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PubMed1984

Pharmacology of the mixed-function radio- and chemosensitizers CB 1954 and RSU 1069.

We have studied the pharmacokinetics and metabolism in mice of CB 1954 and RSU 1069. Containing both nitro and alkylating (aziridine) substituents, these are lead compounds in the mixed-function analogue series, which show particular promise for sensitizer development. Both compounds are degraded extensively, via pathways including nitro reduction, aziridine ring hydrolysis and aziridine ring removal RSU 1069 (plasma t1/2 22 min) was eliminated more rapidly than CB 1954 (blood t1/2 84 min), and the AUC was three times less. Tissue/plasma ratios tended to be rather lower than those for simple nitroimidazoles of intermediate lipophilicity, which are usually close to 100%. With CB 1954, for example, tumor/plasma and brain/plasma ratios were 58 and 37% respectively, whereas with RSU 1069 the values were 29 and 26%. Nevertheless, tumor concentrations were consistent with potent sensitization. There is, however, scope for pharmacokinetic fine-tuning to modify tissue penetration as appropriate.

Animals↗
PubMed1984

Photosensitive interaction of RSU 1069 with DNA.

RSU 1069 is a 2-nitroimidazole radiosensitizer with an aziridine-containing side chain. In light (360 nm) the absorbance maximum of the nitro group at 325 nm disappears, which is accompanied by expulsion of the nitro group as the nitrite ion. We suggest an intramolecular cyclization of the aziridine side chain and the C2 of the imidazole ring as a possible explanation. This photosensitive effect was used to determine separately the damage to DNA induced by the reduced nitro group and the alkylating property of the aziridine. The aziridine-induced DNA damage is maximized in the dark when the nitro group is either absent (electrolytically reduced prior to the addition of DNA) or non functional (unreduced). In the light, damage is reduced. Typical DNA damage includes helix disruption leading to single strand breaks and the release of thymidine. Alkaline filter elution studies show evidence only for strand breakage and none for cross-linking indicating the drug is capable of mono-functional alkylation only.

Aziridines↗
PubMed1984

RSU 1069, a 2-nitroimidazole containing an alkylating group: high efficiency as a radio- and chemosensitizer in vitro and in vivo.

Electron affinity as measured by the one-electron reduction potentian, E7(1), is the major factor influencing radiosensitizing efficiency in vitro. RSU 1069 has an electron affinity (E7(1) = 398 mV) similar to misonidazole; however, the ability of this compound to sensitize hypoxic cells is considerably greater in vitro than that of misonidazole, e.g., 0.2 mM RSU 1069 gives an enhancement ratio of greater than 2.0 compared to 1.4 for the same concentration of misonidazole. Radiosensitization studies with the MT tumor in vivo also showed RSU 1069 to be a more efficient sensitizer than misonidazole. An administered dose of 0.08 mg/g RSU 1069 yielded an enhancement of 1.8 to 1.9 using tumor cell survival and tumor cure as end-points. At least a 10-fold higher dose of misonidazole is required for a similar degree of sensitization. Low doses of RSU 1069 also radiosensitize the Lewis lung and B16 experimental tumors. The ability of RSU 1069 to potentiate the cytotoxic action of melphalan and other cytotoxic drugs towards the MT tumor was also examined. RSU 1069 (0.08 mg/g) given to mice 1 hour before melphalan gave an enhancement of 2.8.

Animals↗
PubMed1984

Potentiation of melphalan activity in the KHT sarcoma by the radiosensitizer RSU 1069.

The radiation sensitizer misonidazole (MISO) has been shown to potentiate the cytotoxic action of a variety of anti-cancer agents. Even larger enhancement ratios than those observed with MISO have been found with certain other nitroimidazoles. One agent reported to be particularly effective in combination with the chemotherapeutic agent melphalan is the sensitizer RSU 1069. The present studies therefore were designed to evaluate the effect of combining these two agents in the treatment of intramuscularly growing KHT sarcomas. Tumor response was assessed using an in vivo to in vitro clonogenic cell survival assay. When given at times ranging from 60 min before to 30 min after melphalan exposure, RSU 1069 was found to increase the tumoricidal activity of the chemotherapeutic agent. Complete dose response curves combining RSU 1069 and a range of melphalan doses then were determined. For comparison the effects of combining MISO or benznidazole (BENZO) with melphalan also were evaluated. All sensitizers were administered i.p. either 30 min before (BENZO) or simultaneously with (MISO, RSU 1069) the chemotherapeutic agent. Survival of clonogenic tumor cells assessed 22 to 24 hr after treatment was used to assay tumor response. When combined with melphalan, doses of RSU 1069 (0.38 mmol/kg), BENZO (0.3 mmol/kg) and MISO (5.0 mmol/kg) were found to yield dose modifying factors of 1.6, 1.5, and 1.4, respectively. These results indicate that potentiation of melphalan activity occurs at RSU 1069 doses which are approximately 10-fold lower than those of MISO, making this sensitizer as effective a potentiator of melphalan as so far tested in the KHT sarcoma.

Animals↗
PubMed1984

Chemopotentiation by CB 1954: the importance of postincubations and the possible involvement of poly(ADP-ribosylation).

CB 1954 potentiates the cytotoxic action of the bifunctional alkylating agent melphalan (L-PAM). In vitro, this potentiation does not require the preincubation in hypoxia normally needed for other nitroaromatic compounds such as misonidazole. Chemopotentiation is observed when cells are held in CB 1954 in air after treatment with L-PAM. This may reflect an inhibition of DNA repair process(es). Structural considerations suggested that CB 1954 might be acting as an inhibitor of poly(ADP-ribosylation). However, an inhibition of the drop in NAD levels consequent on exposure to melphalan was not obtained. Furthermore, unlike the known poly(ADP-ribose) inhibitor, 3-aminobenzamide, CB 1954 does not potentiate the cytotoxicity of the monofunctional alkylator N-methyl-N nitro N-nitrosoguanidine, or inhibit NAD depletion caused by this agent. Therefore the evidence suggests that CB 1954 is not an inhibitor of poly(ADP ribosylation).

Animals↗
PubMed1989

Molecular enzymology of the reductive bioactivation of hypoxic cell cytotoxins.

The hypoxic cell cytotoxins SR 4233, benznidazole (Benzo), and CB 1954 were readily reduced by anaerobic mouse liver microsomes in vitro to their respective amino or single N-oxide derivatives. The reactions were inhibited in air and required reduced cofactors, particularly NADPH. The rates of reductive bioactivation were markedly different for each drug, with SR 4233 much greater than CB 1954 greater than Benzo. Using purified cytochrome P-450 reductase (P-450 reductase) and an inhibitory antibody to this enzyme, we demonstrated that P-450 reductase was involved in the reductive bioactivation of all 3 compounds. It had a minor role in SR 4233 reduction, but a more important involvement in CB 1954 metabolism to its 4-amino metabolite. Using carbon monoxide, a specific inhibitor of cytochrome P-450 (P-450), we demonstrated that P-450 was involved in both SR 4233 and Benzo reduction. P-450 had a major role both in SR 4233 conversion to SR 4317 and in the latter steps of Benzo amine formation. Purified xanthine oxidase was shown to reduce SR 4233 and Benzo in vitro, but cytosolic aldehyde oxidase activity was only detectable with Benzo as substrate. Characterizing the relative participation of the various reductases in tumor versus normal tissues may allow a more rational selection and application of hypoxic cell cytotoxins in cancer therapy.

Animals↗
PubMed1989

Comparative DNA damage and repair induced by misonidazole, CB 1954 and RSU 1069.

We have studied the ability of CB 1954, misonidazole, and RSU 1069 to induce biologically relevant DNA damage in single- and double-stranded phi X174 DNA under oxic, anoxic, and anoxic reductive conditions using a double transfection technique. In addition, the ability of the three drugs to induce the SOS repair response in E. coli under the same conditions was measured. Whereas the relative order of DNA damage was RSU 1069 greater than CB 1954 greater than misonidazole the order in inducing SOS repair was RSU 1069 greater than misonidazole greater than CB 1954. Drug-induced damage by RSU 1069 involves enhanced damage by endonuclease III suggesting drug-induced pyrimidine damage. There appears to be no correlation between drug-induced damage and the degree of SOS repair induction. Thus it appears that enzymes other than, or in addition to, those of the SOS repair system are involved in the repair of DNA damage induced by these drugs.

Antineoplastic Agents↗
PubMed1982

Testicular damage and change in serum LDH isozyme pattern induced by multiple sub-lethal doses of apholate in albino rats.

Treatment with apholate caused degenerative changes in the testes of albino rats. No histological changes were observed in Leydig cells. LDH-X activity was present in the serum of treated rats and absent in controls. Electrophoresis indicates that the activity band present in serum was similar to the activity band found in testes. A colorimetric method for assaying LDH-X activity is reported.

Animals↗
PubMed1984

Effect of the chemosterilant bisazir on the eggs of Earias fabia stoll.

Bisazir-induced inhibition of nucleic acids and protein, and enhancement of free amino acids in the eggs of treated Earias fabia (Lepidoptera; Noctuidae) is reported. The degree of alterations in various crosses followed: T male X T female greater than UT male X T female greater than T male X UT female, which was also reflected in the weight loss of eggs. The alterations have been attributed to the abnormalities in the developing embryos due to genic imbalance in the spermatozoa, nurse cells and oocytes, ultimately leading to embryonic death.

Amino Acids↗
PubMed1985

Gas chromatographic analysis of triethylenethiophosphoramide and triethylenephosphoramide in biological specimens.

Comprehensive pharmacokinetic studies could realise a greater potential for the antitumour agent triethylenethiophosphoramide (ThioTEPA), and these would be aided by the development of a selective and sensitive assay. After extraction of ThioTEPA and its metabolite, triethylenephosphoramide (TEPA), from plasma using Sep-Pak C18 cartridges, the compounds were separated by capillary chromatography, detected using a nitrogen detector and quantified by reference to an internal standard, hexaethylphosphoramide. The limits of sensitivity were 1-5 ng/ml. Analytical recoveries were 74 and 95%, for TEPA and ThioTEPA, respectively, in the therapeutic range. At similar concentrations, extents of protein binding, determined by ultrafiltration, were not significant. Preliminary investigations of the elimination of ThioTEPA show that drug loss occurs more quickly in mice than in humans and in both species the metabolite is extensively recycled.

Animals↗
PubMed1989

Mechanism(s) of bioreductive activation. The example of diaziquone (AZQ).

Bioreduction in the activation of diaziquone (2,5-diaziridinyl-3,6-bis (carboethoxyamino)-1,4-benzoquinone) has been investigated by exploring its reduction by whole cells, rat liver microsomes and purified enzymes. The mechanism of bioreduction was further investigated by exploring the chemical and electrochemical reduction of diaziquone as well as its photochemistry. Reduced diaziquone (by several means) was then tested for activity against parent compound. It appears that reduced diaziquone in most cases is more active than the oxidized form. Diaziquone redox cycles, but it is easily reduced to the hydroquinone which oxidizes to the semiquinone yielding free radicals under aerobiosis. The most probable mechanism of action is that of bioreductive alkylation where the alkylating aziridines are protonated after reduction facilitating the opening of the aziridine rings and thus alkylation.

Animals↗
PubMed1995

Photoaffinity labeling of methyl farnesoate epoxidase in cockroach corpora allata.

The last enzyme in the biosynthetic pathway to juvenile hormone III in the corpora allata of hemimetabolous insects is methyl farnesoate epoxidase, a cytochrome P450 monooxygenase. Assays with intact glands incubated in vitro and with gland homogenates have identified a series of 1,5-disubstituted imidazoles as potent inhibitors of the enzyme. We have designed, synthesized and tested two imidazoles, diazirine-Ice T and benzophenone-Ice T, in which a radiolabeled and photoactivatable diazirine or benzophenone group was introduced to label the hydrophobic substrate binding site of the enzyme. Our results show that these bifunctional compounds inhibit JH III synthesis by intact glands as well as methyl farnesoate epoxidation by gland homogenates. Moreover both compounds selectively label a protein of ca. 55 kDa in corpora allata of the cockroach, Diploptera punctata. These photoaffinity labels, which use an imidazole to coordinate to the heme iron and a photoreactive group to modify the hydrophobic substrate binding pocket, are specific and effective probes for the molecular analysis of methyl farnesoate epoxidase.

Affinity Labels↗
PubMed2006

Array synthesis of progesterone receptor antagonists: 3-aryl-1,2-diazepines.

New non-steroidal chemotypes are required for the development of drugs targeting the steroid hormone receptors. The parallel array synthesis of 3-aryl-1,2-diazepines employing solid-supported reagents is described. The resulting compounds demonstrated high affinity binding to the progesterone receptor.

Azepines↗
PubMed2006

Photocatalytic degradation of agricultural N-heterocyclic organic pollutants using immobilized nanoparticles of titania.

Degradation and mineralization of two agricultural organic pollutants (Diazinon and Imidacloprid as N-heterocyclic aromatics) in aqueous solution by nanophotocatalysis using immobilized titania nanoparticles were investigated. Insecticides, Diazinon and Imidacloprid, are persistent pollutants in agricultural soil and watercourses. A simple and effective method was developed to immobilization of titania nanoparticles. UV-vis, ion chromatography (IC) and chemical oxygen demand (COD) analyses were employed. The effects of operational parameters such as H(2)O(2) and inorganic anions (NO(3)(-), Cl(-) and SO(4)(2-)) were investigated. The mineralization of Diazinon and Imidacloprid was evaluated by monitoring of the formed inorganic anions. The selected pollutants are effectively degraded following first order kinetics model. Results show that the nanophotocatalysis using immobilized titania nanoparticle is an effective method for treatment Diazinon and Imidacloprid from contaminated water.

Agrochemicals↗
PubMed2000

Molecular models of the structural arrangement of subunits and the mechanism of proton translocation in the membrane domain of F(1)F(0) ATP synthase.

Subunit c of the proton-transporting ATP synthase of Escherichia coli forms an oligomeric complex in the membrane domain that functions in transmembrane proton conduction. The arrangement of subunit c monomers in this oligomeric complex was studied by scanning mutagenesis. On the basis of these studies and structural information on subunit c, different molecular models for the potential arrangement of monomers in the c-oligomer are discussed. Intersubunit contacts in the F(0) domain that have been analysed in the past by chemical modification and mutagenesis studies are summarised. Transient contacts of the c-oligomer with subunit a might play a crucial role in the mechanism of proton translocation. Schematic models presented by several authors that interpret proton transport in the F(0) domain by a relative rotation of the c-subunit oligomer against subunit a are reviewed against the background of the molecular models of the oligomer.

Azirines↗
PubMed1997

An amphipathic alpha-helix is the principle membrane-embedded region of CTP:phosphocholine cytidylyltransferase. Identification of the 3-(trifluoromethyl)-3-(m-[125I]iodophenyl) diazirine photolabeled domain.

CTP:phosphocholine cytidylyltransferase (CT), the rate controlling enzyme in phosphatidylcholine biosynthesis, is activated by reversible membrane binding. To investigate the membrane binding mechanism of CT, we have used the photoreactive hydrophobic probe 3-(trifluoromethyl)-3-(m-[l25I]iodophenyl)diazirine ([125I]TID). Association of CT with phosphatidylcholine/oleic acid (1:1) vesicles was first demonstrated by gel filtration analysis. Upon irradiation, CT was covalently labeled by [125I]TID presented in phosphatidylcholine/oleic acid vesicles. This demonstrates an intercalation of part of the protein into the hydrophobic core of the membrane. To identify the membrane-embedded domain, the chymotrypsin digestion products of [125I]TID labeled CT were analysed. Chymotrypsin digestion produced a set of previously defined N-terminal fragments (Craig, L., Johnson, J.E. and Cornell, R.B. (1994) J. Biol. Chem. 269, 3311), as well as several small C-terminal fragments which react with an anti-peptide antibody raised against the proposed amphipathic alpha-helix. All fragments containing the amphipathic helical region of the enzyme had [125I]TID label associated, while the chymotryptic fragment which lacked this region was not highly labeled. Similar fragment labeling patterns were produced when [125I]TID was presented in phosphatidylcholine/oleic acid or phosphatidylcholine/diacylglycerol vesicles, suggesting that the same domain of CT mediates binding to membranes containing either of the two lipid activators. A 62-residue synthetic peptide corresponding in sequence to the amphipathic helical region of CT was labeled with [125I]TID, demonstrating its ability to intercalate independently of the rest of the protein. These results indicate a membrane-binding mechanism for cytidylyltransferase involving the intercalation of the amphipathic alpha-helix region into the hydrophobic acyl chain core of the activating membrane.

Animals↗