John Parrick

Enhancement of Lipid Peroxidation by Indole-3-Acetic Acid and Derivatives: Substituent Effects

The peroxidation of liposomes by a haem peroxidase and hydrogen peroxide in the presence of indole-3-acetic acid and derivatives was investigated. It was found that these compounds can accelerate the lipid peroxidation up to 65 fold and this is attributed to the formation of peroxyl radicals that may react with the lipids, possibly by hydrogen abstraction. The peroxyl radicals are formed by peroxidase-catalyzed oxidation of the enhancers to radical cations which undergo cleavage of the carbon-carbon bond on the side-chain to yield CO2 and carbon-centred radicals that rapidly add oxygen. In competition with decarboxylation, the radical cations deprotonate reversibly from the N1 position. Rates of decarboxylation, pka values and rate of reaction with the peroxidase compound I indicate consistent substituent effects which, however, can not be quantitatively related to the usual Hammett or Brown parameters. Assuming that the rate of decarboxylation of the radical cations taken is a measure of the electron density of the molecule (or radical), it is found that the efficiency of these compounds as enhancers of lipid peroxidation increases with increasing electron density, suggesting that, at least in the model system, the oxidation of the substrates is the limiting step in causing lipid peroxidation.

Fluorescent markers for hypoxic cells: A study of novel heterocyclic compounds that undergo bio-reductive binding

The bioreductive metabolism and binding of nitroaromatic compounds has been suggested as a method for the identification of hypoxic tumour cells. Bound metabolites of suitable nitroaryl compounds (and some other reducible aromatic compounds) may fluoresce, offering an alternative to radiolabelling or NMR etc. as a diagnostic method. In this paper, the synthesis of some heteroaromatic nitro-compounds is given together with the results obtained from testing of these and other mainly nitroaromatic compounds in vitro as potential bioreductive fluorescent probes for hypoxic cells in tumours. Compounds were incubated with oxygenated or hypoxic mammalian cell suspensions for various times before evaluation of the cellular fluorescence from bioreductive metabolites by fluorescence microscopy and flow cytometry. Among those compounds yielding fluorescent metabolites in cells, considerable variation in hypoxic:oxic differential fluorescence was observed. The in vitro mammalian cell test system showed several of the compounds to be sufficiently promising to merit further investigation in vivo.

Synthesis of α-silicon nitride powder from a polymeric precursor

Abstract Methylcyclosiloxanes and methylcyclosilazanes prepared using dichloromethylsilane have been reacted together to prepare a copolymer which was pyrolysed to give a ceramic powder. The copolymer was characterized using proton nuclear magnetic resonance spectroscopy (1H NMR) and Fourier transform infra-red spectroscopy (FT-IR). Thermogravimetric analysis of the pyrolysis process and reactions which could occur during conversion of the copolymer to the ceramic are discussed. The product, which was found to be amorphous, was also studied using FTIR, crystallized by re-heating and characterized using FT-IR, X-ray techniques and scanning electron microscopy. It was identified as α-silicon nitride and its characteristics are compared with a conventionally prepared, widely used, commercially available grade of silicon nitride. The α-silicon nitride synthesised in the present work contains a wide range of particle morphologies, varying from needles (500 nm in length and 100 nm in width) to equiaxed agglomerates (200–500 nm in size with a substructure in the size range 50–120 nm).

Preparation of 3-substituted 6,7-dimethoxyquinoxalin-2(1h)-ones and studies of their potential as fluoroionophores

Improved routes to the quinoxalinone acid chloride 1 and the 3-methyl-quinoxalinone 21 are described. These intermediates are used to obtain the fluoroionophores 15–19 and 27–29, respectively. The effects of the complexation of metal ions by the fluoroionophores is discussed. A red pigment 26 is obtained from 21.

The elimination of an alkoxy group in the photo-Graebe–Ullmann conversion of 1-(2,5-dialkoxyphenyl)triazolopyridines into carbolines, and the preparation of α-, γ- and δ-carboline quinones

Photochemical decomposition of 1-(2,5-dialkoxyphenyl)triazolopyridines 7a, 21 and 33 resulted in elimination of an alkoxy group to give the alkoxycarbolines 9a and 35 in addition to the expected dialkoxycarbolines. The carbolines having either a methoxy and a isopropoxy substltuent 22, 34a and 34b or two methoxy groups 41 were oxidised with ceric ammonium nitrate to yield the α-, γ- or δ-carboline p-quinones 37, 38 and 42.

Synthesis, hydroxyl radical production and cytotoxicity of analogues of bleomycin

Two pyridine analogues of the metal complexing region of the anticancer drug bleomycin and two related but deactivated prodrugs have been linked to a 2,6-diphenylpyridine derivative as a DNA binding unit. The 2,6-diphenylpyridine system is structurally related to known amplifiers of the cytotoxicity of bleomycin. The conjugates were found to bind to DNA more strongly than bleomycin-A2 and were more cytotoxic than the corresponding compounds lacking the DNA binding unit. On exposure of a mixture of cells and prodrugs to hypoxia and then air, the prodrug containing the nitrohistidine unit was not bioreductively activated but the prodrug having an N-oxide group was bioreductively activated. This result represents a novel approach to the improvement of the therapeutic ratio of bleomycin analogues.

A convenient conversion of indoles to 3,3-dibromooxindoles and then to isatins

Abstract 3-Bromoindoles, 3-unsubstituted indoles, or 3-formylindoles on treatment with NBS (2,3, or 4 molar equivalents, respectively) in t -butanol give 3,3-dibromooxindoles, and these readily yield the corresponding isatins on hydrolysis.

Synthesis of silicon oxynitride from a polymeric precursor

In this final part of our investigation, the copolymers prepared (reported in Part III) have been pyrolysed to yield silicon oxynitride. Thermogravimetric studies performed on several copolymers in nitrogen, ammonia/nitrogen mixtures, air and oxygen are discussed in the present paper. One copolymer was used for further investigation and its pyrolysis conditions (variation of pyrolysis atmosphere according to temperature) were optimized to produce the maximum yield of white amorphous residue which was crystallized by heating to 1600°C to produce silicon oxynitride powder. The powder particles were equiaxed in shape and in the size range 50–150 nm but in agglomerates of size 0.3–0.1 μm. Crystallization at higher temperatures resulted in a mixture of a silicon nitride-silicon oxynitride.

Formation of 1-chlorobenzocyclobutene, anthracene or benzofuran by flash vacuum pyrolysis

Abstract pyrolysis of o -substituted benzylidene chlorides is shown to be a useful route to 1-chloro-benzocyclobutene, anthracene or benzofurans; evidence is given for a carbene intermediate in the pyrolysis of o -methoxybenzylidene chloride.

Formation of certain substituted 5H-pyrrolo[2,3-b]pyrazines by thermal cyclisation of pyrazinylhydrazones and a route to 5H-pyrazino[2,3-b]indole; a synthesis of 5H-pyrrolo[2,3-b] pyrazine and some of its properties

Thermal (non-catalytic) cyclisation of the pyrazinylhydrazones (6a—i) caused ring closure on to the carbon atom of the pyrazine nucleus to give the 3-substituted and 2,3-disubstituted 5H-pyrrolo[2,3-b]pyrazines (7a—g), (8), and (9), respectively. 6,7,8,9-Tetrahydro-5H-pyrazino[2,3-b]indole (7g) was dehydrogenated to the parent pyrazino[2,3-b]indole (15). Pyrrolo[2,3-b]pyrazine (7h) has been obtained from 2-amino-3-methylpyrazine and some of its properties have been investigated.