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P Wardman

Publications and source records attributed to P Wardman.

At least 91 records · Page 5Linked to original sources
PubMed1986

One-electron reduction of 2- and 6-methyl-1,4-naphthoquinone bioreductive alkylating agents.

The semiquinones, Q.-, of derivatives of 2- and 6-methyl-1,4-naphthoquinones, some incorporating leaving groups with substituents such as CH2Br or CH2OCONHCH3, have been produced by radiolytic reduction of Q by (CH3)2COH radicals. The absorption spectra and decay kinetics of Q.- were all closely similar to that produced from 2-methyl-1,4-naphthoquinone, with no evidence for unimolecular elimination of a leaving group in the semiquinone form, but immediate loss of leaving group upon two-electron reduction of Q to the hydroquinone. The redox equilibria between Q/Q.- and O2/O2.- were characterized, and reduction potentials of the couples Q/Q.- in water at pH 7.6 were calculated. The implications of these observations for the use of these compounds as bioreductive alkylating agents or as radiosensitizers with potential selective activity toward hypoxic cells are discussed.

Alkylating Agents↗
PubMed1986

A comparison of the tumour concentrations obtainable with misonidazole and Ro 03-8799.

Both Ro 03-8799 and misonidazole were administered to six patients before tumour sampling. Using similar doses, tumour concentrations of Ro 03-8799 were approximately double those of misonidazole. Examination of the data with regard to the relative sensitising efficiencies of these two compounds gives us, as a conservative estimate, a factor of 1.6 in favour of Ro 03-8799. From these observations it is predicted that, when given with radiotherapy in a 25-fraction course Ro 03-8799, is likely to be at least five times more effective as a hypoxic cell sensitiser than misonidazole.

Adult↗
PubMed1985

Cellular uptake of misonidazole and analogues with acidic or basic functions.

Average intracellular concentrations of five radiosensitizers in hamster fibroblast-like V79-379A cells in vitro were measured by high performance liquid chromatography, varying the extracellular pH (pHe) and estimating the apparent intracellular pH from the distribution of 5,5-dimethyloxazolidine-2,4-dione. The intracellular: extracellular concentration ratio for the 2-nitroimidazole, misonidazole was constant at about 0.7 for pHe = 6.6-7.6, whereas the weak base, Ro 03-8799 (1-(2-nitro-1-imidazolyl)-3-N-piperidino-2-propanol) was concentrated intracellularly at pHe = 7.3-7.4 by a factor of 3.3, the factor increasing from about 0.8 at pHe = 6.0, to 7.5 at pHe = 7.85. The weak acid, azomycin (2-nitroimidazole) showed approximately constant uptake (factor 1.1) between pHe = 6.0-7.0, decreasing to 0.8 at pHe = 7.3 and 0.4 at pHe = 7.8. Measurements of intracellular uptake of Ro 31-0052 (the more hydrophilic and less basic 3'-hydroxypiperidino analogue of Ro 03-8799) and of Ro 31-0258 (3-(2-nitro-1-imidazolyl)propionic acid, a stronger acid than azomycin) were made for comparison. The results were compared with theoretical calculations of pH-induced concentration gradients; the time dependence of the uptake of the bases is not at present clearly understood. These measurements of uptake are broadly consistent with the distribution of misonidazole and Ro 03-8799 in human and animal tissues and provide a useful insight into the likely intracellular concentrations in the clinical use of Ro 03-8799 or other basic radiosensitizers. The measurements also resolve the apparent discrepancy in radiosensitizer efficiency for weak bases in vitro and in vivo which has been previously noted.

Animals↗
PubMed1985

Some reactions and properties of nitro radical-anions important in biology and medicine.

Nitroaromatic compounds, ArNO2 have widespread actual or potential use in medicine and cancer therapy. There is direct proof that free-radical metabolites are involved in many applications, and an appreciation of the conceptual basis for their therapeutic differential; however, an understanding of the detailed mechanisms involved is lacking. Redox properties control most biological responses of nitro compounds, and the characteristics of the one-electron couple: ArNO2/ArNO2- are detailed. The "futile metabolism" of nitroaryl compounds characteristic of most aerobic nitroreductase systems reflects competition between natural radical-decay pathways and a one-electron transfer reaction to yield superoxide ion, O2-. Prototropic properties control the rate of radical decay, and redox properties control the rate of electron transfer to O2 or other acceptors. There are clear parallels in the chemistry of ArNO2- and O2-. While nitro radicals have frequently been invoked as damaging species, they are very unreactive (except as simple reductants). It seems likely that reductive metabolism of nitroaryl compounds, although generally involving nitro radical-anions as obligate intermediates (and this is required for therapeutic selectivity towards anaerobes), results in biological damage via reductive metabolites of higher reduction order than the one-electron product.

Antineoplastic Agents↗
PubMed1984

Cis-trans isomerization of the (5-nitro-2-furyl)acrylamide, AF-2, initiated by ascorbate, glutathione, Fe(II) and OH-.

The cis-trans isomerization of the (5-nitro-2-furyl)acrylamide, AF-2, has been investigated using some important biological reducing agents to initiate reaction. Physiological concentrations of L-ascorbic acid, glutathione and iron(II) all accomplish isomerization in a catalytic manner over a period of minutes. Base-catalysed isomerization has also been observed. In all cases, the presence of oxygen severely inhibits isomerization. It is proposed that the mechanism involves a free-radical chain process; AF-2 or analogues are thus extremely sensitive probes for the generation of nitro radicals in biochemical reducing systems because of the high efficiency of isomerization.

Ascorbic Acid↗
PubMed1984

Nitroaryl compounds as potential fluorescent probes for hypoxia. I. Chemical criteria and constraints.

Cellular reduction of nitroaryl compounds is efficiently inhibited by oxygen, and detection of products characteristic of reduction could form the basis for diagnostic tests for the presence of hypoxic cells in tumors. The criteria for suitable compounds include a high sensitivity and selectivity of detection response between oxic and hypoxic cells, which can be provided using fluorescence detection and suitable nitroaryl compounds which have very low fluorescence until reduced. Examples described include a nitroacridine and nitronaphthalimides. Although the intercalating ability of these ring systems lead to high sensitivity for detection of reduced metabolites in vitro by flow cytometry, poor bioavailability is an unwanted consequence of intercalation. The application of several model reducing systems for reduction of potential fluorescent probes for hypoxia is described, and the absorption and fluorescence spectral characteristics of other examples of structures which could form the basis for useful probes are outlined.

Aminacrine↗
PubMed1984

Nitroaryl compounds as potential fluorescent probes for hypoxia. II. Identification and properties of reductive metabolites.

Nitroakridin 3582 (NA) and a nitronaphthalimide (DM113), which fluoresce only upon reduction, have been studied by HPLC. V79-379A cells incubated with NA under 20% or 2% O2 and N2 gave increasing amounts of the fluorescent amine with an hypoxic:oxic differential of 160. Measurement of the uptake of NA showed that it was concentrated within the cell by over 1000-fold. Studies in 3 different cell lines of reduction under hypoxia showed a 7-fold range in amine production. DM113 yields more than one fluorescent product, which show different absorption and fluorescence spectra. Chemical reduction of NA or DM113 using a variety of methods gave, depending on conditions, amine and/or (what was presumed to be) hydroxylamine; the latter was non-fluorescent. In vivo, NA is toxic at greater than 0.19 mumol g-1. At this dose much of the drug is found in the liver and kidneys. Plasma levels at 30 minutes are only 2 microM while tumor concentrations are 10 microM compared to 600 microM in the liver. However, the half life is greater than 1 hr and amine was detectable in these tumors.

Aminacrine↗
PubMed1984

Synthesis and activity of novel nitropyrazines for use as hypoxic cell radiosensitizers.

A series of eight novel nitropyrazines has been prepared by oxidation of sulfoximine intermediates. The partition coefficient, one-electron reduction potential, sensitizer enhancement ratio, and chronic and acute aerobic cytotoxicity have been measured for each. Two representatives of this series were tested in the Ames test and were not found to be mutagenic.

Aerobiosis↗
PubMed1982

Nitroimidazoles as anaerobic electron acceptors for xanthine oxidase.

The rates of anaerobic nitroreduction of 15 nitroimidazoles by xanthine-xanthine oxidase were measured. The compounds studied were mainly 2-nitroimidazoles, including misonidazole and analogues of potential value in cancer therapy; most 5-nitroimidazoles such as metronidazole and nimorazole reacted too slowly for measurement under the conditions used. Using 0.1 mM nitroimidazole, reduction rates varied between ca. 4 and 680 nmole min-1 U-1 xanthine oxidase at 37 degrees and pH 7.4. These rates were correlated with the reduction potential characterizing one-electron reduction to the nitro radical-anion, and compared with those for other nitroaryl compounds and with reduction by free flavin mononucleotide.

Anaerobiosis↗
PubMed1980

Structure-activity relationships in the development of hypoxic cell radiosensitizers. III. Effects of basic substituents in nitroimidazole sidechains.

The effects of substituting 2-nitroimidazoles with groups carrying basic functions were studied. Prototropic, redox, lipophilicity and protein-binding properties were compared with the efficiency in radiosensitizing hypoxic Chinese hamster V79-379A cells in vitro and the cytotoxicities of the compounds after chronic aerobic exposure. Seventeen compounds were (2-nitro-1-imidazolyl)alkylamines in which the effects of changes in the terminating base and of alkyl chain length were investigated. About an order of magnitude increase in sensitization efficiency could be observed in some compounds without any increase in the aerobic cytotoxicity compared to simple, uncharged 2-nitroimidazoles such as misonidazole. The behaviour of five hydrazones was similar to that of uncharged analogues. The methiodide quaternary salts of two of the (2-nitro-1-imidazolyl)alkylamines showed that quaternization considerably reduced sensitization efficiency. (Nitro-1-imidazolyl)alkylamines appear worthy of further investigation as hypoxic cell radiosensitizers in vivo.

Animals↗
PubMed1980

Toxicity of nitro compounds toward hypoxic mammalian cells in vitro: dependence on reduction potential.

Fifteen nitroaromatic and nitroheterocyclic compounds that can act as "radiosensitizers" were tested for their cytotoxicity toward hypoxic Chinese hamster V79 cells in vitro. The cytotoxicity increased markedly as the electron affinity, measured as a one-electron reduction potential, increased. Non-nitro-containing compounds of similar electron affinities (such as quinones) that also act as radiosensitizers did not exhibit this specific toxicity toward hypoxic cells. The implications of the presence of the nitro group as a prerequisite for the hypoxic cell toxicity were discussed, and the mechanism of the cytotoxicity was compared with that of hypoxic cell radiosensitization.

Animals↗
PubMed1979

Enzymic cis-trans isomerization of nitrofuran derivatives: isomerizing activity of xanthine oxidase, lipoyl dehydrogenase, DT-diaphorase and liver microsomes.

Xanthine oxidase (xanthine:oxygen oxidoreductase, EC 1.2.3.2) supplemented with an electron donor could catalyze the cis-trans isomerization of 3-(5-nitro-2-furyl)-2-(2-furyl)acrylamide, 3-(5-nitro-2-furyl)-2-phenylacrylamide and 3-(5-nitro-2-furyl)-2-(2-furyl)acrylonitrile. The direction of isomerization (cis leads to trans, cis in equilibrium trans or trans leads to cis) is dependent on the chemical structure of these nitrofuran derivatives. Lipoyl dehydrogenase (NADH:lipoamide oxidereductase, EC 1.6.4.3), DT-diaphorase (NAD(P)H:(quinone-acceptor) oxidoreductase, EC 1.6.99.2) and liver microsomes could also catalyze the conversion of cis-3-(5-nitro-2-furyl)-2-(2-furyl)acrylamide to its trans isomer in the presence of an appropriate electron donor. Such isomerizing activity of these enzymes is much higher than their nitro-reducing activity. In addition, the cis-trans isomerization of some nitrofuran derivatives was demonstrated with the liver slices and the small intestines of rats. A new cis-trans isomerization mechanism which is based on transfer of a single electron by an enzyme system to a nitrofuran derivative to give the radical-anion was proposed. This postulated mechanism was supported by the preliminary experiments using pulse radiolysis technique.

Animals↗
PubMed1979

Structure-activity relationships in the development of hypoxic cell radiosensitizers. I. Sensitization efficiency.

The efficiency of 35 nitroaromatic and nitroheterocyclic compounds in radiosensitizing hypoxic Chinese Hamster cells in vitro was determined. The concentration C of the compound required to achieve an enhancement ratio of 1.6 was measured, and the redox and partition properties were quantified as the one-electron reduction potential at pH 7, E, and the octanol: water partition coefficient, P, respectively. Most of the compounds studied were 2-nitroimidazoles, but some 4- and 5-nitromidazoles, 5-nitrofurans and nitrobenzenes were investigated for comparison. Together with data for nine nitroimidazoles previously reported, the results were fitted to a structure-activity relationship of the form -log C = b0 + b1E + b2 log P + b3 (log P)2 using multiple linear regression analysis. Statistical tests showed that the coefficients b2 and b3 were not significantly different from zero and the simpler equation, obtained by omitting the terms in log P, explained 85 per cent of the variance in log C. Earlier reports that the radiosensitization efficiency of nitro compounds in vitro largely depends on the reduction potential were confirmed. The conclusive demonstration that P is unimportant in vitro is valuable in interpreting the results of experiments in vivo, where P is expected to have a much greater influence on biological response.

Animals↗