Syntheses, structures, and properties of novel one dimensional copper cyanide coordination polymers

Three new one-dimensional copper coordination polymers have been prepared and fully characterized by single-crystal X-ray diffraction, IR spectroscopy, thermogravimetric analysis, and magnetic susceptibility measurements. The structure of [Cu(CN)₂(bpy)] (1) (bpy = 2,2-bipyridyl) (monoclinic P2₁/c, a = 8.9761(7) Å, b = 16.731(1) Å, c = 8.0224(6) Å, β = 114.437(1)°) consists of Cu(II) metal centers coordinated by three cyanide ligands and chelated by one bpy to form the monomers Cu(CN)₃(bpy) with distorted square pyramidal geometry. Each monomer shares two cyanide ligands with two adjacent monomers to form infinite -Cu(II)-CN-Cu(II)-CN-Cu zigzag chains along the c-axis. The one-dimensional structure of [Cu(CN)(bpy)] (2) (hexagonal P3₂, a = 14.4883(6) Å, b = 12.921(1) Å) is built of tetrahedral Cu(CN)₂bpy metal complexes in which Cu(I) metal centers are coordinated by one nitrogen and one carbon from two different CN ligands, and two nitrogens from one bpy. The two CN ligands act as bridging ligands between adjacent monomers to form helical chains along the 3₂ screw axis. The crystal structure of [Cu₂Cl(CN)(bpy)] (3) (orthorhombic Pbca, a = 17.853(2) Å, b = 6.9724 (9) Å, c = 18.7357 (9) Å) consists of two monomers, CuCl₂(CN) and Cu(bpy)(CN) that share a cyanide ligand to form Cu₂Cl₂(CN)(bpy) dimers. The dimers link to each other by sharing Cl ligands leading to the formation of infinite Cu-Cl-Cu chain decorated by the complex Cu(CN)(bpy). Variable-temperature magnetic measurement shows an overall ferromagnetic behavior for compound 1. The magnetic pathway of compound 1 is through the cyanide bridge connecting apical and equatorial positions of adjacent copper (II) ions.     

Syntheses,structures and properties of three novel coordination polymers with a flexible asymmetrical bridging ligand

Three novel coordination polymers with different structural motifs, [Ag(pmtmb)]_n (1), [Cd(pmtmb)₂(H₂O)]_n (2) and [Cu(pmtmb)₂]_n (3), have been synthesized with a flexible asymmetrical bridging ligand, 4-(2-pyrimidylthiomethyl)benzoic acid (Hpmtmb). X-ray diffraction analyses show that 1 is a 2D layer containing unusual zigzag Ag chains based on mixed ligand-supported and ligand-unsupported Ag–Ag interactions, 2 is a necklace structure that further linked through hydrogen bonding to form a 2D sheet, and 3 is a 3D compact framework full assembled from 1D centipede-like chains via π–π stacking interactions. Interestingly, the ligand pmtmb adopts different configurations and coordination modes in the solid structures of these complexes. Furthermore, three complexes exhibit remarkable thermal stability and the complexes 1 and 2 exhibit intense green and purple luminescence, respectively.     

Determination of alentamol hydrobromide, a novel antipsychotic agent, in human blood plasma and urine by high-performance liquid chromatography with fluorescence detection and solid-phase extraction

Alentamol hydrobromide, (+)-2-(dipropylamino)-2,3-dihydro-1H-phenalen-5-ol monohydrobromide, is a selective dopamine agonist currently being investigated for the treatment of schizophrenia. This paper describes a reversed-phase high-performance liquid chromatographic-based method for the quantification of alentamol in blood plasma and urine. The method utilizes solid-phase extraction with carboxylic acid-derivatized silica columns. A limit of quantitation of 0.1 ng/ml in plasma was achieved by virtue of selective extraction and fluorescence detection. Example chromatograms of plasma and urine specimens from clinical trials demonstrate the utility of the method.     

Antibacterial property of the antipsychotic agent prochlorperazine, and its synergism with methdilazine

The antipsychotic drug prochlorperazine was screened in vitro for possible antimicrobial property against 157 strains of bacteria, belonging to gram positive and gram negative genera. The minimum inhibitory concentration (MIC) of prochlorperazine was determined by agar dilution method, which ranged from 25 to 200 microg/ml with respect to most of the strains. Based on such findings, a further study was undertaken to determine whether the efficacy of this drug could be enhanced in the presence of an antihistaminic agent methdilazine, reported to have remarkable antimicrobial action. Four bacterial strains, sensitive to prochlorperazine as well as to three antibacterial chemotherapeutics, viz., methdilazine, fluphenazine and thioridazine were chosen. Disc diffusion tests with prochlorperazine and methdilazine revealed marked synergism between the combination, compared to their individual effects. The synergism was found to be statistically significant (p<0.01). To assess the degree of synergism, the checkerboard analysis was performed. The FIC index of this combination turned out to be 0.37, which confirmed synergism. Therefore, this synergistic drug combination might open a new therapeutic approach to combat drug-resistance in bacterial infections.     

New perspective on the metabolism of AD-1 in vivo: Characterization of a series of dammarane-type derivatives with novel metabolic sites and anticancer mechanisms of active oleanane-type metabolites

20(R)-25-methoxyl-dammarane-3β,12β,20-triol (AD-1, CN Patent: 201010107476.7) is a novel derivative of dammarane-type ginsenoside. AD-1 has been shown to inhibit cancer cell proliferation without significant host toxicity in vivo, and has excellent development potential as a new anti-cancer agent. This study was designed systematically to explore the metabolic pathway of ginseng sapogenins. The metabolism of drugs in the body is a complex biotransformation process where drugs are structurally modified to different molecules (metabolites) through various metabolizing enzymes. The compounds responsible for the effects of orally administered ginseng are believed to be metabolites produced in the gastrointestinal tract, so understanding the metabolism of the drug candidate can help to optimize its pharmacokinetics. In this study, faeces samples were collected and extracted after oral administration of AD-1. The 16 metabolites of AD-1 were isolated and identified for the first time with various chromatographic techniques, including semi-preparative high performance liquid chromatography, nuclear magnetic resonance spectroscopy, and mass spectrometry; of these 16 metabolites, 10 were novel compounds. We first discovered the biotransformation of dammarane-type sapogenins into oleanane-type sapogenins in rats and found a series of metabolites that changed, mainly at C-25 and C-29. This study provides new ideas for the metabolic pathway of ginseng sapogenins. The isolated compounds were screened for their effect on the viability and proliferation against cancer cell lines (Human A549, MCF-7, HELA, HO-8901 and U87). The discovery of novel active metabolites 3β,12β,21α,22β-Hydroxy-24-norolean-12-ene (M6) may lead to a new or improved drug candidate. For one, M6 could inhibit the growth of all the tested cancer cells. Among the tested cell lines, M6 exhibited the most remarkable inhibitory effect on ovarian cancer HO-8901 cells, with IC₅₀ value of 2.086 μM. On this basis, we studied the anticancer mechanisms of M6. The results indicated that the pro-apoptotic feature of M6 acts via a mitochondrial pathway. Our results indicated that M6 exhibited a higher inhibitory effect on cancer-cell proliferation than AD-1 by inducing cell apoptosis. Our work provides data for future investigations on the metabolic mechanism of AD-1 in vivo and the potential for future research on developing a new drug.     

T2384, a novel antidiabetic agent with unique peroxisome proliferator-activated receptor gamma binding properties

The nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARgamma) plays central roles in adipogenesis and glucose homeostasis and is the molecular target for the thiazolidinedione (TZD) class of antidiabetic drugs. Activation of PPARgamma by TZDs improves insulin sensitivity; however, this is accompanied by the induction of several undesirable side effects. We have identified a novel synthetic PPARgamma ligand, T2384, to explore the biological activities associated with occupying different regions of the receptor ligand-binding pocket. X-ray crystallography studies revealed that T2384 can adopt two distinct binding modes, which we have termed "U" and "S", interacting with the ligand-binding pocket of PPARgamma primarily via hydrophobic contacts that are distinct from full agonists. The different binding modes occupied by T2384 induced distinct patterns of coregulatory protein interaction with PPARgamma in vitro and displayed unique receptor function in cell-based activity assays. We speculate that these unique biochemical and cellular activities may be responsible for the novel in vivo profile observed in animals treated systemically with T2384. When administered to diabetic KKAy mice, T2384 rapidly improved insulin sensitivity in the absence of weight gain, hemodilution, and anemia characteristics of treatment with rosiglitazone (a TZD). Moreover, upon coadministration with rosiglitazone, T2384 was able to antagonize the side effects induced by rosiglitazone treatment alone while retaining robust effects on glucose disposal. These results are consistent with the hypothesis that interactions between ligands and specific regions of the receptor ligand-binding pocket might selectively trigger a subset of receptor-mediated biological responses leading to the improvement of insulin sensitivity, without eliciting less desirable responses associated with full activation of the receptor. We suggest that T2384 may represent a prototype for a novel class of PPARgamma ligand and, furthermore, that molecules sharing some of these properties would be useful for treatment of type 2 diabetes.     

Syntheses, structures and properties of novel 3D lanthanide metal-organic frameworks with paddle-wheel building blocks

Three new complexes Ln(BDC)_1.5(DEF) [Ln = La(1), Ce(2), Nd(3); H₂BDC = 1,4-benzenedicarboxylic acid; DEF = N,N-diethylformamide] have been solvothermally synthesized and characterized by single-crystal X-ray diffraction. Complexes 1–3 are isostructural and crystallize in triclinic space group . They display three-dimensional frameworks and 18.7986 Å × 11.3230 Å rhombic channels along the a axis without interpenetration. Two eight-coordinated metal centers are connected with two dimonodentate BDC groups and two chelating/bridging bidentate BDC groups to give a paddle-wheel building block. The building blocks are connected through two carboxyl groups to lead to a one-dimensional infinite inorganic chain (–M–O–C–O–M–) along the [1 0 0] direction. Thermogravimetric analyses (TGA) and X-ray powder diffraction (XPRD) were determined for the three complexes. An observed intense blue luminescence with an emission band peaking at 372 nm for them may result from ligand-to-metal charge transfer (LMCT). Variable-temperature magnetic susceptibility of 2 and 3 was investigated and found deviated from the Curie–Weiss law.     

Determination of two major metabolites of the novel anti-tumour agent 5,6-dimethylxanthenone-4-acetic acid in hepatic microsomal incubations by high-performance liquid chromatography with fluorescence detection

High-performance liquid chromatographic methods have been developed and validated for the glucuronidated and oxidative metabolites of the novel anti-tumour agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA), produced in human liver microsomal incubations. Calibration curves for DMXAA acyl glucuronide (DMXAA-Glu) and 6-hydroxymethyl-5-methylxanthenone-4-acetic acid (6-OH-MXAA) were constructed over the concentration ranges of 0.25 to 20 and 0.5 to 40 μM, respectively. Assay performance was determined by intra- and inter-day accuracy and precision of quality control (QC) samples. The difference between the theoretical and measured concentration, and the coefficient of variation, were less than 15% at low QC concentrations, and less than 10% at medium and high QC concentrations for both analytes. The methods presented good accuracy, precision and sensitivity for use in kinetic studies of the glucuronidated and oxidative metabolites of DMXAA in human liver microsomes.     

From a cytotoxic agent to the discovery of a novel antimalarial agent

A novel cytotoxin 3,5-bis(4-chlorobenzylidene)-1-[4-{2-(4-morpholinyl)ethoxy}phenyl-carbonyl]-4-piperidone hydrochloride 2 demonstrated potent antimalarial properties with IC₅₀ values of 0.60 and 1.97 μM against the drug sensitive D6 strain and the C235 drug-resistant strain of Plasmodium falciparum. This compound concentrates in red blood cells, lowers glutathione concentrations in erythrocytes and permeates across CACO-2 cells. These data reveal 2 to be a promising lead compound in the quest for novel antimalarial agents.     

The pharmacology of prazosin, a novel antihypertensive agent

During the past few years a large amount of pharmacological and physiological evidence has been obtained in favor of two distinct types of α-adrenoceptors. As a working hypothesis, it is feasible to assume that both α₁- and α₂-adrenoceptors are abundant on the vascular effector site, whereas the α-adrenoceptors (the blockade of which increases norepinephrine release) predominate at the level of peripheral sympathetic nerve endings. Prazosin is a novel, selective antagonist of α₁-adrenoceptors and can be considered an important advancement both pharmacologically and therapeutically since this compound in contrast to classical α-adrenoceptor blocking agents, is effective for the treatment of high blood pressure. Prazosin lacks direct myorelaxant properties and, unlike many vasodilators, in doses lowering blood pressure it does not produce undesirable increases in heart rate and plasma renin activity. Prazosin has proved to be a very useful pharmacological tool since it has permitted us the furtherance of our knowledge with respect to the subclassification of receptors mediating the effects produced by α-adrenoceptor agonists, particularly clonidine. Pharmacokinetic and metabolic studies on prazosin given orally indicate that in animals and in man this compound has a low bioavailability, short half life and undergoes extensive biotransformation. The most common clinical use of prazosin is as an antihypertensive agent and is often given in association with established blood pressure lowering drugs. Recently, it was shown to be useful in the treatment of congestive heart failure, but for this application tolerance has been described. Generally, patients treated chronically with prazosin suffer only minor unwanted effects. This is in contrast to past experience with traditional α-adrenoceptor antagonist. The most serious side effect of prazosin is known as the “first dose phenomenon” which can sometimes lead to syncope. However, it can be avoided if prazosin therapy is initiated with minimally effective doses and individually tailored to obtain the desired antihypertensive effect. Presently, the interesting clinical profile of prazosin is attributed to its novel property of being a selective antagonist of postsynaptic α₁-adrenoceptors. Howeverm this is probably an over simplification since some therapeutic observations are not entirely consistent with results which would have been expected for a selective α₁-adrenoceptor. For example, prazosin, like the classical antagonists, would be expected to produce sexual dysfunction but, in fact, does not to any significant degree. Future studies with new chemical structures sharing the pharmacological profile of prazosin will clarify the real role of the selectivity towards α₁-adrenoceptors in the therapeutic success of prazosin.     

The identification of some human metabolites of norgestrel, a new progestational agent

Norgestrel 1 (racemic 13-beta-ethyl-17-alpha-hydroxygon-4-en-3-one) a progestational agent with an angular ethyl group between Rings C and D, was studied by mass spectrometry to discover its structural characteristics. Synthesis of postulated metabolites of Norgestrel 1 for use in identification is described and structural formulas are given. Urine was used as a source to characterize fractions via mass spectra, and the fraction spectra are listed. The major metabolite was 13-beta-ethyl-17-alpha-ethynl-5-beta-gonan-3-alpha-1m-beta-diol 8c.     

Design,synthesis, and evaluation of a novel macrocyclic anti-EV71 agent

We describe here the design, synthesis, and evaluation of a macrocyclic peptidomimetic as a potent agent targeting enterovirus A71 (EV71). The compound has a 15-membered macrocyclic ring in a defined conformation. Yamaguchi esterification reaction was used to close the 15-membered macrocycle instead of the typical Ru-catalyzed ring-closing olefin metathesis reaction. The crystallographic characterization of the complex between this compound and its target, 3C protease from EV71, validated the design and paved the way for the generation of a new series of anti-EV71 agents.     

Syntheses, structures and properties of three metal pyridinecarboxylates

Three new metal pyridinecarboxylates, namely [Co₂(pydc)₂(H₂O)₅] (1), [Mn(pydc)(H₂O)₂] (2) and [Cd₂(OH)₂(2,4-pydc)] (3), were hydrothermally synthesized. X-ray single crystal structural analysis revealed: 1 and 2 have polymeric one-dimensional chain-like structure constructed by dinuclear cobalt units and Mn-O chains, respectively; 3 has a three-dimensional layer pillared structure constructed from inorganic Cd-O layer and pydc pillars. 1 shows antiferromagnetic interaction but 2 shows alternative antiferromagnetic and ferromagnetic interactions.     

Development of a physiologically based toxicokinetic model for butadiene and four major metabolites in humans: global sensitivity analysis for experimental design issues

1,3-Butadiene (BD) is metabolized in humans and rodents to mutagenic and carcinogenic species. Our previous work has focused on developing a physiologically based toxicokinetic (PBTK) model for BD to estimate its metabolic rate to 1,2-epoxy-3-butene (EB), using exhaled breath BD concentrations in human volunteers exposed by inhalation. In this paper, we extend our BD model to describe the kinetics of its four major metabolites EB, 1,2:3,4-diepoxybutane (DEB), 3-butene-1,2-diol (BDD), and 3,4-epoxy-1,2-butanediol (EBD), and to test whether the extended model and experimental data (to be collected for BD and metabolites in humans) are together adequate to estimate the metabolic rate constants of each of the above chemicals. Global sensitivity analyses (GSA) were conducted to evaluate the relative importance of the model parameters on model outputs during the 20min of exposure and the 40min after exposure ended. All model parameters were studied together with various potentially measurable model outputs: concentrations of BD and EB in exhaled air, concentrations of BD and all metabolites in venous blood, and cumulated amounts of urinary metabolites excreted within 24h. Our results show that pulmonary absorption of BD and subsequent distribution and metabolism in the well-perfused tissues compartment are the critical processes in the toxicokinetics of BD and metabolites. In particular, three parameters influence numerous outputs: the blood:air partition coefficient for BD, the metabolic rate of BD to EB, and the volume of the well-perfused tissues. Other influential parameters include other metabolic rates, some partition coefficients, and parameters driving the gas exchanges (in particular, for BD outputs). GSA shows that the impact of the metabolic rate of BD to EB on the BD concentrations in exhaled air is greatly increased if a few of the model's important parameters (such as the blood:air partition coefficient for BD) are measured experimentally. GSA also shows that all the transformation pathways described in the PBTK model may not be estimable if only data on the studied outputs are collected, and that data on a specific output for a chemical may not inform all the transformations involving that chemical.     

Dolichols, ubiquinones, geranylgeraniol and farnesol as the major metabolites of mevalonate in Phytophthora cactorum

Farnesol, geranylgeraniol, dolichols and ubiquinones were the main radioactive components of the unsaponifiable lipid recovered from Phytophthora cactorum grown in aerated cultures containing [2-¹⁴C]mevalonate. The ¹⁴C recovered in each of these components was in the approximate proportion 2:4:3:5. When the culture was not aerated no radioactive ubiquinone was recovered. Most of the ¹⁴C recovered in the dolichols was found in dolichol-15 (37%), with decreasing amounts in dolichol-14 (30%) and -13 (14%) and only a little (5%) in dolichol-16, whereas the major components, by weight, of the mixture (13μg/g of damp-dry tissue) were dolichol-14, -15 and -16 in the approximate proportion of 1:3:1. Radioautography of appropriate chromatograms indicated the presence also of traces of radioactivity in dolichol-9, -10, -11, -12 and -17. Most (80%) of the ¹⁴C recovered in the ubiquinones was associated with ubiquinone-9, the rest being in ubiquinone-8. Most (80%) of the weight of ubiquinones (19μg/g of damp-dry tissue) was also ubiquinone-9. The identification of these compounds was by chromatographic methods and, for the ubiquinones and dolichols, was confirmed by mass spectrometry. In addition, the incorporation of 4R- and/or 4S-³H from [4-³H]-mevalonates showed the expected stereochemistry of biosynthesis, namely that farnesol, geranylgeraniol and ubiquinones were biogenetically all trans and the dolichols each contained three biogenetically trans isoprene residues, the remaining residues being biogenetically cis. The distribution of ¹⁴C in the components of the whole lipid of the fungus was consistent with 97% of both the farnesol and geranylgeraniol being present as the fatty acid ester. The corresponding value for dolichols was 37%. The observation by other workers, that this fungus does not form either squalene or sterol, was confirmed.     

Determination of imipramine, desipramine and their hydroxy metabolites by reversed-phase chromatography with ultraviolet and coulometric detection

A reversed-phase high-performance liquid chromatographic method is described which analyzes imipramine, desipramine and their corresponding 2-hydroxy metabolites with sequential ultraviolet and coulometric detection from a single common extraction step, so that a wider dynamic range of plasma concentrations can be measured requiring smaller sample volumes. Applicability is broader including single-dose pharmacokinetic studies as well as steady-state concentrations. The extraction procedure gives excellent recoveries for imipramine, desipramine and their metabolites (mean ± S.D.): ultraviolet detection, imipramine 99.5±0.68%, desipramine 100±0.0%, 2-hydroxyimipramine 97.8±3.5% and 2-hydroxydesipramine 93.1±4.22%; coulometric detection, imipramine 97.5±1.9%, desipramine 98.3±1.2%, 2-hydroxyimipramine 90.3±4.0% and 2-hydroxydesipramine 86.6±7.5%.     

High-performance liquid chromatographic method for the estimation of the novel investigational anti-cancer agent SR271425 and its metabolites in mouse plasma

A simple and reliable HPLC method was developed for the estimation of a new anti-cancer agent that belongs to the thioxanthone class, SR271425 in mouse plasma. SR271425, it’s metabolites and internal standard (SR233377) were separated from plasma by liquid–liquid extraction using dichloromethane after quenching the plasma proteins with acetonitrile. Chromatography was performed on a reversed-phase C₁₈ column using methanol–10 mM phosphate buffer, pH 3.5 (45:55) as mobile phase at a flow-rate of 0.8 ml/min for first 10 min and 1.4 ml/min for the next 15 min with UV–Vis detection at 264 nm and SR233377 as internal standard. The retention times of SR271425 and internal standard were 18.6 and 14.8 min, respectively. The limit of detection was 40 ng/ml and the limit of quantification was 78 ng/ml. This method was also able to detect the three metabolites of SR271425. The intra- and inter-day relative standard deviations were less than 13% at all concentrations. This analytical method was precise and reproducible for pharmacokinetics and metabolism studies of the drug in mice. SR271425 is proceeding to phase I clinical trials in 2001.