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PubMed2005

A comparison of PET imaging characteristics of various copper radioisotopes.

PURPOSE: PET radiotracers which incorporate longer-lived radionuclides enable biological processes to be studied over many hours, at centres remote from a cyclotron. This paper examines the radioisotope characteristics, imaging performance, radiation dosimetry and production modes of the four copper radioisotopes, ( 60)Cu,( 61)Cu,( 62)Cu and( 64)Cu, to assess their merits for different PET imaging applications. METHODS: Spatial resolution, sensitivity, scatter fraction and noise-equivalent count rate (NEC) are predicted for( 60)Cu,( 61)Cu,( 62)Cu and( 64)Cu using a model incorporating radionuclide decay properties and scanner parameters for the GE Advance scanner. Dosimetry for( 60)Cu,( 61)Cu and( 64)Cu is performed using the MIRD model and published biodistribution data for copper(II) pyruvaldehyde bis(N(4)-methyl)thiosemicarbazone (Cu-PTSM). RESULTS: (60)Cu and( 62)Cu are characterised by shorter half-lives and higher sensitivity and NEC, making them more suitable for studying the faster kinetics of small molecules, such as Cu-PTSM.( 61)Cu and( 64)Cu have longer half-lives, enabling studies of the slower kinetics of cells and peptides and prolonged imaging to compensate for lower sensitivity, together with better spatial resolution, which partially compensates for loss of image contrast.( 61)Cu-PTSM and( 64)Cu-PTSM are associated with radiation doses similar to [(18)F]-fluorodeoxyglucose, whilst the doses for( 60)Cu-PTSM and( 62)Cu-PTSM are lower and more comparable with H(2) (15)O. CONCLUSION: The physical and radiochemical characteristics of the four copper isotopes make each more suited to some imaging tasks than others. The results presented here assist in selecting the preferred radioisotope for a given imaging application, and illustrate a strategy which can be extended to the majority of novel PET tracers.

Computer Simulation↗
PubMed1987

Use of fluorescein hydrazide and fluorescein thiosemicarbazide reagents for the fluorometric determination of protein carbonyl groups and for the detection of oxidized protein on polyacrylamide gels.

Highly fluorescent thiosemicarbazide and hydrazide prepared by reaction of fluorescein isothiocyanate with hydrazine or adipic acid dihydrazide have been used to monitor the presence of carbonyl groups in oxidatively modified proteins. After oxidation, proteins react with these reagents under anaerobic conditions in the dark to yield fluorescent protein conjugates (presumably thiosemicarbazones or hydrazones) which can be visualized as fluorescent bands following electrophoresis (0-4 degrees C) on lithium dodecyl sulfate-polyacrylamide gels. These reagents do not react with unoxidized proteins. The conjugates formed dissociate readily at room temperature but are fairly stable at pH 6-9, 0 degrees C. Current data suggest that these reagents will be useful in the detection and quantitation of oxidatively modified proteins in biological systems.

Electrophoresis, Polyacrylamide Gel↗
PubMed1982

Effect of hydroxyurea and 5-fluorodeoxyuridine on deoxyribonucleoside triphosphate pools early in phytohemagglutinin-stimulated human lymphocytes.

The induction of deoxyribonucleoside triphosphate pools was studied in phytohemagglutinin-stimulated human lymphocytes in the presence of metabolic inhibitors. The dATP pool was completely inhibited in cells treated with hydroxyurea, in contrast to the dTTP pool. However, 1-formyl-isoquinoline thiosemicarbazone inhibited the formation of these pools equally. During approximately 3 hr of treatment of stimulated cells with hydroxyurea, the dATP, dGTP and dCTP pools were depleted to the base levels observed in the cells before the pools were induced. The base level of the dTTP pool was achieved only in the presence of 5-fluorodeoxyuridine, but the inhibition was completely prevented by addition of thymidine. It is suggested that, when resting lymphocytes were stimulated to enter the growth cycle, the formation of deoxyribonucleoside triphosphates in the early transformation was due to the de novo pathway.

DNA↗
PubMed1985

Inhibition of ribonucleotide reductase and L1210 cell growth by N-hydroxy-N'-aminoguanidine derivatives.

A series of N-hydroxy-N'-aminoguanidine derivatives was studied for their effects on L1210 cell growth and ribonucleotide reductase activity. With the twelve compounds studied, there was a good correlation between the inhibition of L1210 cell growth and the inhibition of ribonucleotide reductase activity. The most potent compound required concentrations of only 1.4 and 2 microM for 50% inhibition of L1210 cell growth and ribonucleotide reductase activity respectively. These guanidine analogs specifically inhibited the conversion of [14C]cytidine and deoxycytidine nucleotides in the nucleotide pool and the incorporation of [14C]cytidine into DNA without altering the incorporation of [14C]cytidine into RNA. Ribonucleotide reductase activity in drug-treated cells was reduced markedly. Iron-chelating agents did not either increase or decrease the inhibition caused by the N-hydroxy-N'-aminoguanidine derivatives. No evidence was obtained that these derivatives selectively inactivated one of the subunits of ribonucleotide reductase. These compounds appear to inhibit ribonucleotide reductase by a mechanism different from hydroxyurea or the thiosemicarbazone derivatives.

Animals↗
PubMed1986

Efficient targeted insertion of an unselected marker into the vaccinia virus genome.

A method is described by which an unselected marker can be inserted into the vaccinia virus genome. Cells were infected with defective virus (either isatin-beta-thiosemicarbazone dependent or temperature sensitive) and then cotransformed with a mixture of full-length wild-type genomic vaccinia virus DNA and a cloned vaccinia DNA molecule containing an allele for phosphonoacetic acid resistance. After incubation under conditions which are nonpermissive for the defective virus but which do not select for incorporation of phosphonoacetic acid resistance, the virus yields were assayed for the presence of all markers involved. Phosphonoacetic acid resistance was inserted into an otherwise wild-type genome with an efficiency of 25-33%. This represents an increase in efficiency of 150-to 3000-fold relative to controls. The procedure should be extremely useful for engineering the vaccinia virus genome.

DNA, Viral↗
PubMed1984

Studies on the differential mechanisms of inhibition of ribonucleotide reductase by specific inhibitors of the non-heme iron subunit.

The data presented here show that while the non-heme iron subunit of ribonucleotide reductase is inhibited by IMPY, hydroxyurea and MAIQ, the mechanism of inhibition by hydroxyurea and IMPY is distinct from that for MAIQ. This difference in mechanisms is expressed not only in effects of iron-chelating agents on enzyme activity and of L1210 cell growth in culture, but also in differences in responses to catalase and peroxidase. Further, these data suggest that the inhibition of reductase activity by IMPY and IMPY/iron-chelator occurs through different pathways. The same conclusion can be drawn for the inhibition of reductase by hydroxyurea and hydroxyurea/iron-chelator. It is clear that additional studies will be required to understand the exact mechanism by which hydroxyurea or IMPY and the thiosemicarbazones inhibit the non-heme iron component of ribonucleotide reductase. It will also be necessary to better define the pathways of inhibition of reductase activity by IMPY and the IMPY/iron-chelator combination (or hydroxyurea and hydroxyurea/iron-chelator combination). From these studies may come information which will allow these antitumor agents to have greater utilization in the clinical management of neoplastic diseases.

Anaerobiosis↗
PubMed1986

Prophylaxis of Rift Valley fever with antiviral drugs, immune serum, an interferon inducer, and a macrophage activator.

Rift Valley fever virus (RVFV), a member of the family Bunyaviridae, extended its range from sub-Saharan Africa into Egypt in 1977. Its clinical spectrum is recognized to include severe manifestations such as hemorrhagic fever and encephalitis. For these reasons, as well as the limited knowledge of specific therapy for Bunyaviridae infections, we investigated several prophylactic regimens for RVF in a mouse model. Rimantadine, thiosemicarbazone, and inosiplex were ineffective. Pretreatment with glucan was of some use, but the most encouraging results were obtained with the antiviral drug ribavirin, passive antibody, or an interferon inducer polyriboinosinic-polyribocytidylic acid complexed with poly-L-lysine and carboxymethylcellulose (poly[ICLC]). Ribavirin and poly(ICLC) were also shown to be efficacious in preventing disease in hamsters. Ribavirin (loading dose of 50 mg/kg followed by 10 mg/kg at 8-h intervals for 9 days) suppressed viremia in RVF-infected rhesus monkeys. Ribavirin also reduced virus yield in infected cell cultures; sensitivity varied markedly with cell type but not with virus strain. Immune mouse ascitic fluid, with a plaque reduction neutralization titer of 1:1024, was effective in a dose of 4 ml/kg, a volume approximately equivalent to administration of a unit of convalescent plasma to a human. Poly(ICLC) may well have functioned through interferon induction, since RVFV was shown to be sensitive to interferon in cell culture, and since another macrophage activator (glucan) was only marginally effective. These studies suggest that ribavirin, poly(ICLC), and convalescent plasma may have a role in prevention or therapy of human RVF.

Animals↗
PubMed1990

Ambazone as a membrane active antitumor drug.

Ambazone (1,4-benzoquinone guanylhydrazone thiosemicarbazone) was found to be active against various transplantable tumors in mice as well as rats. When administered orally for 4-9 days, the effective therapeutic dose ranged between 60 and 125 mg/kg. The antineoplastic effect of ambazone appeared to be mediated, at least in part, by the immune system. In order to characterize the drug, biophysical and biophysicochemical studies were carried out using thin-layer chromatography, absorption spectroscopy and polarographic measurements. The distribution of ambazone in an n-octanol/water system indicated low hydrophobicity, thereby excluding the possibility of a preferential contribution from hydrophobic forces to the mode of action of ambazone. Ambazone undergoes three protonation reactions with pK values at 10.69 (equilibrium between the negatively charged and neutral forms), 7.39 (equilibrium between the neutral and singly positively charged form) and 6.22 (equilibrium between the singly and doubly positively charge form). Interaction of the drug with model membrane system was monitored by spectrophotometric and fluorescence measurements. Using the fluorescence label 1-anilino-8-naphthalenesulfonic acid (ANS) as a probe pointed to the interaction of ambazone with the inner area of the phospholipid bilayer matrix of liposomes as being nonspecific. Ambazone induces an overall increase in the cellular cAMP content of leukemia cells and macrophages. So far, membrane interaction has provided a molecular basis for both immunological and antineoplastic activities of the drug. By performing DNA melting experiments, it was shown that neutral or singly positively charged ambazone species stabilize the secondary structure of DNA, while the doubly positively charged form binds more strongly and destabilizes the DNA. After oral administration to rats and mice, ambazone was found to be incompletely absorbed from the gastrointestinal tract, to an extent of about 35-50%. Absorbed ambazone binds only weakly to plasma proteins, whereas its binding to red blood cells is relatively strong. The mutagenic potential of ambazone shown in bacterial systems and human lymphocytes corresponds to its relatively weak interaction with DNA. The toxic action of ambazone on the intestine is believed to be due to inhibition by the drug of bacterial DNA, RNA and protein syntheses. It is assumed that the reported affinity of ambazone for different cellular targets, i.e., membranes, nucleic acids and proteins, contributes to the overall antibacterial effect. The weak antiviral activity of ambazone in the Sendai virus/chicken embryo fibroblast system is probably the result of the interaction with Sendai virus NH glycoprotein.

Animals↗
PubMed1986

Preparation and biodistribution of 99mTc chelate of strophanthidin--a cardiac aglycone.

Cardiac glycosides are well known to exert a specific and powerful effect on myocardial tissue, and there is a possibility that this class of compound with a 99mTc radiolabel may behave as a superior myocardial imaging agent in comparison to 201Tl which is at present used clinically. Because of the extreme chemical complexity of cardiac glycosides a simpler aglycone, strophanthidin was selected as the pilot compound for preliminary labelling and in vivo distribution studies. Strophanthidin was converted to 19-thiosemicarbazone which nicely accommodated 99mTc to produce a pure radiopharmaceutical of high specific activity. The distribution pattern in animal models was studied which is in accordance with the metabolic studies performed earlier with the ligand itself.

Animals↗
PubMed1988

Preparation and evaluation of technetium-99m labeled cardiac glycoside derivatives as potential myocardial imaging agent.

Three cardiac glycosides, two natural, cymarin and convallotoxin and one synthetic, strophanthidin-beta-D-glucoside were converted to their thiosemicarbazone and subsequently radiolabeled with 99mTc by chelation. The resulting radioactive chelate complexes were evaluated in animals to determine the suitability of this class of compounds for myocardial imaging. It was observed from the animal biodistribution data of the three radioactive compounds, there was a considerable variation in the heart to non-target organ uptake ratio. A possible explanation of this variation was offered in the light of their lipophilic character, protein binding ability and affinity towards non-target receptors. It is anticipated that this study may help to develop a 99mTc-cardiac glycoside complex with better distribution characteristics, and such a compound may offer a suitable alternative to 201Tl, which is at present used for myocardial imaging.

Animals↗
PubMed1996

Effect of regional angiotensin II infusion on the relationship between tumour blood flow and fluorouracil uptake in a liver metastasis animal model.

The aim of this study was to assess the relationship between tumour:liver blood flow and 5-fluorouracil (5-FU) uptake ratios in a hypovascular liver metastasis animal model, and examine whether they were similarly affected by a 5 min infusion of angiotension II via the hepatic artery. Tumour:liver blood flow ratio was measured using the isotope tracer 64Copper (II)-pyruvaldehyde bis(n-4 methyl thiosemicarbazone, and 5-FU was tritiated. There was a wide variation in tumour:liver blood flow and 5-FU uptake ratios which could only partly be explained by between animal variation, and was not related either to individual tumour size or overall tumour burden within the liver. There was a close correlation (r = 0.957, P < 0.0001) between tumour:liver blood flow and 5-FU uptake ratios. Angiotensin II infusion significantly increased tumour:liver blood flow (nested analysis of variance, P= 0.05) but not 5-FU uptake (P = 0.29) ratios. There was a poor correlation (r = 0.51, P = 0.13) between tumour:liver blood flow and 5-FU uptake ratios with angiotensin II infusion. Thus, despite an increased 5-FU blood concentration arising from angiotensin-induced reduction in blood flow at constant 5-FU infusion dose, tumour:liver 5-FU uptake ratio did not increase as expected, and there ceased to be a significant correlation between tumour:liver blood flow and 5-FU uptake ratios. We conclude that the vasoactive changes within the hypovascular tumour circulation produced by a 5 min angiotensin II infusion did not significantly increase tumour 5-FU uptake.

Analysis of Variance↗
PubMed2005

Antiparasitic activity of a triphenyl tin complex against Leishmania donovani.

Visceral leishmaniasis is a life-threatening human disease commonly known as kala-azar. Leishmania donovani is the causative agent of this parasitic disease transmitted by the sand fly vector to infect hosts. Triphenyl tin salicylanilide thiosemicarbazone [Ph(3)Sn(OSal.TSCZH)] (TTST) which is an organometallic complex of triphenyl tin has been evaluated to explore possibility to develop a potent chemotherapeutic agent against visceral leishmaniasis. Effect of triphenyl tin complex on growth inhibition and host--parasite interaction were examined both in vitro and in vivo. Release of toxic superoxide radical was measured spectrophotometrically through the formation of blue formazan derived from reduced nitrobluetetrazolium. To understand mode of action of Ph(3)Sn(OSal.TSCZH), superoxide dismutase activity was determined spectrophotometrically by measuring ability of this enzyme to inhibit pyrogallol autoxidation and also by activity staining of the non-denaturing polyacrylamide gels after separating superoxide dismutase. Antileishmanial activity of triphenyl tin complex were found to be effective both in vitro and in vivo at lower concentrations compared to the existing toxic drugs available. IC(50) of Ph(3)Sn(OSal.TSCZH) was calculated as 0.05+/-0.01mg/L. Intracellular survival of the parasite in host macrophages was inhibited by TTST in a dose dependent manner. Parasite burden in spleen was reduced to 87% under TTST treatment (10mg/kg body weight) and under sodium antimony gluconate (20mg/kg body weight) reduced nearly to 65%. Its action as a chemotherapeutic agent is found to be mediated through inhibition of superoxide dismutase and simultaneous release of toxic superoxide radical. We propose that Ph(3) Sn(OSal.TSCZH) may be considered as a prospective candidate to establish a better line of therapeutic process against experimental visceral leishmaniasis.

Animals↗
PubMed2005

Design, synthesis and anti-plasmodial evaluation in vitro of new 4-aminoquinoline isatin derivatives.

A new class of 4-aminoquinoline derivatives based on the natural product isatin scaffold were designed and synthesized for biological evaluation against three strains of the malaria parasite Plasmodium falciparum. These derivatives showed anti-plasmodial IC(50) values in the ranges of 1.3-0.079 and 2.0-0.050muM against a chloroquine-sensitive (D10) and two resistant (K1 and W2) strains of P. falciparum, respectively. In order to determine potential targets for this class of compounds in P. falciparum, selected compounds were also tested against the parasitic cysteine protease falcipain-2. In terms of further development of this class of isatin derivatives, two of the compounds based on a flexible alkyl chain linker and a thiosemicarbazone moiety warrant further investigation as potential anti-plasmodial leads. These two derivatives showed good in vitro activity against K1 and W2 with IC(50) values of 51 and 54nM, respectively, while retaining potency against the D10 strain with IC(50) values of 79 and 95nM, respectively. Generally speaking, the inhibitory potency of all compounds in the series against the parasites did not strongly correlate with inhibitory potency against falcipain-2 for selected compounds tested, which at best was weak to moderate, suggesting other mechanisms of inhibition may also be involved or compounds may be selectively taken up by Plasmodium falciparum.

Aminoquinolines↗
PubMed2006

Design, synthesis, and biochemical evaluation of novel cruzain inhibitors with potential application in the treatment of Chagas' disease.

A series of compounds bearing tetrahydronaphthalene, benzophenone, propiophenone, and related rigid molecular skeletons functionalized with thiosemicarbazone or unsaturated carbonyl moieties were prepared by chemical synthesis and evaluated for their ability to inhibit the enzyme cruzain. As potential treatment agents for Chagas' disease, three compounds from the group demonstrate potent inhibition of cruzain with IC(50) values of 17, 24, and 80 nM, respectively.

Carbon↗
PubMed2006

Tri-substituted triazoles as potent non-nucleoside inhibitors of the HIV-1 reverse transcriptase.

A new series of 1,2,4-triazoles was synthesized and tested against several NNRTI-resistant HIV-1 isolates. Several of these compounds exhibited potent antiviral activities against efavirenz- and nevirapine-resistant viruses, containing K103N and/or Y181C mutations or Y188L mutation. Triazoles were first synthesized from commercially available substituted phenylthiosemicarbazides, then from isothiocyanates, and later by condensing the desired substituted anilines with thiosemicarbazones.

Enzyme Inhibitors↗
PubMed2004

Tetrazolo[1,5-a]quinoline as a potential promising new scaffold for the synthesis of novel anti-inflammatory and antibacterial agents.

Three series of tetrazolo[1,5-a]quinoline derivatives have been synthesized. The first series was synthesized starting by the condensation of tetrazolo[1,5-a]quinoline-4-carboxaldehyde 2 with substituted thiosemicarbazides, followed by cyclization of the resulting thiosemicarbazones 3 with malonic acid in the presence of acetyl chloride to give pyrimidyl derivatives 4a-c. The second series was prepared by the condensation of the latter compounds 4a-c with the selected aromatic aldehydes to afford the arylidene derivatives 5a-f. The third series 7a-c was synthesized by condensation of tetrazolo[1,5-a]quinoline-4-carboxaldehyde 2 with the appropriate acetophenone, followed by cyclocondensation of the formed alpha,beta-unsaturated ketones with thiourea. The newly synthesized compounds were evaluated for their anti-inflammatory and antimicrobial activities. Four compounds were proved to be as active as indomethacin in animal models of inflammation.

Animals↗
PubMed2004

New 4-aminobicyclo[2.2.2]octane derivatives and their activities against Plasmodium falciparum and Trypanosoma b. rhodesiense.

A series of new 2-substituted 4-dialkylaminobicyclo[2.2.2]octane derivatives was prepared and the compounds were investigated for their activity against causative organisms of tropical diseases. The tests were performed as microplate assays using the K1 strain of Plasmodium falciparum (resistant to chloroquine and pyrimethamine) and Trypanosoma brucei rhodesiense (STIB 900). The results were compared to the activities of former tested compounds of the bicyclo[2.2.2]octane series and to known drugs. Most of the 4-amino-6,7-diphenylbicyclo[2.2.2]octan-2-one thiosemicarbazones were compounds with attractive antimalarial potency (IC(50)=0.84-0.99microM, chloroquine: IC(50)=0.12microM). One of the bicyclo[2.2.2]octan-2-yl 4-tert-butylbenzenesulfonates showed the highest antitrypanosomal activity (IC(50)=0.68microM) of the so far prepared 4-amino-6,7-diarylbicyclo[2.2.2]octane derivatives, but is distinctly less active than suramin (IC(50)=0.0075microM).

Animals↗
PubMed2006

A gold(I) complex with a vitamin K3 derivative: characterization and antitumoral activity.

Reaction of the vitamin K(3) derivative menadione sodium bisulfite thiosemicarbazone (NaK(3)TSC) with chloro(triethylphosphine)gold(I) afforded the complex [AuPEt(3)(K(3)TSC)]. This compound consists of discrete molecules in which the metal is almost linearly coordinated to P and S. Preliminary in vitro screening showed significant anti-cancer activity, notably against the cisplatin-resistant cell line A2780cis.

Cell Line, Tumor↗