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PubMed1999

Quantitative determination of clenbuterol enantiomers in human plasma by high-performance liquid chromatography using the macrocyclic antibiotic chiral stationary phase teicoplanin.

We report a method for the high-performance liquid chromatographic (HPLC) chiral separation of racemic clenbuterol in human plasma. Human plasma was spiked with stock solutions of clenbuterol hydrochloride and practolol as the internal standard. Following a liquid-liquid extraction procedure with 10% (+/-)-2-butanol/isopropyl ether under alkaline conditions, the dried samples were reconstituted in methanol and chromatographed using a macrocyclic antibiotic chiral stationary phase (CSP) known as Chirobiotic T(trade mark) (teicoplanin). The mobile phase composition was methanol:acetonitrile (70:30, v/v), containing 0.3% (v/v) acetic acid and 0.2% (v/v) triethylamine. The resulting chromatogram achieved baseline separation for the clenbuterol enantiomers. Calibration curves (peak area ratio vs plasma concentration, n = 10) were constructed for the (-)-R-and (+)-S-clenbuterol enantiomers with a plasma concentration range of 0. 25-10 microM. The correlation coefficient (r) range was 0.99988-0. 99999 (mean = 0.99999). The lowest concentration measured was 0.25 microM. Inter- and intra-assay variation was determined for the lowest, medium and highest plasma concentration (0.25, 2 and 10 microM) by calculating the analytical recoveries with a range of 96-104%. The percentage recoveries for the clenbuterol enantiomers were 88.4-102% over the concentration range used. Detailed methodology is presented.

Chromatography, High Pressure Liquid↗
PubMedDate not supplied

Molecular recognition by natural macrocycles. I. d-tubocurarine as a host molecule for organic anions.

The binding of 8-anilino-1-naphthalenesulfonate and 15 anions of substituted benzoic, aliphatic dicarboxylic, and N-acetyl-alpha-amino acids to a macrocyclic alkaloid d-tubocurarine in aqueous solution has been studied by fluorometry, conductometry, and 1H NMR. The binding constants vary from ca. 50 to 3300 M-1 depending on the guest structure, charge and hydrophobicity. The results of fluorescence and NMR studies show that the host-guest complexation of the anions of aromatic acids involves the formation of a salt bridge between the quaternary nitrogen of the alkaloid and the anionic group of the guest as well as hydrophobic/Van der Waals interactions between the guest and host aromatic moieties. The binding of dianions of aliphatic dicarboxylic acids most probably is purely electrostatic. In general, d-tubocurarine possesses binding ability comparable to that of synthetic cyclophanes. It binds enantiospecifically anions of N-acetyl-alpha-amino acids and discriminates between positional isomers of anions of hydroxy and carboxy substituted benzoic acids.

Anions↗
PubMed1998

Highly enantioselective HPLC separations using the covalently bonded macrocyclic antibiotic, ristocetin A, chiral stationary phase.

The macrocyclic glycopeptide, ristocetin A, was covalently bonded to a silica gel support and evaluated as a liquid chromatographic (LC) chiral stationary phase (CSP). Over 230 racemates were resolved in either the reversed-phase mode, the normal-phase mode, or the polar-organic mode. The retention behavior and selectivity of this CSP were examined in each mode. Optimization of separations on this column is discussed. The ristocetin A CSP appeared to be complimentary to other glycopeptide CSPs (i.e., vancomycin and teicoplanin). Column stability was excellent. The CSP was not irreversibly altered when going from one mobile phase to another.

Anti-Bacterial Agents↗
PubMed2000

Macrocyclization of alpha-(alkynyloxy)silyl-alpha-diazoacetates by inter-/intramolecular

Thermally induced intra-/intermolecular [3 + 2] cycloaddition reaction sequences of alpha-(alkynyloxy)silyl-alpha-diazoacetates 1 lead to [3.3](1,4)pyrazolophanes (2)2 and higher cyclooligomers thereof [(2)n, n > 2]. In most cases, the cyclodimer was isolated by crystallization, while a complete separation of the mixture of the higher cyclooligomers was not possible. Solid state structures of cyclodimers (2b)2 and (2c)2, cyclotrimer (2b)3, and cyclotetramer (2e)4 were determined by X-ray diffraction analysis. Field-desorption mass spectra were used to characterize the cyclooligomer mixtures. The relative amounts of the cyclooligomers depend on the substitution pattern of the diazo compound. The cyclooligomerization reactions reported herein demonstrate, for the first time, the involvement of diazo functions in macrocyclization reactions via 1,3-dipolar cycloaddition.

Journal Article↗
PubMed1999

Enantiomeric separations of dansyl amino acids using the macrocyclic antibiotic A35512B as a chiral selector in capillary electrophoresis.

The macrocyclic antibiotic A35512B was examined as a chiral selector for capillary electrophoresis (CE) using thirteen racemic dansyl amino acids as test analytes. The chiral selectivity of A35512B was evaluated as a function of the run buffer pH, antibiotic concentration, and organic modifier composition. After optimizing these parameters, the macrocylic antibiotic A35512B provided high resolutions of all the enantiomers for the thirteen dansyl amino acids tested in this study.

Amino Acids↗
PubMed2001

Synthesis and biological evaluation of nonylprodigiosin and macrocyclic prodigiosin analogues.

Nonylprodigiosin (4) and various of its analogues have been prepared by Suzuki cross-coupling reactions of a well accessible pyrrolyl triflate with (hetero)aryl boronic acid derivatives bearing alkenyl side chains. The resulting alkenes or dienes were subjected to metathesis dimerization or ring-closing metathesis (RCM) reactions, respectively, by using a ruthenium indenylidene complex as the catalyst. The biological activity of the products thus obtained was tested in two different assays monitoring i) the proliferation of murine spleen cells induced by lipopolysaccharides (LPS) and concanavalin A (Con A), and ii) the vacuolar acidification of baby hamster kidney (BHK) cells. Compounds 4 and 21 suppressed Con A-induced T-cell proliferation much more potently than LPS-induced B-cell proliferation. Furthermore, compounds 4 and 26 markedly inhibited vacuolar acidification, although other compounds exhibited no or only marginal effects. Thus, the immunosuppressive activity of prodigiosins toward T-cell proliferation seems to be mediated through cellular targets distinct from vacuolar acidification, and the prodigiosin analogues might be powerful tools to dissect these biological responses. The X-ray crystal structure of the macrocyclic product 25 has been determined, showing that the replacement of one pyrrole ring of the parent compound 4 by a phenyl group does not alter the overall electronic features of the remaining heterocyclic ring system of these alkaloids.

Animals↗
PubMed2000

A flexible cyclophane: design, synthesis, and structure of a multibridged tris-tetrathiafulvalene (TTF) macrocycle

The tris-tetrathiafulvalene (TTF) macrocycles 3 with a large end-cavity were effectively synthesized from the readily available tetrakis(cyanoethylthio)TTF by means of a selective deprotection/realkylation sequence followed by an intramolecular coupling reaction. Crystar structure analyses revealed that the neutral molecules include two (3a) or one chloroform molecule (3b) as solvent of crystallization inside the cavity, whereas the I3- salt of 3b, obtained by electrocrystallization, has a molecular structure which is different from that of the neutral molecule in that the cavity has completely collapsed.

Journal Article↗
PubMed2000

Synthesis and an X-ray structure of soluble phenylacetylene macrocycles with two opposing bipyridine donor sites

The synthesis of the shape-persistent macrocycles 10a and 10b with two bipyridine units in opposing sides by Hagihara/Sonogashira cross-coupling chemistry of suitably functionalized building blocks is reported. X-ray analysis of single crystals of 10b shows a layered structure with channels filled with solvent molecules and parts of the flexible chains. with which the cycle is decorated for solubility reasons.

Journal Article↗
PubMed2001

Relaxivity and water exchange studies of a cationic macrocyclic gadolinium(III) complex.

We conducted relaxometric and water exchange studies of the cationic [Gd((S,S,S,S)-THP)(H2O)]3+ complex (THP 1,4,7,10-tetrakis(2-hydroxy-propyl)-1,4,7,10-tetraazacyclododecane). While the NMRD profiles obtained are typical for DOTA-like complexes (DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate), variable-temperature 7O NMR investigations revealed a relatively high water exchange rate (k(298)(ex) = 1.89 x 10(7) s(-1)). These results differ from those reported for other cationic tetraamide macrocyclic Gd(III) complexes, which exhibit characteristically low exchange rates. Since the low exchange rates are attributed partially to the geometry of the M isomer (square antiprismatic) in the tetraamide derivatives, the atypical water exchange rate observed in [Gd((S,S,S,S)-THP-(H2O)]3+ may result from a twisted square antiprismatic structure in this complex and from the relatively high steric strain at the water coordination site as a result of the presence of methyl groups at the alpha-position with respect to the Gd(III)-bound O atoms of THP.

Journal Article↗
PubMed2002

Templating and selection in the formation of macrocycles containing [[P(micro-NtBu)(2)](micro-NH)](n) frameworks: observation of halide ion coordination.

Amination of [ClP(micro-NtBu)](2) (1) using NH(3) in THF gives the cyclophospha(III)zane dimer [H(2)NP(micro-NtBu)](2) (2), in good yield. (31)P NMR spectroscopic studies of the reaction of 1 with 2 in THF/Et(3)N show that almost quantitative formation of the cyclic tetramer [[P(micro-NtBu)](2)(micro-NH)](4) (3) occurs. The remarkable selectivity of this reaction can (in part) be attributed to pre-organisation of 1 and 2, which prefer cis arrangements in the solid state and solution. The macrocycle 3 can be isolated in yields of 58-67 % using various reaction scales. The isolation of the major by-product of the reaction (ca. 0.5-1 % of samples of 3), the pentameric, host-guest complex [[P(micro-NtBu)(2)](2)(micro-NH)](5)(HCl).2 THF] (4.2 THF), gives a strong indication of the mechanism involved. In situ (31)P NMR spectroscopic studies support a stepwise condensation mechanism in which Cl(-) ions play an important role in templating and selection of 3 and 4. Amplification of the pentameric arrangement occurs in the presence of excess LiX (X=Cl, Br, I). In addition, the cyclisation reaction is solvent- and anion-dependent. The X-ray structures of 2 and 4.2 THF are reported.

Journal Article↗
PubMed2002

Heterodinuclear Ln[bond]Na complexes with an asymmetrical macrocyclic compartmental Schiff base.

Heterodinuclear lanthanide(III)-sodium(I) complexes [LnNa(L)(Cl)(2)(CH(3)OH)] (Ln=La[bond]Nd, Sm[bond]Lu), where H(2)L is a [1+1] asymmetric compartmental macrocyclic ligand containing a N(3)O(2) Schiff base and a O(3)O(2) crown-ether-like coordination site, have been prepared and characterized by IR, (1)H, (13)C, and (23)Na NMR spectroscopy, mass spectrometry, and electron microscopy. In the solid state, the lanthanide(III) ions coordinate the Schiff-base N(3)O(2) site, and the sodium ion occupies the O(3)O(2) crownlike cavity, as shown by the X-ray crystal structures of the Nd, Eu, Gd, and Yb derivatives. In these complexes, the lanthanide(III) ion is coordinated by two chlorine atoms in the trans position and by three nitrogen and two negatively charged phenol oxygen atoms of the Schiff base, and the ion is heptacoordinated with a pentagonal bipyramidal geometry. The sodium ion is coordinated by three etheric oxygen atoms and the two phenolic oxygens that act as a bridge. A methanol molecule is also coordinated in the apical position of the resulting pentagonal pyramidal polyhedron. A detailed (1)H and (13)C NMR study was carried out in CD(3)OD for both diamagnetic and paramagnetic heterodinuclear complexes [LnNa(L)(Cl)(2)(CH(3)OH)]. The complexes are also isostructural in solution, and their structures parallel those found in the solid state. Moreover, some significative distances determined in the solid state and in solution are comparable. Finally, the potential use of these complexes as molecular probes for the selective recognition of specific metal ions has been tested. In particular, their ability to act as shift reagents and the selectivity of the O(3)O(2) site towards Li(+), Ca(2+), and K(+) were investigated by (23)Na NMR spectroscopy.

Journal Article↗
PubMed2001

A comparative study of the enantiomeric resolution of several tetralone derivatives on macrocyclic antibiotic chiral stationary phases using HPLC under normal phase mode.

The enantiomeric resolution of five substituted 2-(4-pyridylalkyl)-1-tetralone derivatives has been achieved on three macrocyclic glycopeptide antibiotic chiral stationary phases namely, Chirobiotic R, T, and V columns. The mobile phase used was hexane-ethanol-triethylamine (12:8:0.01, v/v/v). The flow rates were 1 mL/min for Chirobiotic T and 2 mL/min for Chirobiotic R and V respectively. The UV detection was carried out at 254 nm. The values of alpha of the resolved enantiomers of the reported tetralone derivatives were in the range of 1.32 to 2.51 on Chirobiotic R, 2.02 to 2.88 on Chirobiotic T and 1.55 to 2.54 on Chirobiotic V respectively while the values of Rs were in the range of 1.00 to 2.50 on Chirobiotic R, 1.00 to 1.95 on Chirobiotic T and 1.00 to 1.60 on Chirobiotic V respectively. The best resolution was achieved on Chirobiotic R column.

Anti-Bacterial Agents↗
PubMed2006

Fast and versatile microwave-assisted intramolecular Heck reaction in peptide macrocyclization using microwave energy.

We have revisited the intramolecular Heck reaction and investigated the microwave-assisted macrocyclization on preformed peptides using a model series of ring-varying peptides acryloyl-Gly-[Gly](n)-Phe(4-I)NHR; n = 0-4. The method was applied to both solution and solid supported cyclizations. We demonstrate that the intramolecular Heck reaction can be performed in peptides both in solution and solid support using a modified domestic microwave within 1 to 30 minutes in DMF under reflux with moderate yields ranging from 15 to 25% for a scale between 2-45 mg of linear precursors. The approach was applied to the synthesis of a constrained biologically relevant peptidomimetic bearing an Arg-Gly-Asp (RGD) sequence. These results make the microwave-assisted Heck reaction an attractive renovated approach for peptidomimetics.

Amino Acid Sequence↗
PubMed2005

Thin-layer chromatography separation of enantiomers of verapamil using macrocyclic antibiotic as a chiral selector.

Silica gel thin-layer chromatography plates impregnated with macrocyclic antibiotic, vancomycin, as chiral selector were prepared and used for the resolution of (+/-)-verapamil. A mobile phase system of acetonitrile-methanol-water (15:2.5:2.5, v/v) was worked out systematically. The effects of chiral selector, temperature and pH on resolution were also studied. The spots were detected with iodine vapors and the detection limit was found to be 0.074 microg of each enantiomers.

Chromatography, Thin Layer↗
PubMed2006

Chiral and achiral macrocyclic copper(II) complexes: Synthesis, characterization, and comparative binding studies with calf-thymus DNA.

The new chiral macrocyclic complexes [1,2-bis(1H-benzimidazol-2-yl)-1-(1,8-dihydro-1,3,5,8,10,12-hexaazacyclotetradecane)-2-hydroxyethanolate] copper(II) and -nickel(II) perchlorate, 3 and 4, respectively, were synthesized by the reaction of 1,2-bis(1H-benzimidazol-2-yl)ethane-1,2-diol (L) and (1,8-dihydro-1,3,5,8,10,12-hexaazacyclotetradecane)copper(II) and -nickel(II) diperchlorate complexes, 1 and 2, respectively. All complexes were characterized by various spectroscopic techniques. Molar-conductance measurements showed that all of the complexes are ionic in nature. In complexes 3 and 4, the metal center is encapsulated by the ligand L in a pentacoordinated environment. The optical-rotation values ([alpha](D)) of 3 and 4 at 25 degrees indicate that the complexes are chiral. Absorption- and fluorescence-spectral studies, cyclic voltammetry, and viscosity measurements have been carried out to assess the comparative binding of complexes 1 and 3 with calf thymus (CT)-DNA. Analysis of the results suggests that the new chiral complex 3 binds to CT-DNA through a partial intercalation mode that is different from the binding mode of parent achiral complex 1. The complexes 1 and 3 bind to CT-DNA with binding constants K(b) of 2.7 x 10(4) and 6.6 x 10(4) M(-1), respectively. Circular-dichroism (CD) studies have been further employed to ascertain the binding mode of complex 3, which is consistent with the other spectral studies.

Animals↗
PubMed2003

Synthesis of a hexagonal nanosized macrocyclic fluorophore with integrated endotopic terpyridine metal-chelation sites.

A rigid nanosized hexagonal phenylethynyl cyclophane 5 has been prepared, which incorporates two 2,2':6',2"-terpyridines as integral structural units, for the purpose of binding metal ions. Macrocycle 5 was obtained by a 14-step synthesis in an overall yield of 11 %, and was characterised by spectroscopic techniques. The efficiency and ease of all transformations, and the relatively enhanced yield of the final macrocyclisation suggests that the entire synthetic pathway should be amenable to scale-up. Cyclophane 5 possesses four bulky triisopropylsilyl(TIPS)-protected ethyne substituents which serve a dual role. Firstly, they solubilise the structure thereby facilitating purification and subsequent handling. Secondly, they enable post-synthetic modification in which additional functionality may be attached to the periphery of the ring. Significantly, 5 was found to be a fluorescent chromophore, and may therefore potentially function as a new sensory platform for the detection of metal ions and H-bond donating biological substrates. The structurally well-defined nanosized morphology of 5, coupled with its interesting spectroscopic properties, supports the expectation that 5 and related architectures will attain a wealth of future applications within the developing fields of nanochemistry and nanoscience.

Journal Article↗
PubMed2004

Macrocyclic glycoclusters: from amphiphiles through nanoparticles to glycoviruses.

Macrocyclic glycocluster amphiphiles are intended to be a covalent-bundle mimic of clustering glycolipid motifs on the cell membrane. They are irreversibly micellized to give glycocluster nanoparticles (GNPs); their masked hydrophobicity endows them with remarkable saccharide specificities in the interactions with biological saccharide receptors. The GNPs also exhibit unprecedented hydrogen-bond capacities; they are agglutinated with Na(2)HPO(4) and assembled on plasmid DNA in a number-, size-, and shape-controlled manner to give artificial glycoviral particles capable of transfection. Thus, the intrinsic function of viruses, that is, cell invasion followed by gene expression, is also intrinsic to size-regulated (approximately 50 nm) glycoviruses. The growth of glycocluster amphiphiles through nanoparticles to glycoviruses reveals a hierarchical adhesion control of the saccharide clusters.

Cell Line, Tumor↗
PubMed2003

Macrocycles from perhalogenated heterocycles.

Perhalogenated heteroaromatic systems, such as trichloro-s-triazine and pentafluoropyridine, are multifunctional "building blocks" that react with a number of appropriate difunctional nucleophiles to provide access to a variety of macrocyclic and even cage-like molecular architectures. Unusual structural and complexation characteristics of the systems reported so far, such as the recognition of anions, provide a further stimulus for the development of this area.

Bridged-Ring Compounds↗