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Structural Analogs (structural + analog)
Selected AbstractsActivation of a calcium entry pathway by sodium pyrithione in the bag cell neurons of AplysiaDEVELOPMENTAL NEUROBIOLOGY, Issue 4 2004Ronald J. Knox Abstract The ability of sodium pyrithione (NaP), an agent that produces delayed neuropathy in some species, to alter neuronal physiology was accessed using ratiometric imaging of cytosolic free Ca2+ concentration ([Ca2+]i) in fura PE-filled cultured Aplysia bag cell neurons. Bath-application of NaP evoked a [Ca2+]i elevation in both somata and neurites with an EC50 of ,300 nM and a Hill coefficient of ,1. The response required the presence of external Ca2+, had an onset of 3,5 min, and generally reached a maximum within 30 min. 2-Methyl-sulfonylpyridine, a metabolite and close structural analog of NaP, did not elevate [Ca2+]i. Under whole-cell current-clamp recording, NaP produced a ,14 mV depolarization of resting membrane potential that was dependent on external Ca2+. These data suggested that NaP stimulates Ca2+ entry across the plasma membrane. To minimize the possibility that a change in cytosolic pH was the basis for NaP-induced Ca2+ entry, bag cell neuron intracellular pH was estimated with the dye 2,,7,-bis(carboxyethyl-5(6)-carboxy-fluorescein acetoxy methylester. Exposure of the neurons to NaP did not alter intracellular pH. The slow onset and sustained nature of the NaP response suggested that a cation exchange mechanism coupled either directly or indirectly to Ca2+ entry could underlie the phenomenon. However, neither ouabain, a Na+/K+ ATPase inhibitor, nor removal of extracellular Na+, which eliminates Na+/Ca2+ exchanger activity, altered the NaP-induced [Ca2+]i elevation. Finally, the possibility that NaP gates a Ca2+ -permeable ion channel in the plasma membrane was examined. NaP did not appear to activate two major forms of bag cell neuron Ca2+ -permeable ion channels, as Ca2+ entry was unaffected by inhibition of voltage-gated Ca2+ channels using nifedipine or by inhibition of a voltage-dependent, nonselective cation channel using a high concentration of tetrodotoxin. In contrast, two potential store-operated Ca2+ entry current inhibitors, SKF-96365 and Ni2+, attenuated NaP-induced Ca2+ entry. We conclude that NaP activates a slow, persistent Ca2+ influx in Aplysia bag cell neurons. © 2004 Wiley Periodicals, Inc. J Neurobiol 411,423, 2004 [source] Surprising Coordination Geometry Differences in CeIV - and PuIV -Maltol Complexes,EUROPEAN JOURNAL OF INORGANIC CHEMISTRY, Issue 13 2008Géza Szigethy Abstract As part of a study to characterize the detailed coordination behavior of PuIV, single-crystal X-ray diffraction structures have been determined for PuIV and CeIV complexes with the naturally occurring ligand maltol (3-hydroxy-2-methylpyran-4-one) and its derivative bromomaltol (5-bromo-3-hydroxy-2-methylpyran-4-one). Although CeIV is generally accepted as a structural analog for PuIV, and the maltol complexes of these two metals are isostructural, the corresponding bromomaltol complexes are strikingly different with respect to ligand orientation about the metal ion: All complexes exhibit trigonal dodecahedral coordination geometry but the CeIV,bromomaltol complex displays an uncommon ligand arrangement not found in the PuIV complex.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008) [source] Thimerosal induces apoptosis and G2/M phase arrest in human leukemia cells,MOLECULAR CARCINOGENESIS, Issue 9 2006Kyung Jin Woo Abstract Thimerosal is an organomercury compound with sulfhydryl-reactive properties. The ability of thimerosal to act as a sulfhydryl group is related to the presence of mercury. Due to its antibacterial effect, thimerosal is widely used as preservatives and has been reported to cause chemically mediated side effects. In the present study, we showed that the molecular mechanism of thimerosal induced apoptosis in U937 cells. Thimerosal was shown to be responsible for the inhibition of U937 cells growth by inducing apoptosis. Treatment with 2.5,5 µM thimerosal but not thiosalicylic acid (structural analog of thimerosal devoid of mercury) for 12 h produced apoptosis, G2/M phase arrest, and DNA fragmentation in a dose-dependent manner. Treatment with caspase inhibitor significantly reduced thimerosal-induced caspase 3 activation. In addition, thimerosal-induced apoptosis was attenuated by antioxidant Mn (III) meso-tetrakis (4-benzoic acid) porphyrin (Mn-TBAP). These data indicate that the cytotoxic effect of thimerosal on U937 cells is attributable to the induced apoptosis and that thimerosal-induced apoptosis is mediated by reactive oxygen species generation and caspase-3 activation. © 2006 Wiley-Liss, Inc. [source] Isoamylcobalamin,acetone,water (1/0.385/12.650)ACTA CRYSTALLOGRAPHICA SECTION C, Issue 4 2004Christopher B. Perry The title compound, [Co(C5H11)(C62H88N13O14P)]·0.385C3H6O·12.650H2O, contains the isoamyl (3-methylbutyl) anion bonded to the CoIII ion through a C atom. The compound is thus a structural analog of the two biologically important vitamin B12 coenzymes adenosylcobalamin and methylcobalamin. The lower axial Co,N bond length [2.277,(2),Å] is one of the longest ever reported for a cobalamin and reflects the strong ,-donor ability of the isoamyl group. [source] Simultaneous RP-HPLC-DAD quantification of bromocriptine, haloperidol and its diazepane structural analog in rat plasma with droperidol as internal standard for application to drug-interaction pharmacokineticsBIOMEDICAL CHROMATOGRAPHY, Issue 7 2010Johnique Billups Abstract A simple and rapid RP-HPLC-DAD method was developed and validated for simultaneous determination of the dopamine antagonists haloperidol, its diazepane analog, and the dopamine agonist bromocriptine in rat plasma, to perform pharmacokinetic drug-interaction studies. Samples were prepared for analysis by acetonitrile (22.0,,g/mL) plasma protein precipitation with droperidol as an internal standard, followed by a double-step liquid-liquid extraction with hexane,:,chloroform (70:30) prior to C-18 separation. Isocratic elution was achieved using a 0.1% (v/v) trifluoroacetic acid in deionized water, methanol and acetonitrile (45/27.5/27.5, v/v/v). Triple-wavelength diode-array detection at the ,max of 245,nm for haloperidol, 254,nm for the diazepane analog and droperidol, and 240,nm for bromocriptine was carried out. The LLOQ of DAL, HAL, and BCT were 45.0, 56.1, and 150,ng/mL, respectively. In rats, the estimated pharmacokinetic parameters (i.e., t1/2, CL, and Vss) of HAL when administered with DAL and BCT were t1/2 = 16.4,min, Vss = 0.541,L/kg for HAL, t1/2 = 28.0,min, Vss = 2.00,L/kg for DAL, and t1/2 = 24.0,min, Vss = 0.106,L/kg for BCT. The PK parameters for HAL differed significantly from those previously reported, which may be an indication of a drug-drug interaction. Copyright © 2009 John Wiley & Sons, Ltd. [source] Bimatoprost: A Novel Antiglaucoma AgentCARDIOVASCULAR THERAPEUTICS, Issue 2 2004D. F. Woodward ABSTRACT The aim of glaucoma therapy is to preserve vision by reducing intraocular pressure (IOP). Following recent National Eye Institute sponsored studies, it is becoming increasingly apparent that every mmHg of extra IOP lowering counts. Bimatoprost is the newest and most effective addition to the physician's armamentarium of ocular hypotensive drugs. Direct clinical comparisons have demonstrated that it is more efficacious than the prostaglandin (PG) FP receptor agonist prodrugs, latanoprost and travoprost, as well as a ,-adrenoceptor antagonist, timolol, alone or in fixed combination with the carbonic anhydrase inhibitor, dorzolamide. Moreover, patients that are refractory to latanoprost therapy may be successfully treated with bimatoprost. Such evidence provides support, at the clinical level, for the contention that bimatoprost is pharmacologically distinct from PG FP receptor agonist prodrugs. Bimatoprost is a structural analog of PGF2, -ethanolamide (prostamide F2,), which is formed from the endocannabinoid anandamide by a biosynthetic pathway involving cyclooxygenase-2 (COX-2). Their pharmacology is remarkably similar, such that bimatoprost may be regarded as a prostamide mimetic. The target receptor for bimatoprost and the prostamides appears unique and unrelated to PG- and endocannabinoid-sensitive receptors. Extensive ocular distribution/metabolism studies in non-human primates demonstrate that bimatoprost is not a prodrug, it remains essentially intact. Its profound ocular hypotensive effects may, therefore, be attributed to its prostamide-mimetic properties. [source] Further studies on the interaction of loperamide with capacitative calcium entry in Leukemic HL-60 cells,DRUG DEVELOPMENT RESEARCH, Issue 11 2006John W. Daly Abstract Loperamide at 3,10,µM has augmentative effects on calcium levels elevated by capacitative calcium entry (CCE) in leukemic HL-60 cells after release of intracellular calcium by ATP or thapsigargin (Harper et al. [1997] Proc Natl Acad Sci USA 94:14912,14917). The effect of loperamide on calcium levels was absent at a pH value of 6.8, a pH at which CCE is not active in HL-60 cells. Further investigations of HL-60 cells in recent years revealed a great reduction in the magnitude of the loperamide response. However, when preceded by a CCE blocker, namely N-methylnitrendipine (MRS 1844) or N-propargylnitrendipine (MRS 1845), loperamide caused a significant reversal of the blockade. Six structural analogs of loperamide were synthesized, but only two showed loperamide-like activity. Drug Dev. Res. 67:842,851, 2006. Published 2007 Wiley-Liss, Inc. [source] Facile route for the synthesis of benzothiazoles and benzimidazoles in the presence of tungstophosphoric acid impregnated zirconium phosphate under solvent-free conditionsHETEROATOM CHEMISTRY, Issue 4 2009Hamid Aliyan Rapid and efficient condensation reactions of o -phenylenediamine and o -aminothiophenol with various aldehydes were carried out using tungstophosphoric acid impregnated zirconium phosphate in solvent-free conditions to afford the corresponding 2-substituted arylbenzimidazole and arylbenzothiazole derivatives in good to excellent yields. This procedure constitutes a simple and practical green synthetic method for 2-arylbenzimidazoles and 2-arylbenzothiazoles and their structural analogs. Furthermore, the catalyst can be reused for several times but it will be less active. © 2009 Wiley Periodicals, Inc. Heteroatom Chem 20:202,207, 2009; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20534 [source] Anthelmintic paraherquamides are cholinergic antagonists in gastrointestinal nematodes and mammalsJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 4 2002Erich W. Zinser Oxindole alkaloids in the paraherquamide/marcfortine family exhibit broad-spectrum anthelmintic activity that includes drug-resistant strains of nematodes. Paraherquamide (PHQ), 2-deoxoparaherquamide (2DPHQ), and close structural analogs of these compounds rapidly induce flaccid paralysis in parasitic nematodes in vitro, without affecting adenosine triphosphate (ATP) levels. The mechanism of action of this anthelmintic class was investigated using muscle tension and microelectrode recording techniques in isolated body wall segments of Ascaris suum. None of the compounds altered A. suum muscle tension or membrane potential. However, PHQ blocked (when applied before) or reversed (when applied after) depolarizing contractions induced by acetylcholine (ACh) and the nicotinic agonists levamisole and morantel. These effects were mimicked by the nicotinic ganglionic blocker mecamylamine, suggesting that the anthelmintic activity of PHQ and marcfortines is due to blockade of cholinergic neuromuscular transmission. The effects of these compounds were also examined on subtypes of human nicotinic ACh receptors expressed in mammalian cells with a Ca2+ flux assay. 2DPHQ blocked nicotinic stimulation of cells expressing ,3 ganglionic (IC50 , 9 µm) and muscle-type (IC50 , 3 µm) nicotinic cholinergic receptors, but was inactive at 100 µm vs. the ,7 CNS subtype. PHQ anthelmintics are nicotinic cholinergic antagonists in both nematodes and mammals, and this mechanism appears to underlie both their efficacy and toxicity. [source] Sequence-selective DNA binding drugs mithramycin A and chromomycin A3 are potent inhibitors of neuronal apoptosis induced by oxidative stress and DNA damage in cortical neuronsANNALS OF NEUROLOGY, Issue 3 2001Sukalyan Chatterjee PhD Global inhibitors of RNA or protein synthesis such as actinomycin D or cycloheximide abrogate neuronal apoptosis induced by numerous pathological stimuli in vitro and in vivo. The clinical application of actinomycin D or cycloheximide to human neurological disease has been limited by the toxicities of these agents. To overcome these toxicities, strategies must be developed to inhibit selectively the expression of deleterious proapoptotic proteins, while leaving the expression of antiapoptotic, proregeneration, and other critical homeostatic proteins unperturbed. Mithramycin A (trade name Plicamycin) is an aureolic acid antibiotic that has been used in humans to treat hypercalcemia and several types of cancers. This class of agents is believed to act, in part, by selectively inhibiting gene expression by displacing transcriptional activators that bind to G-C-rich regions of promoters. Here we demonstrate that mithramycin A and its structural analog chromomycin A3 are potent inhibitors of neuronal apoptosis induced by glutathione depletion-induced oxidative stress or the DNA-damaging agent camptothecin. We correlate the protective effects of mithramycin A with its ability to inhibit enhanced DNA binding of the transcription factors Sp1 and Sp3 to their cognate "G-C" box induced by oxidative stress or DNA damage. The protective effects of mithramycin A cannot be attributed to global inhibition of protein synthesis. Together, these results suggest that mithramycin A and its structural analogs may be effective agents for the treatment of neurological diseases associated with aberrant activation of apoptosis and highlight the potential use of sequence-selective DNA-binding drugs as neurological therapeutics. Ann Neurol 2001;49:345,354 [source] New potent and selective inhibitors of anandamide reuptake with antispastic activity in a mouse model of multiple sclerosisBRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2006Alessia Ligresti We previously reported that the compound O-2093 is a selective inhibitor of the reuptake of the endocannabinoid anandamide (AEA). We have now re-examined the activity of O-2093 in vivo and synthesized four structural analogs (O-2247, O-2248, O-3246, and O-3262), whose activity was assessed in: (a) binding assays carried out with membranes from cells overexpressing the human CB1 and CB2 receptors; (b) assays of transient receptor potential of the vanilloid type-1 (TRPV1) channel functional activity (measurement of [Ca2+]i); (c) [14C]AEA cellular uptake and hydrolysis assays in rat basophilic leukaemia (RBL-2H3) cells; (d) the mouse ,tetrad' tests (analgesia on a hot plate, immobility on a ,ring', rectal hypothermia and hypolocomotion in an open field); and (e) the limb spasticity test in chronic relapsing experimental allergic encephalomyelitis (CREAE) mice, a model of multiple sclerosis (MS). O-2093, either synthesized by us or commercially available, was inactive in the ,tetrad' up to a 20 mg kg,1 dose (i.v.). Like O-2093, the other four compounds exhibited low affinity in CB1 (Ki from 1.3 to >10 ,M) and CB2 binding assays (1.3 Cellular Analysis of Disorazole C1 and Structure,Activity Relationship of Analogs of the Natural ProductCHEMICAL BIOLOGY & DRUG DESIGN, Issue 1 2006Peter Wipf Structure,activity analyses of synthetic disorazole C1 and eight of its analogs indicate that the presence of a vinyl oxirane moiety or a tetraene sequence is not necessary for potent cytotoxic and antimitotic properties. Using an automated multiparameter fluorescence-based cellular assay to simultaneously probe the effects of disorazole analogs on cellular microtubules, mitotic arrest, and cytotoxicity, we found that disorazole C1 enhanced the mitotic index and chromatin condensation and arrested cells in the G2/M phase of the cell cycle. All structural analogs and synthesis precursors of disorazole C1 were at least two orders of magnitude less potent than the parent compound, thus indicating that both the functional group array and the three-dimensional conformation of the parent compound are critical for interaction with the biological target. We conclude that disorazole C1 is a potent inducer of mitotic arrest and hypothesize that this biological activity may be mediated by microtubule perturbation. [source] Increased expression of collagen receptors: ,1,1 and ,2,1 integrins on blood eosinophils in bronchial asthmaCLINICAL & EXPERIMENTAL ALLERGY, Issue 9 2006S. Bazan-Socha Summary Background Eosinophils are one of the major effector cells in bronchial asthma. Their infiltration of airways correlates with the asthma severity. Recruitment and activation of eosinophils are partially mediated by integrins ,4,1 and ,4,7. Collagens type I and IV constitute important components of extracellular matrix and vascular basement membrane, respectively. Therefore, collagen-binding integrins (,1,1 and ,2,1) may also play a role in eosinophil lung infiltration. Objective To evaluate the possible presence of ,1,1 and ,2,1 integrins on peripheral blood eosinophils from asthmatic subjects. Methods Collagen receptors were studied on eosinophils separated by immunomagnetic CD16-negative method from healthy donors (n=13) and patients with moderate persistent atopic bronchial asthma (n=15). Surface receptor identification was performed by flow cytometry and cell adhesion assay. Results Eosinophils isolated from the patients showed increased expression of both ,1,1 and ,2,1 integrins as compared with healthy controls. Moreover, adhesive function of eosinophils to collagen type IV was inhibited by snake venom disintegrins: viperistatin and obtustatin. These disintegrins contain KTS active motif and are specific inhibitors of ,1,1 integrin. Conclusion We demonstrated for the first time that collagen receptors: ,1,1 and ,2,1 integrins are overexpressed on the surface of peripheral blood eosinophils of asthmatic subjects. Further studies may reveal potential application of KTS-disintegrins or their structural analogs for therapy of bronchial asthma. [source]
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