New NO donors with antithrombotic and vasodilating activities, part 25. Hydroxylamine derivatives

Twelve ethoxycarbonyl or phenylsulfonyl derivatives as prodrugs of hydroxylamine or phenylhydroxylamine were prepared and tested for antiplatelet (in vitro, Born test) antithrombotic (in vivo thrombosis model), and antihypertensive (in vivo, SHR rats) effects. In the Born test N,N-bisphenylsulfonylhydroxylamine (10) was most active (IC50 = 11 mumol/L). The N-ethoxycarbonyl-phenylhydroxylamine (7) was the most potent antithrombotic compound. It inhibited the thrombus formation in mesenteric arterioles of rats by 39% after a single p.o. dose of 60 mg/kg. Compound 7 lacked any antihypertensive activity. It, therefore, had been possible to separate completely the antithrombotic activities from antihypertensive properties in suitable hydroxylamine derivatives.     

NO donors with antithrombotic and vasodilating activities, Part 23. Organic azides

Twenty eight organic azides were synthesized and tested for their antithrombotic and blood pressure lowering activities in rats (60 mg/kg, p.o.). In fifteen compounds significant antithrombotic effects were observed. In thirteen cases a significant lowering of the blood pressure of spontaneously hypertensive rats (SHR) was seen. The peak activities in both systems were found for hexyl azide (4), 2-phenylethyl azide (14), and 4-pyridinecarboxylic acid azide (23). In these compounds the inhibition of thrombus formation in mesenteric arterioles was > 20%. The lowering of blood pressure was > 10% and long lasting (> 6 h) in 4 and 14 while 23 had a shorter duration of action (approximately 4 h). In two classes of azides, namely branched aliphatic azides (e.g. 2-azidopentane 9) and aliphatic carbonyl derivatives (e.g. benzoyl-azido-methane 17), only antithrombotic properties were observed. A lack of endothelial metabolism is suggested to be the reason for this therapeutically favorable behaviour.     

New NO-donors with antithrombotic and vasodilating activities, Part 14. 1,3,4-Triazol-1-oles

Five 1,3,4-triazol-1-oles (5a-f) with different alkyl, aryl, and arylalkyl substituents in 2,5-position were synthesized and tested for their antithrombotic properties. The 2,5-dimethyl derivative 5a was most active. 2 h after administration of 60 mg/kg to rats thrombus formation by a laser beam was inhibited by 42% in arterioles and by 33% in venules. At the same dose the blood pressure of SHR rats was slightly (5%) but significantly decreased even 4 h after application of 5a. This pattern of activities suggests a nitric oxide mediated mechanism of action. 1,1'-Azo-bis-ethanone oxime(7)-the synthetic precursor of 5a-inhibited the aggregation of blood platelet (Born test) with an IC50 = 15 mumol/L.     

New NO-donors with antithrombotic and vasodilating activities, Part 17. Arylazoamidoximes and 3-arylazo-1,2,4-oxadiazol-5-ones

Seven arylazoamidoximes (3), six phenoxycarbonyl derivatives (4), and six 1,2,4-oxadiazol-5-ones (5) have been prepared and their structure and purity established by spectroscopy and elemental analysis. In the EI mass spectra ready elimination of NO from the title amidoximes was observed. A new addition reaction of 3a with hydrochloric acid to 4-chlorophenylhydro-azoamidoxime 7 is described. The compounds were tested for nitric oxide dependent biological properties, i.e. platelet aggregation, antithrombotic effects, and decrease in blood pressure. In arterioles of rats 5/19 compounds inhibited the formation of thrombi with a laser beam by > or = 20% 2 h after oral administration of 60 mg/kg. Among these are three amidoximes (3a, 3e, 3f), one phenoxycarbonyl derivative (4a), and one oxadiazolone (5a). With the 4-chlorophenylazoamidoxime 3c a long lasting (24 h) decrease of blood pressure in spontaneously hypertensive rats was observed. Microsomal fractions of rat liver oxidize arylazoamidoximes and generate nitric oxide (e.g. 3a and 3b). NO was measured by the oxyhemoglobin assay. The influence of SOD, pretreatment of the rats with dexamethasone, as well as kinetic parameters were determined. Type 3 compounds, therefore, are a new class of NO donors. Type 4 and 5 compounds function as their prodrugs.     

Forskolin derivatives. I. Synthesis, and cardiovascular and adenylate cyclase-stimulating activities of water-soluble forskolins

Water-soluble forskolin and 7-deacetylforskolin derivatives with an aminoacetyl, a 3-aminopropionyl, or a 4-aminobutyryl group at the 6- or 7-position were prepared, and their positive inotropic as well as vasodilative activities were evaluated in anesthetized dogs. 7-Deacetylforskolin (2) and 7-deacetyl-1-silylforskolin (6) were converted to the corresponding 7-chloroacylderivatives (3, 7, 10), which were reacted with amines to obtain 7-aminoacyl-7-deacetylforskolins (4a-f, 9a, b, 11). The 7-acyl substituents migrated to the 6-position with sodium hydroxide in acetonitrile-water to afford 6-aminoacyl-7-deacetylforskolins (12a-f). The 7-position of 12a, d-f was selectively acetylated with acetyl chloride to obtain the corresponding 6-aminoacylforskolins (13a-d). Among the 6-aminoacylforskolins, 6-(3-dimethylaminopropionyl)forskolin (13b) and 6-(4-dimethylaminobutyryl)forskolin (13d) exhibited potent positive inotropic and vasodilative activities comparable to those of forskolin (1). The activities of 13b and 13d were approximately ten times more potent than those of 7-aminoacyl- and 6-aminoacyl-7-deacetylforskolins (4a-f, 9a, 12a-c, f). 6-Dimethylaminoacetylforskolin (13a) and 6-(3-diethylaminopropionyl)forskolin (13c) were less potent than 1. The effects of the soluble forskolins on adenylate cyclase activity were also examined in vitro. 6-Aminoacylforskolins (13a-d) exhibited potent adenylate cyclase-stimulating activity, comparable to that of 1.     

New pleuromutilin derivatives with enhanced antimicrobial activity. I. Synthesis

Structural modification of the antibiotic pleuromutilin has afforded several derivatives with considerably enhanced activity against bacteria and mycoplasmas, and has permitted conclusions to be reached about structure-activity relationships. The carbonyl group in the five-membered ring and the hydroxyl group at C11 seem to be essential for activity. The vinyl group can be hydrogenated without loss of activity. Chemical modification at C14 offers the most possibilities for achieving the best activity and solubility properties. Mutilin, and other compounds with a free OH at C14, are inactive. It was shown that mutilin esters of substituted thioglycolic acids had distinctly superior MIC values, especially in combination with a tertiary amino group in the side chain, the latter group of derivatives having MIC values better than pleuromutilin by a factor of more than 10. Further variation within this group led to the development of 14-deoxy-14-[(2-diethylaminoethyl) thioacetoxy]-mutilin hydrogen fumarate (81.723 hfu, tiamulin) for extensive investigation of its chemotherapeutic potential.     

Novel cephalosporin derivatives possessing a bicyclic heterocycle at the 3-position. Part I: Synthesis and biological activities of 3-(benzothiazol-2-yl)thiocephalosporin derivatives, CP0467 and related compounds

Insertional mutagenesis in transgenic mice is a powerful method to study structure/function relationships between individual genes and complex developmental traits in the whole organism. Unlike spontaneous or chemical-induced mutations, insertional mutations have the advantage that the mutant locus is "tagged" with the transgene and, therefore, readily accessible at the molecular level. Starting with the work on the limb deformity locus, we describe here the characterization of several mouse mutants generated by insertional mutagenesis with the pronuclear microinjection procedure. These transgenic lines have proven to be ideal as models for human disease and for studying the function of novel genes during development. We also describe the unique features of insertional mutations that arise in transgenic mice produced with the pronuclear microinjection procedure and provide recommendations on how to clone and characterize these mutations at the molecular level. Finally, we discuss future prospects for the use of this unique form of germline mutagenesis in the mouse.     

45钢、40Cr钢调质热处理新工艺研究

文章介绍一种有色金属加工工具用45钢、40Cr钢调质热处理新工艺,与传统的调质热处理工艺不同,45钢、40Cr钢在达到淬火温度后,不需保温立即淬火(又称零保温时间),再经回火处理。试验发现,经过新工艺处理后的工具综合性能与传统工艺处理的大体相当,但新工艺具有缩短保温时间,节约能源,降低生产成本,并改善工具表面耐磨性和内部组织性能等优点。     

Polyunsaturated fatty acids, Part 1: Occurrence, biological activities and applications

Polyunsaturated fatty acids form a unique class of food constituents that show a wide range of functions in biological systems. Investigations over the past two decades have uncovered their roles and those of their eicosanoid metabolites, and have highlighted their homeostatic functions in mammals. A growing number of common human medical conditions are thought to be traceable to dysfunctions in the eicosanoid system, which could in turn be due to imbalances in the intake and/or metabolism of polyunsaturated fatty acids. This, together with medical advances, has spurred the introduction of biomedical products, nutritionals, fortified foods and health supplements.     

Investigation on cyclic guanidine derivatives. Part III. Synthesis and properties of 2-piperidino and 2-homopiperidino-tetrahydropyrimidine-4,6-dione derivatives

Two cases of intoxication by diphenoxylate, inespecific antidiarrheal, depressor of the intestinal motility, are presented. Diphenoxylate is chemically related with meperidine. One case was caused by hipersensitivity and the other one by overdose. Both had a favourable outcome. Existent bibliography was reviewed and clinical signs of this intoxication pointed-out. It is suggested that diphenoxylate should not be prescribed to children under thirty months.     

5-Fluorouracil derivatives. XXII. Synthesis and antitumor activities of 1-carbamoyl-5-fluorouracils

Fifty-four 1-carbamoyl-5-fluorouracils were synthesized from 5-fluorouracil and isocyanate or amine. Antitumor activity was tested in the L-1210 tumor system, and 11 compounds gave better values of therapeutic ratio than HCFU (1-hexylcarbamoyl-5-fluorouracil). 1-(4-Methoxycyclohexylcarbamoyl)-5-fluorouracil gave the best result.     

Heart surgery, cardiopulmonary bypass, and organic inflammatory response. Part II: changes in leukocytes, arachidonic acid derivatives, and hormones

The use of cardiopulmonary bypass for surgical cardiac procedures is characterized by a whole-body inflammatory reaction due to the contact of blood through nonendothelialized surfaces; this stimulates the organism to recognize the cardiopulmonary bypass system as "nonself" and to activate specific (immune) and nonspecific (inflammatory) responses. These responses are then related with postoperative damage to many body systems of the body, like pulmonary, renal or brain dysfunction, excessive bleeding and postoperative sepsis. In this paper, present knowledge on untoward responses of the patient to cardiopulmonary bypass in cardiac surgery is reviewed and discussed, particularly focusing on the perturbation of the leukocytes, of the hormones and of the products of the arachidonic acid cascade.     

Synthesis and 5 alpha-reductase inhibitory activities of benzofuran derivatives with a carbamoyl group

Pentoxifylline, which has immunomodulatory effects in addition to its better known rheologic effects, might potentiate the effectiveness of traditional immunosuppressive drugs. We therefore studied the suppressive effect of pentoxifylline in combination with clinically relevant concentrations of prednisolone, methylprednisolone, cyclosporine, tacrolimus, rapamycin, and mycophenolic acid on mitogen-stimulated lymphocytes from 29 patients with glomerular diseases. Inhibition of lymphocyte proliferation obtained with 10(-7) and 10(-8) mol/L concentrations of the glucocorticoids and with 300 ng/mL cyclosporine was significantly increased when each was combined with 5, 25, or 50 microg/mL of pentoxifylline. The additive inhibitory effect of pentoxifylline in combination with 10(-7) mol/L glucocorticoids was inversely proportional to the inhibitory effect of the 10(-7) mol/L concentration of glucocorticoid alone, suggesting that the less sensitive the patient's cells, the greater the potentiation by pentoxifylline. The greatest degree of potentiation by pentoxifylline occurred when combined with the lower (10(-8) mol/L) concentration of glucocorticoids. Pentoxifylline also significantly increased lymphocyte suppression in combination with 150 and 300 ng/mL concentrations of cyclosporine, 5 ng/mL of tacrolimus, 2.5 x 10(-7) mol/L mycophenolic acid, and 10 ng/mL of rapamycin. These in vitro results suggest that pentoxifylline might have steroid-sparing effects and contribute to improved clinical outcomes from immunosuppressive treatment of renal diseases.     

Chemistry of pseudomonic acid. Part 16. Aryl and heteroaryl ketone derivatives of monic acid

The synthesis, antibacterial activities, murine pharmacokinetic and infection model data for a range of aryl and heteroaryl ketone derivatives of monic acid (2a) are reported. The best results were found for the 3-furyl and 2-methoxy thiazol-5-yl analogues.     

Novel antiallergic agents. Part I: Synthesis and pharmacology of pyrimidine amide derivatives

Cytolytic T cells use two mechanisms to kill virally infected cells, tumor cells, or other potentially autoreactive T cells in short-term in vitro assays. The perforin/granule exocytosis mechanism uses preformed cytolytic granules that are delivered to the target cell to induce apoptosis and eventual lysis. FasL/Fas (CD95 ligand/CD95)-mediated cytolysis requires de novo protein synthesis of FasL by the CTL and the presence of the death receptor Fas on the target cell to induce apoptosis. Using a CD8(+) CTL clone that kills via both the perforin/granule exocytosis and FasL/Fas mechanisms, and a clone that kills via the FasL/Fas mechanism only, we have examined the requirement of intra- and extracellular Ca2+ in TCR-triggered cytolytic effector function. These two clones, a panel of Ca2+ antagonists, and agonists were used to determine that a large biphasic increase in intracellular calcium concentration, characterized by release of Ca2+ from intracellular stores followed by a sustained influx of extracellular Ca2+, is required for perforin/granule exocytosis. Only the sustained influx of extracellular Ca2+ is required for FasL induction and killing. Thapsigargin, at low concentrations, induces this small but sustained increase in [Ca2+]i and selectively induces FasL/Fas-mediated cytolysis but not granule exocytosis. These results further define the role of Ca2+ in perforin and FasL/Fas killing and demonstrate that differential Ca2+ signaling can modulate T cell effector functions.     

Neurogenetics. Part 3. New developments in gene mapping and diagnosis

The addition of poly(ethylene glycol) (PEG) to a DNA solution induces phase separation of droplets of condensed DNA. These droplets possess liquid crystalline properties and their ordering is cholesteric. It was recently proved that daunomycin, by binding to DNA chains, inverts the long-range chirality of their tertiary packing into aggregates. The present paper suggests one possible mechanism by which this inversion can take place. Daunomycin bears a cationic group in its sugar residue. Its intercalation adds a helicoidal distribution of transverse dipoles to DNA chains. By this mechanism, in favourable cases, ionic or strongly polar groups in drugs which bind DNA can induce handedness inversion of the cholesteric ordering of its condensates. This inversion mechanism was tested experimentally using several, charged and uncharged, homologues of daunomycin. All those bearing the cationic ammonium group inverted the long-range chirality of the PEG-induced DNA mesomorphic state. The effects of the uncharged desamino homologues could not be evaluated because of their lower solubility and binding affinity for DNA.     

Philosophic issues, Division 24, and the future.

Since the present condition of psychology as a theoretical science is chaotic, the overwhelming demand of the future will be for a massive onslaught of sophisticated theoretical-philosophic analysis and synthesis. It is also anticipated that the interaction of philosophy and science will involve the continual naturalization of philosophy. Intractable philosophic issues that may become more tractable as a result of empirical investigation include the problems of value, epistemology, and the nature of humankind and of mental illness. Those issues that will continue to remain intractable, at least for the near future, include free will vs determinism, the mind–body problem, and the problem of induction. Specific suggestions are made concerning how psychologists can upgrade the theoretical-philosophic expertise that will be needed in the future. Recommendations for action by Division 24 include division-sponsored postdoctoral workshops and introduction of annual convention innovations such as seminars-in-the-round and distinguished contribution awards in theory construction and philosophical analysis. (51 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Studies on novel bone resorption inhibitors. II. Synthesis and pharmacological activities of fused aza-heteroarylbisphosphonate derivatives

Two new series of fused aza-heteroarylbisphosphonates (5, 8), which are structurally quite different from incadronate (YM175), and related compounds were synthesized and evaluated for antiresorptive activity using a parathyroid hormone(PTH)-induced hypercalcemia model in rats (PIH model). Among these compounds, several exhibited more potent antiresorptive activity than pamidronate. In particular, [1-hydroxy-2-(imidazo[1,2-a]pyridin-3-yl)ethylidene]bisphosphonic acid (5b, minodronate) was 100-fold more potent than pamidronate in not only the PIH model, but also in an immobilization bone atrophy model in rats (DA model), and was selected for clinical development. The structure-activity relationships in these new series of bisphosphonates are discussed.