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At least 1,189 records · Page 66Linked to original sources
PubMed1977

Comparative study of the antiviral activity of acyl derivatives of 2,2'-anhydro-1-beta-D-arabinofuranosylcytosine and other nucleosides against encephalitis in mice.

Anti-deoxyribonucleic acid virus activities of 3'-O-acyl derivatives of 2,2'-anhydro-1-beta-d-arabinofuranosyl cytosine (cyclo-C) and 1-beta-d-arabinofuranosylcytosine (Ara-C) were evaluated by using an in vivo test system in mice. Among the derivatives tested, 3'-O-decanoyl cyclo-C hydrochloride was the most effective against herpes simplex virus-induced encephalitis in mice when the drug was administered directly into infected brains of mice (target-organ treatment). A comparative study of the treatment of herpetic encephalitis in mice with 3'O-decanoyl cyclo-C and other nucleosides, including Ara-C, 9-beta-d-arabinofuranosyladenine (Ara-A), and 5-iodo-2'-deoxyrudine (IUdR), proved Ara-A to be more efficacious than the other nucleosides, followed by 3'-O-decanoyl cyclo-C, which was more active than Ara-C and IUdR. Administration of 3'-O-acyl cyclo-C's by intraperitoneal injection, however, failed to demonstrate activity against herpetic encephalitis in mice. The antivaccinial activity of 3'-O-decanoyl cyclo-C was also compared with that of other compounds against encephalitis and dermal tail lesions in mice caused by vaccinia virus infection. Interaperitoneally administered 3'-O-decanoyl cyclo-C and Ara-C also showed no significant activity against the diseases. Under these test conditions, N-methylisatin-beta-thiosemicarbazone (Marboran) was the most active compound, followed by Ara-A.

Animals↗
PubMed1978

Effect of zinc and other chemical agents on foot-and-mouth-disease virus replication.

Chemical agents reported to inhibit the growth of various ribonucleic acid and deoxyribonucleic acid viruses were tested against foot-and-mouth disease virus in cell culture. These included Zn(2+), aurintricarboxylic acid, polyribocytidylic acid, polyriboinosinic acid, phosphonoacetic acid, and the viral contact inactivator N-methyl isatin beta-thiosemicarbazone alone and with CuSO(4). The most effective agent, Zn(2+), inhibited foot-and-mouth disease virus production in primary calf kidney cells by 1 log unit at 0.05 mM Zn(2+) and completely at 0.50 mM. Zinc was inhibitory even when added late in infection and was nontoxic to uninfected cells as measured by protein and nucleic acid syntheses. Polyacrylamide gel patterns of [(35)S]methionine-labeled, virus-specific proteins showed increasing amounts of higher-molecular-weight material, in accord with reports that Zn(2+) inhibits post-translational cleavages of other picornavirus precursor polypeptides.

Antiviral Agents↗
PubMed1987

Inhibitory effects of antiviral compounds on respiratory syncytial virus replication in vitro.

We examined the inhibitory effect of 20 antiviral compounds, including ribavirin, on the replication of respiratory syncytial virus in HeLa and HEp-2 cell cultures. Of the compounds studied, pyrazofurin and 3-deazaguanine emerged as more potent inhibitors of respiratory syncytial virus than ribavirin. Based on their inhibitory effect on the cytopathogenicity of respiratory syncytial virus in HeLa cells, the average 50% effective dose of pyrazofurin and 3-deazaguanine for eight strains was 0.07 and 1.65 micrograms/ml, respectively; that of ribavirin was 5.82 micrograms/ml. The cytotoxicity of these compounds for HeLa cells was examined by monitoring the incorporation of radiolabeled uridine into cellular RNA. The selectivity indexes of pyrazofurin and 3-deazaguanine exceeded that of ribavirin by 70- and 11-fold, respectively. Pyrazofurin, 3-deazaguanine, and ribavirin inhibited both viral antigen expression and syncytium formation in HeLa cell cultures, as assessed by an indirect immunofluorescence assay. In these assays, pyrazofurin and 3-deazaguanine again proved more potent than ribavirin. 2,5-Diamidinoindole and carbodine were less potent than ribavirin. Various other compounds, i.e., 3-adenin-9-yl-2-hydroxypropanoic acid isobutyl ester, 3-deazauridine, 3'-C-methyluridine, 5'-deoxy-5-fluorouridine, 5-cyanoimidazole-4-carboxamide, and its ribofuranosyl derivative, did not inhibit the cytopathic effect of the Long strain of respiratory syncytial virus at concentrations greater than or equal to 125 micrograms/ml. Tubercidin, 5-chlorotubercidin, xylotubercidin, neplanocin A, thiosemicarbazone R, and 3-methylquercetine were too toxic to HeLa cells for their inhibitory effects on respiratory syncytial virus to be examined.

Antiviral Agents↗
PubMed1989

Resolution of vaccinia virus DNA concatemer junctions requires late-gene expression.

Vaccinia virus replicates in the cytoplasm of infected cells, generating transient replicative intermediates containing the DNA for the terminal sequences as concatemeric junctions. The processing of the terminal sequences for a series of vaccinia virus conditional lethal mutants at the nonpermissive temperature was analyzed by restriction enzyme digestion and Southern blot hybridization of DNA isolated from infected cells. Three phenotypes were observed: DNA replication negative (Rep-), DNA replication positive but concatemer resolution negative (Rep+ Res-), and DNA replication positive and concatemer resolution positive (Rep+ Res+). Interestingly, all six Rep+ Res- mutants from separate complementation groups were defective in late protein synthesis. Isatin beta-thiosemicarbazone, a drug that blocks late protein synthesis, also prevented resolution of concatemers. Orthogonal field gel electrophoresis of the DNA generated by the late defective mutants revealed a distribution of linear genome multimers. The multimers were processed into mature monomers after a shift to the permissive temperature in the presence of cytosine arabinoside for all the Rep+ Res- mutants except ts22, an irreversible mutant which cleaves RNA late in infection (R.F. Pacha and R.C. Condit, J. Virol. 56:395-403, 1985). Genome formation can be divided into two stages: DNA replication, which generates concatemers, and resolution, which processes concatemers into monomers with hairpin termini. Early viral genes are required for the former, and late viral genes are required for the latter.

Animals↗
PubMed1996

Phenotypic characterization of mutants in vaccinia virus gene G2R, a putative transcription elongation factor.

The phenotypic defects of two mutants of vaccinia virus, the lesions of which map to gene G2R, were characterized in vivo, and the results suggest a role for the G2R protein in viral transcription elongation. Both a temperature-sensitive mutant, Cts56, and an isatin-beta-thiosemicarbazone-dependent deletion mutant, G2A, in gene G2R have a characteristic and unique defect in late viral gene expression. The G2R mutants synthesize early viral RNA, early viral proteins, and viral DNA normally under nonpermissive conditions. In G2R mutants, late viral protein synthesis begins at the normal time, low-molecular-weight viral proteins are synthesized in normal quantities, but synthesis of high-molecular-weight viral proteins is reduced in amount. Intermediate and late promoter utilization is normal in G2R mutants, but intermediate and late RNAs are reduced in size. The reduction in length of the intermediate and late mRNAs represents a truncation of mRNA 3' ends. Thus, intermediate and late RNAs are too short to encode large proteins but long enough to encode small proteins, therefore accounting for the protein synthesis phenotype. These results suggest that the G2R protein acts to regulate the elongation potential of the viral RNA polymerase late during a vaccinia virus infection.

Animals↗
PubMed2006

Selective toxicity of NSC73306 in MDR1-positive cells as a new strategy to circumvent multidrug resistance in cancer.

ATP-binding cassette (ABC) proteins include the best known mediators of resistance to anticancer drugs. In particular, ABCB1 [MDR1/P-glycoprotein (P-gp)] extrudes many types of drugs from cancer cells, thereby conferring resistance to those agents. Attempts to overcome P-gp-mediated drug resistance using specific inhibitors of P-gp has had limited success and has faced many therapeutic challenges. As an alternative approach to using P-gp inhibitors, we characterize a thiosemicarbazone derivative (NSC73306) identified in a generic screen as a compound that exploits, rather than suppresses, P-gp function to induce cytotoxicity. Cytotoxic activity of NSC73306 was evaluated in vitro using human epidermoid, ovarian, and colon cancer cell lines expressing various levels of P-gp. Our findings suggest that cells become hypersensitive to NSC73306 in proportion to the increased P-gp function and multidrug resistance (MDR). Abrogation of both sensitivity to NSC73306 and resistance to P-gp substrate anticancer agents occurred with specific inhibition of P-gp function using either a P-gp inhibitor (PSC833, XR9576) or RNA interference, suggesting that cytotoxicity was linked to MDR1 function, not to other, nonspecific factors arising during the generation of resistant or transfected cells. Molecular characterization of cells selected for resistance to NSC73306 revealed loss of P-gp expression and consequent loss of the MDR phenotype. Although hypersensitivity to NSC73306 required functional expression of P-gp, biochemical assays revealed no direct interaction between NSC73306 and P-gp. This article shows that NSC73306 kills cells with intrinsic or acquired P-gp-induced MDR and indirectly acts to eliminate resistance to MDR1 substrates.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1982

Membrane stabilization and inhibition of lipid peroxidation by anti-inflammatory indoles.

Nine 2-aryl-3-[4-(substituted phenyl)-3-thiosemicarbazone] indoles were evaluated for their ability to protect the human erythrocyte membrane against hypo-osmotic hemolysis and inhibit lipid peroxidation in rat liver homogenate in vitro. All compounds caused membrane stabilization and inhibition of lipid peroxidation when tested at final concentrations of 5 X 10(-4) and 2.5 X 10(-5) mol/l, respectively. These biochemical effects were not related to the anti-inflammatory property exhibited by the compounds.

Animals↗
PubMed1980

Estrogen receptor cytochemistry by fluorescent estrogen.

A recently synthesized fluorescein-labeled estrogen (17FE, 1-(N)-fluoresceinyl-estrone-thiosemicarbazone) interacts with estrogen-target cells like the native hormone and visualizes the uptake, transport, and distribution of estrogen in intact target cells. Moreover, estrogen binding sites are traced by 17FE in cryostat sections of estrogen target tissues as well. Cell and tissue 17FE binding sites fulfill the accepted criteria for specific estrogen receptors (finite binding capacity, high affinity, steroid and tissue specificity). This fluorescent probe allows estrogen receptors to be studied in a wide variety of cell and tissue preparations under varying conditions of physiologic and pathophysiologic interest.

Animals↗
PubMed1985

ESR of copper and iron complexes with antitumor and cytotoxic properties.

The relatively few iron and copper metal complexes which have been examined in cells and tissues for their redox properties, radical generation properties, and antitumor activity are discussed for studies which utilized electron spin resonance spectroscopy (ESR). A common property of a number of metal complexes, which include bleomycin, adriamycin, and thiosemicarbazones described in this review, is that they are readily reduced by thiol compounds and oxidized by oxygen or reduced species of oxygen to produce radicals. Structural features of these reactions are identified by ESR spectroscopy in model systems and often in cells. Furthermore, ESR spectroscopy has been most useful to probe the environment of the complexes in cells and to measure the rate of reduction of their oxidized forms. As a result of these studies, it is anticipated that more attention will be given to the exploration of redox-active metal complexes as drugs.

Anti-Bacterial Agents↗
PubMed2001

A microsomal ecdysone-binding cytochrome P450 from the insect Locusta migratoria purified by sequential use of type-II and type-I ligands.

A dual-affinity method was established to purify, for the first time, a microsomal ecdysone-binding cytochrome P450 protein from locust Malpighian tubules. This method involved, after prepurification on omega-octylamino-agarose and hydroxylapatite, binding of cytochrome P450 to an immobilized triazole-based general P450 inhibitor (type-II ligand) followed by elution with the substrate ecdysone (type-I ligand) of the bound cytochrome. The isolated material showed a typical cytochrome P450 spectrum, a specific heme content of 13 nmol/mg protein, and a prominent protein of about 60 kDa on SDS-PAGE. Based on a tryptic undecapeptide sequence the isolated protein may be identical to CYP6H1, a putative ecdysone 20-monooxygenase recently cloned from the same tissue. Ecdysone 20-monooxygenase activity could be partially reconstituted from microsomal detergent extracts, when supplemented with purified bovine cytochrome P450 reductase and detergent-extracted microsomes; reconstitution was not successful with any chromatographic fraction, however. Therefore, purification of the locust cytochrome P450 was monitored by ecdysone-induced type-I difference spectra, whenever applicable, in addition to carbon monoxide spectra. Affinity columns with matrix-bound diethylstilbestrol and testosterone 3-thiosemicarbazone, but not with the 17beta-hemisuccinate, yielded elution profiles with ecdysone that were comparable to those of the triazole matrix. The concept of dual-affinity chromatography described here may be generally applicable to the isolation of cytochromes P450.

Aging↗
PubMed2002

Evolving role of ribonucleoside reductase inhibitors in hematologic malignancies.

Ribonucleotide reductases catalyze the de novo biosynthesis of deoxyribonucleosides for DNA synthesis. Increased ribonucleotide reductases activity has been associated with malignant transformation and tumor cell growth. The ribonucleotide reductases inhibitors may bind with the R1 subunit of the enzyme (Class 1) or the nonheme iron (Class 2). This review focuses on the therapeutic use of ribonucleotide reductases inhibitors in hematologic malignancies. Hydroxyurea, fludarabine and cladribine have established roles in the management of hematologic malignancies, while other ribonucleotide reductases inhibitors, such as gemcitabine, tezacitabine and heterocyclic carboxaldehyde thiosemicarbazones (e.g., triapine) are being evaluated in clinical trials.

Antineoplastic Agents↗
PubMed2006

An improved colorimetric determination of lead(II) in the presence of nonionic surfactant.

Phenanthraquinone monophenyl thiosemicarbazone (PPT), an excellent color-forming chelating agent, combines to Pb(II) to form a slightly soluble complex in aqueous solution. To determine this metal ion, a tedious and time-consuming separation technique, such as liquid-liquid extraction, has to be performed. However, the Pb(II)-PPT complex could be determined conveniently by ultraviolet-visible (UV-Vis) spectrophotometry at 520 nm in a Tween 80 micellar medium that has polyoxyethylene groups. After conditions, such as the pH, the concentration of PPT and the stability, were adjusted to their optimum values, the sensitivities of the Pb(II) ions in the Tween 80 micellar medium and in chloroform were compared. It was shown that the sensitivity of Pb(II) in the Tween 80 micellar medium was higher than in chloroform. The interference from different cations and anions was studied. Beer's law was obeyed over a concentration range of 0-40 microg ml(-1). The detection limit of Pb(II) was 0.036 microg ml(-1). The recovery yields of the lead(II) in the synthetic mixtures and water samples ranged from 98 to 99.8%, and their relative standard deviations (RSD) were below 4%. The proposed method was successfully applied to the determination of lead in certified reference samples, biological samples and in environmental water samples.

Journal Article↗
PubMed2003

Iron chelators as anti-neoplastic agents: current developments and promise of the PIH class of chelators.

The chelator currently used to treat iron (Fe) overload disease, desferrioxamine (DFO), has shown anti-proliferative activity against leukemia and neuroblastoma cells in vitro, in vivo and in clinical trials. Collectively, these studies suggest that Fe-deprivation may be a useful anti-cancer strategy. However, the efficacy of DFO is severely limited due to its poor ability to permeate cell membranes and bind intracellular Fe pools. These limitations have encouraged the development of other Fe chelators that are far more effective than DFO. One group of ligands that have been extensively investigated are those of the pyridoxal isonicotinoyl hydrazone (PIH) class. In this review the marked anti-proliferative effects of the PIH analogs are discussed with reference to their mechanisms of action and structure-activity relationships. In particular, we discuss the activity of a novel group of ligands that are "hybrid" chelators derived from our most effective PIH analogs and thiosemicarbazones. The anti-tumor activity of the PIH analogs and other chelators such as tachpyridine, O-trensox and the desferrithiocin analogs have been well characterized in vitro. However, further studies in animals are critical to evaluate their selective anti-tumor activity and potential as therapeutic agents.

Animals↗
PubMed2003

The role of iron chelation in cancer therapy.

This review focuses on advances and strategies in the use of iron chelators as anti-tumor therapies. Although the development of iron chelators for human disease has focused primarily on their use in the treatment of secondary iron overload, chelators may also be useful anti-tumor agents. They can deplete iron or cause oxidative stress in the tumor due to redox perturbations in its environment. Iron chelators have been tested for their anti-tumor activity in cell culture experiments, animal models and human clinical trials. Largely for pragmatic reasons, clinical studies of the anti-tumor activity of iron chelators have generally focused on desferrioxamine (DFO), a drug approved for the treatment of iron overload. These studies have shown that DFO can retard tumor growth in many different experimental contexts. However, the activity of DFO is modest, and advances in the use of chelators as anti-cancer agents will require the development of new chelators based on new paradigms. Examples of iron chelators that have shown promising anti-tumor activity (in various stages of development) include heterocyclic carboxaldehyde thiosemicarbazones, analogs of pyridoxal isonicotinoyl hydrazone, tachpyridine, O-trensox, desferrithiocin, and other natural and synthetic chelators. Apart from their use as single agents, chelators may also synergize with other anti-cancer therapies. The development of chelators as anticancer agents is largely an unexplored field, but one with extraordinary potential to impact human cancer.

Animals↗
PubMed2004

Iron chelators in cancer chemotherapy.

Iron chelators may be of value as therapeutic agents in the treatment of cancer. They may act by depleting iron, a necessary nutrient, and limiting tumor growth. Alternatively or additionally, they may form redox-active metal complexes that cause oxidative stress via production of reactive oxygen species, damaging critical intracellular targets and thereby eliciting a cytotoxic response. Studies in vitro have evaluated the structure-activity relationships and mechanism of action of many classes of iron chelators, including desferrioxamine (DFO), pyridoxal isonicotinoyl hydrazone (PIH) analogs, desferrithiocin (DFT) analogs, tachpyridine, the heterocyclic carboxaldehyde thiosemicarbazones, and O-Trensox. Animal studies have confirmed the antitumor activity of several chelators. Dexrazoxane has been approved for use in combination with doxorubicin, and its effectiveness in allowing higher doses of doxorubicin to be administered is, in part, based on the interactions of both drugs with iron. Clinical trials of the antitumor activity of chelators have been largely limited to DFO, which has been extensively studied as a consequence of its approved use for treatment of secondary iron overload. While the modest antitumor effects of DFO are encouraging, it is likely that more effective iron chelators may be identified.

Animals↗
PubMed2005

New anticonvulsant agents.

The search for antiepileptic compounds with more selective activity and lower toxicity continues to be an area of intensive investigation in medicinal chemistry. This review describes new anticonvulsant agents representing various structures for which the precise mechanism of action is still not known. Many of the compounds presented in this review have been tested according to the procedure established by the Antiepileptic Drug Development Program of the Epilepsy Branch of the National Institute of Neurological Disorders and Stroke, National Institute of Health, USA. The newer agents include sulfonamides, amino acids, amides (analogs of gamma-vinyl GABA, N-benzylamides, 2,6-dimethylanilides, carboxyamides, hydroxyamides, alkanoamides); heterocyclic agents ((arylalkyl)imidazoles, pyrrolidin-2,5-diones, lactams, semi- thiosemicarbazones, thiadiazoles, quinazolin-4(3H)-ones, 2,5-disubstituted 1,2,4-thadiazoles, xanthones, derivatives of isatin) and enaminones. These new structural classes of compounds can prove useful for the design of future targets and development of new drugs.

Animals↗
PubMed1999

Evaluation of semicarbazones for anticonvulsant and sedative-hypnotic properties.

A series of semicarbazones and thiosemicarbazones were synthesized and evaluated for anti-convulsant activity. Some compounds provided significant protection against Maximal Electroshock (MES) and subcutaneous strychnine induced seizures. Compound 1 was the most active in the series with activity in a dose of 30 mg/kg in the strychnine seizure pattern test and an ED50 of 10 mg/kg in the MES test. Hence it could serve as a prototype molecule for future development. Also compounds with a p-nitrophenyl substitution in place of the amino hydrogen of semicarbazone moiety showed activity in a dose of 30 mg/kg and an ED50 of 83 mg/kg in the MES test.

Animals↗
PubMed2000

Cytotoxicity of rhenium(I) alkoxo and hydroxo carbonyl complexes in murine and human tumor cells.

The rhenium(I) alkoxo/hydroxo carbonyl complexes were shown to be very potent in suspended tumor cell lines in suppressing growth but were more selective in inhibiting the growth of cultures from solid tumors. Their mode of action in L1210 lymphoid leukemia cells indicated that they were not alkylating agents but interfered with nucleic acid metabolism at multiple enzyme sites, e.g. dihydrofolate reductase, PRPP-amido transferase, thymidine kinase, with DNA strand scission after 60 min incubation. These compounds did not function mechanistically exclusively as cisplatin derivatives causing intrastrand linkages of DNA but rather they mimicked the metal complexes of aminecarboxyboranes, furan oximes, N-substituted thiosemicarbazones, trifluoromethyl borons and ferratricarbadecarbanyl complexes acting as antimetabolites.

Animals↗