AIMTo study the synthetic method and antibacterial activity of amino-heterocyclic compounds coupled oxime-ether group.

METHODSThe treatment of 4-amino-3-methyl-5-mercapto-s-triazole (3) with beta-chlorophenyl-propanone to form amino-s-triazole sulfanylphenyl-propanone (4) sequentially followed by oximation with hydroxyl-amine to produce the oximes (5) and etherification with various oxadiazole chloromethanes (6a - j) to yield the title compounds (1a - j). The in vitro antibacterial activities of all newly synthesized compounds were tested against Gram positive bacteria and Gram negative bacteria with the standard 2-fold agar dilution method.

RESULTSTwelve new compounds including two intermediates were synthesized and their structures were confirmed by IR, 1H NMR, MS and elemental analyses. The ten title compounds exhibited the potential antibacterial activities in vitro.

CONCLUSIONTheses compounds should be optimized.

Anti-Bacterial Agents ; chemical synthesis ; pharmacology ; Oxadiazoles ; chemical synthesis ; pharmacology ; Oximes ; chemical synthesis ; pharmacology ; Triazoles ; chemical synthesis ; pharmacology

OBJECTIVEInhibition of acetylcholinesterase (AChE) in human brain caused by phoxim or phoxim oxon, their reactivation with oxime and aging of phosphorylated AChE were studied and compared in vitro.

METHODSMicro-colorispectrophotometric assay was used to determine the activity of AChE.

RESULTSThe pI(50) of inhibition of AChE in human brain by phoxim and phoxim oxon were 5.39 and 5.77, respectively, whereas the pI(90) were 4.60 and 5.00, respectively. The reactivation rate of 0.1 mmol/L of pralidoxime (2-PAM), obidoxime (LüH(6)), trimedoxime (TMB-4) and pyramidoxime (HI-6) for phoxim-inhibited AChE in human brain was 65%, 97%, 91% and 56%, respectively, and their reactivation rate for phoxim oxon-inhibited AChE in human brain was 97%, 87%, 99% and 89%, respectively. The optimal reactivator for phoxim and phoxim oxon-inhibited AChEs was LüH(6) and TMB-4, respectively. The half aging time of phoxim and phoxim oxon inhibited phosphorylated AChEs were 39 and 28 hours, respectively, and the 99% aging time were 256 and 186 hours, respectively.

CONCLUSIONSLüH(6) or TMB-4 should be used at the earlier as possible after poisoning with phoxim and phoxim oxon, and the reactivator should be consecutively used for more than seven days, even after their acute symptoms have been well controlled.

Acetylcholinesterase ; metabolism ; Brain ; drug effects ; enzymology ; Cholinesterase Inhibitors ; pharmacology ; Cholinesterase Reactivators ; pharmacology ; Enzyme Stability ; Humans ; In Vitro Techniques ; Obidoxime Chloride ; pharmacology ; Organothiophosphorus Compounds ; pharmacology ; Oximes ; pharmacology ; Paraoxon ; pharmacology ; Pralidoxime Compounds ; pharmacology ; Time Factors ; Trimedoxime ; pharmacology

BACKGROUNDMultidrug resistance (MDR) is a main reason for paclitaxel (TAX) treatment failure. Indirubin-3'-monoxime (IRO) and Matrine are traditional Chinese medicines, which may reverse the resistance of tumor cells to some chemotherapy drugs, but the relationship between paclitaxel resistance and Matrine is still unclear. The aim of this study was to explore the potential molecular mechanism of IRO and Matrine in reversal of TAX resistance.

METHODSIn this study, MTT assay was used to measure the non-cytotoxic dosage of IRO and Matrine on NCI-H520/TAX25 cells and determine the reversal extent of TAX resistance under non-toxic doses. In addition, RT-PCR and Western blotting were used to evaluate the mRNA expression and the protein level of survivin, Oct-4, and Sox-2 in NCI-H520/TAX25 cells using semi-quantitative methods.

RESULTSThere was no obvious inhibition on sensitive cell strains and drug-resistant strains, when the final concentration was at lest 4 µmol/L for IRO and 100 µmol/L for Matrine. So 4 µmol/L of IRO and 100 µmol/L of Matrine were considered as the reversal dosage. When 4 µmol/L of IRO or 100 µmol/L of Matrine were used together with TAX, the sensitivity to TAX increased evidently in NCI-H520/TAX2 cells; the reversal rate of IRO and Matrine was about 1.92 (43.56/22.6 nmol/L) and 1.74 (43.56/25.0 nmol/L), respectively. The mRNA expression and the protein level of survivin, Oct-4, and Sox-2 in NCI-H520/TAX25 decreased significantly (P < 0.05) after addition of IRO or Matrine in TAX treatment, compared to that of TAX treatment alone.

CONCLUSIONThe decrease in both mRNA expression and protein level of survivin, Oct-4, and Sox-2 might be the molecular mechanism, by which IRO and Matrine mediate the reversal of TAX resistance.

Alkaloids ; pharmacology ; Blotting, Western ; Cell Line, Tumor ; Drug Resistance, Neoplasm ; Humans ; Indoles ; pharmacology ; Inhibitor of Apoptosis Proteins ; genetics ; metabolism ; Octamer Transcription Factor-3 ; genetics ; metabolism ; Oximes ; pharmacology ; Paclitaxel ; pharmacology ; Quinolizines ; pharmacology ; SOXB1 Transcription Factors ; genetics ; metabolism

The present study was undertaken to explore the role of gamma-aminobutyric acid transporters in the neuropathic pain. On the chronic constriction injury (CCI) rats 4 doses (5, 10, 20, 40 microg in group N5, N10, N20, N40, respectively) of specific gamma-aminobutyric acid transporter-1 inhibitor NO-711 or normal saline (in group NS) were intrathecally administered before sciatic nerve ligation (pre-treatment) or at the third day after ligation (post-treatment). The paw withdrawl latency (PWL) from a noxious thermal stimulus and paw withdrawl mechanical threshold (PWMT) of von Frey filament was used as measure of thermal hyperalgesia and tactile allodynia respectively. The results demonstrated that post-treatment of NO-711 significantly suppressed thermal hyperalgesia and allodynia in CCI rats (P<0.05, P<0.01), the inhibitory effect lasted for 2 h (N40 group) and 4 h (N20 group) respectively. NO-711 inhibited thermal hyperalgesia induced by CCI in a dose-dependent manner. Intrathecal pretreatment with different doses of NO-711 delayed the occurrence of thermal hyperalgesia, but could not delay the emergence of allodynia induced by CCI. This study indicates that gamma-aminobutyric acid transporter inhibitor has anti-thermal hyperalgesia and anti-tactile allodynia effects in neuropathic rats.
Animals ; GABA Antagonists ; administration & dosage ; pharmacology ; Hyperalgesia ; drug therapy ; physiopathology ; Injections, Spinal ; Male ; Neurotransmitter Uptake Inhibitors ; administration & dosage ; pharmacokinetics ; Nipecotic Acids ; administration & dosage ; pharmacology ; Oximes ; administration & dosage ; pharmacology ; Pain ; physiopathology ; Rats ; Rats, Sprague-Dawley ; Sciatic Neuropathy ; drug therapy ; physiopathology

This paper is to report the development of a high-throughput in vitro system to screen hPXR/CAR mediated CYP2B6 drug inducers, and the application of it into the quick determination of induction activity toward CYP2B6 by various commonly used traditional Chinese medicines (TCMs) extract. Dual reporter gene assays were performed. The hPXR/CAR expression vectors and the reporter vector pGL3-CYP2B6-Luc involved in the distal and proximal promoters of CYP2B6 were co-transfected into HepG2 cells. Relative luciferase activities in cell lysate were analyzed after 48 h treatment of blank vehicle or drugs to determine the induction activity toward CYP2B6 by various commonly used TCMs extract. The positive hPXR/hCAR activators rifampicin and CITCO were applied to make sure that the reporter gene model was successfully established. Then 5 kinds of commonly used TCM extracts and 1 herbal compound were successfully investigated, some were found to activate hPXR or hCAR and therefore have the potential to induce CYP2B6 enzyme. This is the first domestic article to report the hCAR3-mediated CYP2B6 induction model and the establishment of a reporter gene system for hPXR/CAR-mediated CYP2B6 induction can be an effective and systemic in vitro method to investigate the drug inducers of CYP2B6 and to explain the mechanism involved.
Aryl Hydrocarbon Hydroxylases ; genetics ; metabolism ; Cytochrome P-450 CYP2B6 ; Drugs, Chinese Herbal ; isolation & purification ; pharmacology ; Genes, Reporter ; Genetic Vectors ; Hep G2 Cells ; High-Throughput Screening Assays ; Humans ; Luciferases ; genetics ; metabolism ; Oximes ; pharmacology ; Plants, Medicinal ; chemistry ; Plasmids ; Receptors, Cytoplasmic and Nuclear ; genetics ; metabolism ; Receptors, Steroid ; genetics ; metabolism ; Rifampin ; pharmacology ; Thiazoles ; pharmacology ; Transfection

AIM: In a search for new cardiovascular drug candidates, a series of novel oxime ethers derived from a natural isochroman-4-one were synthesized. METHOD: Compounds 3 and 6, derived from the natural antihypertensive compound 7, 8-dihydroxy-3-methyl-isochroman-4-one (XJP), were designed and synthesized. Subsequently, a series of novel isochroman-4-one oxime ether hybrids were prepared by hybridizing various N-substituted isopropanolamine functionalities to isochroman-4-one oxime. Furthermore, β1-adrenergic blocking activities of the synthesized compounds were assayed using the isolated rat left atria. RESULTS: Twenty target compounds were obtained, and the preliminary structure-activity relationships were deduced. The most promising compound Ic exhibited β1-adrenoceptor blocking activity (inhibition: 52.2%) at 10(-7) mol·L(-1), which was superior to that of propranolol (inhibition: 49.7%). CONCLUSION The results suggested that natural product XJP/isopropanolamine moiety hybrids may provide a promising approach for the discovery of novel cardiovascular drug candidates.
Adrenergic beta-Antagonists ; chemical synthesis ; chemistry ; pharmacology ; Animals ; Antihypertensive Agents ; chemical synthesis ; chemistry ; pharmacology ; Benzopyrans ; chemical synthesis ; chemistry ; pharmacology ; Drugs, Chinese Herbal ; chemical synthesis ; chemistry ; pharmacology ; Humans ; Hypertension ; drug therapy ; physiopathology ; Male ; Molecular Structure ; Oximes ; chemistry ; Rats ; Rats, Sprague-Dawley ; Structure-Activity Relationship

It has been known that O-linked beta-N-acetylglucosamine (O-GlcNAc) modification of proteins plays an important role in transcription, translation, nuclear transport and signal transduction. The increased flux of glucose through the hexosamine biosynthetic pathway (HBP) and increased O-GlcNAc modification of protein have been suggested as one of the causes in the development of insulin resistance. However, it is not clear at the molecular level, how O-GlcNAc protein modification results in substantial impairment of insulin signaling. To clarify the association of O-GlcNAc protein modification and insulin resistance in rat primary adipocytes, we treated the adipocytes with O-(2-acetamido-2deoxy-D-glucopyranosylidene)amino-N-phenylcarbamate (PUGNAc), a potent inhibitor of O-GlcNAcase that catalyzes removal of O-GlcNAc from proteins. Prolonged treatment of PUGNAc (100 micrometer for 12 h) increased O-GlcNAc modification on proteins in adipocytes. PUGNAc also drastically decreased insulin-stimulated 2-deoxyglucose (2DG) uptake and GLUT4 translocation in adipocytes, indicating that PUGNAc developed impaired glucose utilization and insulin resistance in adipocytes. Interestingly, the O-GlcNAc modification of IRS-1 and Akt2 was increased by PUGNAc, accompanied by a partial reduction of insulin-stimulated phosphorylations of IRS-1 and Akt2. The PUGNAc treatment has no effect on the expression level of GLUT4, whereas O-GlcNAc modification of GLUT4 was increased. These results suggest that the increase of O-GlcNAc modification on insulin signal pathway intermediates, such as IRS-1 and Akt2, reduces the insulin-stimulated phosphorylation of IRS-1 and Akt2, subsequently leading to insulin resistance in rat primary adipocytes.
Acetylglucosamine/*analogs & derivatives/metabolism/pharmacology ; Adipocytes/*metabolism ; Animals ; Deoxyglucose/pharmacokinetics ; Glycosylation ; Immunoprecipitation ; *Insulin Resistance ; Male ; Monosaccharide Transport Proteins/metabolism ; Oximes/*pharmacology ; Phenylcarbamates/*pharmacology ; Phosphoproteins/*metabolism ; Phosphorylation ; Protein-Serine-Threonine Kinases/*metabolism ; Proto-Oncogene Proteins/*metabolism ; Rats ; Rats, Sprague-Dawley ; Research Support, Non-U.S. Gov't ; Subcellular Fractions/metabolism ; beta-N-Acetylhexosaminidase/antagonists & inhibitors

Retinoid X receptor α (RXRα) and its N-terminally truncated version tRXRα play important roles in tumorigenesis, while some RXRα ligands possess potent anti-cancer activities by targeting and modulating the tumorigenic effects of RXRα and tRXRα. Here we describe NSC-640358 (N-6), a thiazolyl-pyrazole derived compound, acts as a selective RXRα ligand to promote TNFα-mediated apoptosis of cancer cell. N-6 binds to RXRα and inhibits the transactivation of RXRα homodimer and RXRα/TR3 heterodimer. Using mutational analysis and computational study, we determine that Arg316 in RXRα, essential for 9-cis-retinoic acid binding and activating RXRα transactivation, is not required for antagonist effects of N-6, whereas Trp305 and Phe313 are crucial for N-6 binding to RXRα by forming extra π-π stacking interactions with N-6, indicating a distinct RXRα binding mode of N-6. N-6 inhibits TR3-stimulated transactivation of Gal4-DBD-RXRα-LBD by binding to the ligand binding pocket of RXRα-LBD, suggesting a strategy to regulate TR3 activity indirectly by using small molecules to target its interacting partner RXRα. For its physiological activities, we show that N-6 strongly inhibits tumor necrosis factor α (TNFα)-induced AKT activation and stimulates TNFα-mediated apoptosis in cancer cells in an RXRα/tRXRα dependent manner. The inhibition of TNFα-induced tRXRα/p85α complex formation by N-6 implies that N-6 targets tRXRα to inhibit TNFα-induced AKT activation and to induce cancer cell apoptosis. Together, our data illustrate a new RXRα ligand with a unique RXRα binding mode and the abilities to regulate TR3 activity indirectly and to induce TNFα-mediated cancer cell apoptosis by targeting RXRα/tRXRα.
Apoptosis ; drug effects ; Cell Line, Tumor ; Enzyme Activation ; drug effects ; Humans ; Ligands ; Molecular Docking Simulation ; Nuclear Receptor Subfamily 4, Group A, Member 1 ; genetics ; metabolism ; Oximes ; metabolism ; pharmacology ; Protein Conformation ; Proto-Oncogene Proteins c-akt ; metabolism ; Pyrazoles ; metabolism ; pharmacology ; Retinoid X Receptor alpha ; chemistry ; genetics ; metabolism ; Thiazoles ; metabolism ; pharmacology ; Transcription, Genetic ; drug effects ; Transcriptional Activation ; drug effects ; Tumor Necrosis Factor-alpha ; metabolism