Upregulation of HIV-1 replication in chronically infected cells by ingenol derivatives

We have previously reported that ingenol derivatives are highly potent inhibitors of human immunodeficiency virus type 1 (HIV-1) replication in acutely infected cells. In this study, however, we have found that some ingenol derivatives strongly enhance the replication of HIV-1 in chronically infected cells at nanomolar concentrations. One of the derivatives could activate nuclear factor kappa B (NF-kappa B), a potent inducer of HIV-1 replication, through the activation of protein kinase C (PKC). Whereas another derivative, which affected neither PKC nor NF-kappa B, significantly enhanced HIV-1 replication, suggesting that a PKC-independent mechanism may also exist in ingenol derivative-induced HIV-1 upregulation.     

Studies on 5-lipoxygenase inhibitors. Synthesis of and structure--activity relationship in p-hydroxyarylalkenylbenzoazoles

In a previous paper we reported that 2-(p-hydroxyarylbutadienyl)benzoxazoles are highly potent 5-lipoxygenase inhibitors. We synthesized their ethenyl homologues and benzothiazole derivatives, and evaluated their 5-lipoxygenase inhibitory activity in vitro with cell-free rat basophilic leukemia (RBL-1). In most cases the replacement of benzoxazolyl with benzothiazolyl resulted in an enhancement of the activity. All compounds with butadienyl spacers tested herein exhibited strong inhibitory activities. While most of the ethenyl homologues showed weaker activities than their corresponding butadienyl homologues, some ethenyl compounds in the benzothiazole derivatives were found to be as potent as their corresponding butadienyl homologues. The inhibitory activity was also affected by the variation in the p-hydroxyaryl functionality.     

Differential role for protein kinase C-mediated signaling in the proliferation of medulloblastoma cell lines

7-beta-D-Ribofuranosylxanthine, a previously unreported isomer of xanthosine, was prepared in four steps from 7-benzylxanthine. The procedure, which involves the use of pivaloyloxymethyl groups to protect the xanthine ring, was also applied to preparation of some 1-N-alkyl derivatives of 7-ribosylxanthine. Adenosine receptor affinity for these compounds was determined. 7-beta-D-Ribofuranosylxanthine was found to have higher affinity and greater selectivity for the A1 receptor than previously reported xanthine nucleosides, and to be a partial agonist.     

Design of novel tripeptides with macrophage migration-enhancing activity

A new approach to the generation of biologically active peptides from non-peptide lead was demonstrated. C,N-termini protected Phe-Phe-His derivatives possessing macrophage migration-enhancing activity were designed on the basis of the structure of imidazoline derivative 1, and these structure-activity relationships were also described.     

Synthesis and Herbicidal Activity of Novel Sulfonylurea Derivatives

Suifonylurea herbicides have been applied worldwide in agriculture.Some sulfonylurea residues might exist in soil longer than that people expected.However,flupyrsulfuron-methyl-sodium which was firstly reported as a new 5-substituted sulfonylurea herbicide has less than one month residual life.Therefore,5-substituted benzenesulfonylureas are potential molecules to regulate its residual situation.In order to develop new sulfonylurea derivatives,the substituent on the critical 5-posotion of the benzene ring was optimized.On the basis of our former work on sulfonylureas which contains a characteristic mono-substituted pyrimidine moiety,twenty-six new suifonylurea derivatives were synthesized and their structures were confirmed by 1H NMR,31P NMR and elemental analysis.The greenhouse bioassay tests show that some title compounds exhibit potent herbicidal activity.     

Viruses and virus-like particles identified in ostrich gut contents

Several postsynaptic nondepolarizing muscle relaxants are used today mainly for maintenance of muscular relaxation in surgical operations. They possess a highly selective effect on the cholinoceptors (CC) of the skeletal muscle postsynaptic membrane. Aminosteroid derivatives are important among them. The first to be suggested was pancuronium, and later pipecurium and the monoquaternary aminosteroid derivatives vecoronium and rocuronium. Highly selective muscle relaxants are atracurium and its isomers, cisatracurium in particular, as well as some atracurium derivatives: mivacurium and doxacurium. Tercuronium also has a highly selective effect on the CC of the skeletal muscles.     

Hypersensitive urticarial vasculitis after natisedine intake

BACKGROUND: Various skin and mucosal reactions can be observed after administration of quinidine derivatives. CASE REPORT: A patient who was taking Natisédine (quinidine phenylethyl barbiturate) intermittently and at reintroduction developed a papulopurpuric eruption (without thrombopenia) producing extensive centrifugal annular infiltration and central healing which regressed approximately one week after drug withdrawal. This eruption was associated with moderate 24 h proteinuria. The clinical aspect was that of vasculitis purpura as confirmed histology. Direct immunofluorescence only demonstrated C3 deposits in the vessel walls of the superficial dermis. The quinidine moiety of this drug (currently removed from the formulation) appears to be the responsible agent (imputability score: 13 B3). DISCUSSION: Thrombopenic purpura by synthesis of anti-platelet antibodies induced by quinidine derivatives is well known. Inversely, cases of non-thrombopenic purpura imputable to these same derivatives is uncommon (7 reported cases). The pathophysiological mechanisms involved might be similar (antigenic similarity between the platelet surface and endothelium).     

An oxazine reagent for derivatization of carboxylic acid analytes suitable for liquid chromatographic detection using visible diode laser-induced fluorescence

This study reports the use of Nile Blue, an oxazine dye, as a derivatization reagent that fluoresces in the far-red spectral region and is suitable for derivatization with carboxylic-acid-containing analytes. Model carboxylic acid analytes such as benzoic acid, acetic acid, phenylacetic acid and hexanoic acid have been reacted as acid chlorides to form Nile Blue derivatives. The synthesis product of the Nile Blue benzoic acid derivative was confirmed using electrospray-mass spectrometry, infrared spectrometry, 1H and 13C nuclear magnetic resonance, reversed phase liquid chromatography (RP-HPLC), normal phase-thin layer chromatography, and spectral characterization. The synthesized Nile Blue derivatives, separated from reaction by-products with RP-HPLC, all demonstrated an approximately 10-fold drop in molar absorptivity and relative quantum yield. In addition, a 40 nm increase in Stokes shift was observed. A portion of the fluorescence was regained through post-column ionization of the Nile Blue benzoic acid derivative at pH 12. A RP-HPLC limit of detection of 88.25 fmol on column has been reported with conventional fluorescence detection-post-column ionization of the Nile Blue benzoic acid derivative. A limit of detection of 1.99 fmol on column (3.98 x 10(-11) M) has been demonstrated for the Nile Blue benzoic acid derivative with the use of a laboratory-constructed visible diode laser fluorescence detector.     

ATP-sensitive potassium channels and substances affecting them

ATP-sensitive potassium channels are the site of action of the sulphonylurea derivatives that are used to treat non-insulin-dependent diabetes mellitus. These ATP-sensitive potassium channels are also found in myocardial cells and in vascular smooth muscle cells. The sulphonylurea derivatives have been reported to cancel the cardioprotective effects by blocking the opening of these channels in myocardium and vascular smooth muscles. A new sulphonylurea derivative, glimepiride, has been shown to be devoid of vascular ATP-sensitive potassium channel binding properties. The so called potassium-channel-openers, on the other hand, are expected to be used in the treatment of hypertension, ischemic heart disease and asthma bronchiale.     

Newly synthesized dihydropyridine derivatives as modulators of P-glycoprotein-mediated multidrug resistance

Newly synthesized 1,4-dihydropyridine derivatives possessing alkyl chains at the 4-position screened whether they could overcome P-glycoprotein-mediated multidrug resistance in cultured cancer cells and also leukemia-bearing animals. Of these derivatives, some could overcome drug resistance to doxorubicin and vincristine in multidrug resistant human cancer cell lines. Combined administration of vincristine and some of the derivatives significantly increased the life span of P-glycoprotein overexpressing multidrug-resistant P388 leukemia-bearing mice. The calcium antagonistic activities, an undesirable effects, were weaker than that of verapamil. These results suggested that the introduction of alkyl groups at the 4-position were effective for both overcoming multidrug resistance and reducing the calcium antagonistic activity.     

Microbial transformation of antibiotics II. Additional transformation products of maridomycin III

Streptomyces sp. strain No. K-245 was found to transform maridomycin III into four derivatives (A1, A2, A3 and A4) in addition to the transformation products reported previously. Isolation of the main product A1 was carried out by column chromatography on silica gel developed with CHCl3-MeOH (19:1). From the partial investigation of the structure of A1, it proved to have a C-18-aldehyde group and C 4'-propionyl group but no antimicrobial activity. The relationships between A group's derivatives and known derivatives of maridomycin III are also discussed.     

Circulating bile is the main factor responsible for atrial natriuretic peptide release in experimental obstructive jaundice

A series of 18 aporphinoids have been tested in vitro against human poliovirus. The aporphines (+)-glaucine fumarate (1), (+)-N-methyllaurotetanine (4), (+)-isoboldine (7), and (-)-nuciferine, HCl (10) were found to be active with selectivity indices > 14. The nature of the 1, 2-substituents of the isoquinoline moiety appeared to be critical for antipoliovirus activity. An SAR study demonstrated the importance of a methoxyl group at C-2 on the tetrahydroisoquinoline ring for the induction of antipoliovirus activity. Molecular modeling of some compounds in this series revealed the close similarities between the three-dimensional conformational features of the inactive 1,2-substituted derivatives (+)-boldine (6) and (+)-laurolitsine (5) with derivatives containing the 1,2-(methylenedioxy) moiety, which were generally found to be inactive as exemplified by (+)-cassythicine (9).     

Preparation and properties of the O-methyl derivatives of 9-beta-D-arabinofuranosyladenine

The previously reported resistance of 9-substituted adenines to ring alkylation in alkaline medium was profited from to prepare all seven possible O' methyl derivatives of the therapeutically important 9-beta-D-arabinofuranosyladenine (araA) by mild methylation of the latter with dimethylsulfate in aqueous alkaline medium. All the products were fractionated and isolated in a single step on a Dowex OH- column. The sequence of elution of the various derivatives was strikingly similar to that for the O' methyl derivatives of 1-beta-D-arabinofuranosylcytosine, previously reported, suggestive of a similar sequence of acidities of the sugar hydroxyls. The products were identified by various criteria, including PMR spectroscopy, extensive data for which are supplied. The 2'-O-methyl and 3'-O-methyl derivatives of araA exhibited appreciably lower susceptibility to calf intestinal adenosine deaminase than the parent araA. The 5'-O-methyl analogue was fully resistant to enzymatic deamination.     

Sphingolipid base metabolism. Sphinganine-1-phosphate lyase: identification of ethanolamine 1-phosphate as product

Ethanolamine 1-phosphate has been characterized as a product of the action of rat liver microsomal sphinganine 1-phosphate lyase on erythro-sphinganine 1-phosphate. The product was characterized by various forms of chromatography, gas-liquid chromatography-mass spectral analysis of appropriate derivatives, and by conversion to ethanolamine. The results of detailed studies of the mass spectral fragmentation of the tetra-trimethylsilyl derivative of ethanolamine 1-phosphate are also reported.     

Does knowledge about attention-deficit/hyperactivity disorder impact teachers' reported behaviors and perceptions?

This study surveyed elementary school teachers in Melbourne, Australia to investigate their knowledge about attention-deficit/hyperactivity disorder (ADHD) and its impact on their reported behavior toward and perceptions of children with ADHD. Consistent with previous international findings, teachers demonstrated good overall knowledge about ADHD, with strengths in knowledge of symptoms/diagnosis and weaknesses in knowledge of causes and treatments. To investigate how knowledge impacted reported behaviors and perceptions, teachers also read vignettes of children with ADHD symptoms and rated their reactions to these children. In general, teachers with high, and to some extent average, knowledge about ADHD reported more helpful behaviors (e.g., help-seeking for their students) and perceptions (e.g., perceive the benefit of behavioral and educational treatments). However, teachers with high and average knowledge also predicted that these children would be more disruptive in the classroom, and reported having less confidence in their ability to manage these children. Implications and need for future research are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Anticonvulsant activity of novel derivatives of 2- and 3-piperidinecarboxylic acid in mice and rats

The relative ability of derivatives of 2-piperidinecarboxylic acid (2-PC; pipecolic acid) and 3-piperidinecarboxylic acid (3-PC; nipecotic acid) to block maximal electroshock (MES)-induced seizures, elevate the threshold for electroshock-induced seizures and be neurotoxic in mice was investigated. Protective index (PI) values, based on the MES test and rotorod performance, ranged from 1.3 to 4.5 for 2-PC benzylamides and from < 1 to > 7.2 for 3-PC derivatives. PI values based on elevation of threshold for electroshock-induced seizures and rotorod performance ranged from > 1.6 to > 20 for both types of derivatives. Since preliminary data indicated that benzylamide derivatives of 2-PC displace [3H]1-[1-(2-thienyl)-cyclohexyl]piperidine (TCP) binding to the phencyclidine (PCP) site of the N-methyl-D-aspartate (NMDA) receptor in the micromolar range and such low affinity uncompetitive antagonists of the NMDA receptor-associated ionophore have been shown to be effective anticonvulsants with low neurological toxicity, the 2-PC derivatives were evaluated in rat brain homogenates for binding affinity to the PCP site. Although all compounds inhibited [3H]TCP binding, a clear correlation between pharmacological activity and binding affinity was not apparent. Select compounds demonstrated minimal ability to protect against pentylenetetrazol-, 4-aminopyridine- and NMDA-induced seizures in mice. Corneal and amygdala kindled rats exhibited different sensitivities to both valproic acid and the nonsubstituted 2-PC benzylamide, suggesting a difference in these two models. Enantiomers of the alpha-methyl substituted benzylamide of 2-PC showed some ability to reduce seizure severity in amygdala kindled rats.     

Inhibition of chemotactic motility and trans-endothelial migration of human neutrophils by sphingosine 1-phosphate

In previous studies, we reported that sphingosine 1-phosphate (Sph-1-P) inhibits the chemotactic motility of some cancer cell lines such as mouse melanoma cells, as well as human smooth muscle cells, at a very low concentration, as demonstrated by a transwell migration assay method (Proc. Natl. Acad. Sci. USA 89, 9698, 1992; J. Cell Biol. 130, 193, 1995). In this study, we investigated the effect of Sph-1-P on the chemotactic motility and invasiveness of human neutrophils, utilizing three different assay systems: (a) a transwell migration assay where IL-8 or fLMP was added as a chemotactic factor, (b) a phagokinetic assay with gold colloids, and (c) a trans-endothelial migration assay with human umbilical vein endothelial cells (HUVECs) plated on collagen layers. We found that among various sphingosine derivatives, Sph-1-P specifically inhibited the IL-8- or fLMP-induced chemotactic migration of neutrophils at concentrations below 1 microM. Phagokinetic activity of neutrophils was also suppressed by Sph-1-P, but more moderately than by the PKC inhibitory sphingosine analog, trimethylsphingosine. Finally, Sph-1-P inhibited trans-endothelial migration and invasiveness of neutrophils into HUVEC-covered collagen layers, whereas no effect on their adhesion to HUVECs was observed. These observations strongly suggest that Sph-1-P can act as a specific and effective motility regulator of human neutrophils, raising the possibility of future applications of Sph-1-P, or its analogs, as anti-inflammatory agents regulating invasive migration of neutrophils through endothelial layers at injured vascular sites.     

Mesangial involvement in hemolytic-uremic syndrome. A light and electron microscopic study

Electron microscopic analysis of the mesangial injury in the hemolytic-uremic syndrome was performed in 10 patients. Proteinaceous material similar to that found in the subendothelial region was also seen focally in the mesangium altering the matrix and imparting a reticular appearance. This degenerative process was associated with reparative changes in the glomerular tuft. Many of the mesangial cells were hypertrophied and demonstrated phagocytic activity and peripheral extension of their cytoplasmic processes. Mitotic figures in endothelial as well as mesangial cells were regarded as evidence of a reparative process. Severe mesangial insudation of material containing fibrinogen derivatives resulted in segmental tuft necrosis with almost complete replacement and destruction of the mesangial matrix. On some occasions, a break of the glomerular basement membrane was accompanied by the escape of intraluminal contents into the urinary space, leading to crescentic epithelial cell proliferation.     

In vitro platelet-activating factor receptor binding inhibitory activity of pinusolide derivatives: a structure-activity study

Pinusolide, a labdane-type diterpene lactone isolated from Biota orientalis, was found to be a potent platelet-activating factor (PAF) receptor binding antagonist. To investigate the structure-activity relationship and find derivatives with improved pharmacological profiles, 17 pinusolide derivatives were prepared and tested for their ability to inhibit the PAF receptor binding. The results demonstrated that the carboxymethyl ester group at C-19, the integrity of the alpha,beta-unsaturated butenolide ring, and the exocyclic olefinic function of pinusolide are all necessary for its maximum PAF receptor binding inhibitory activity. Among the derivatives, the 17-nor-8-oxo derivative 8 was found to be as potent as pinusolide. The results also suggested that several derivatives warrant further pharmaceutical and pharmacological studies due to their improved water solubility (8 and 11) and apparent lack of susceptibility to Michael-type nucleophilic addition (13 and 18).