the aqueous solutions.

Amino Acids↗
PubMed2005

Asymmetric indolylmaleimide derivatives and their complexation with zinc(II)-cyclen.

The spectroscopic properties of two asymmetric indolylmaleimide derivatives, 4-bromo-3-(1'H-indol-3'-yl)maleimide and 4-methyl-3-(1'H-indol-3'-yl)maleimide, are investigated. The bromo derivative was crystallized and its X-ray structure was determined. Both compounds are strongly colored while their separate components (indole and maleimide) absorb in the UV region only. To understand the ground- and excited-state behavior, the photophysical properties of the two compounds were studied in detail by steady state and time-resolved absorption and emission spectroscopy. Their solvatochromic behavior was investigated by using the Kamlet-Taft approach, which indicates some charge transfer (CT) character in the excited state. Nano- and femtosecond transient absorption spectroscopy was used for the identification and investigation of the CT state. Furthermore, the effect of the complexation with zinc(II) 1,4,7,11-tetraazacyclododecane (Zn-cyclen) on the photophysical properties of these two compounds was studied. An enhancement of the fluorescence intensity upon self-assembly (up to 90 times) and high association constants were observed, which illustrate the potential use of these compounds as luminescent sensors. DFT calculations indicate that HOMO-1 to LUMO excitation is mainly responsible for the charge transfer character and that this transition changes its character drastically when Zn-cyclen complexation occurs, thus giving it sensor properties.

Computer Simulation↗
PubMed2006

One- and two-photon absorption and emission properties of a Zn(II) chemosensor.

This paper presents the synthesis and two photon-induced absorption (TPA) properties of a functionalized distyrylbenzene (DSB) 1 containing a tetra-azacyclododecane (cyclen) receptor for Zn(II). The influence of Zn(II) on one- and two-photon absorption characteristics of 1 has been investigated in dimethyl sulfoxide. The experiments show that the TPA action spectrum of uncomplexed 1, at 750 nm employing nanosecond-long excitation pulses, is 5 times more intense than that of the complexed form. This moderate contrast between the bound and unbound species confirms, however, the potential of this design scheme for the development of molecular structures with enhanced sensitivity and contrast to be used as Zn(II) sensors through TPA-induced fluorescence microscopy.

Absorption↗