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W J Firth

Publications and source records attributed to W J Firth.

7 recordsLinked to original sources
PubMed1984

Induction of cytoplasmically inherited respiration-deficient ('petite') mutants by photodynamic action of acridine compounds.

All acridines used (acriflavine, proflavine, acridine orange and 3-azido-10-methylacridinium chloride) produced killing in yeast cells when activated with visible light. Acriflavine, proflavine and 3-azido-10-methylacridinium chloride, but not acridine orange, produced petite and sectored colonies. Both cell killing and petite induction by light activation of acriflavine resulted apparently from photodynamic action mediated by singlet oxygen (1O2) since the effect were prevented by either sodium azide or anaerobiosis. The biological effects of 3-azido-10-methylacridinium chloride, which was developed as a potential photoaffinity probe for studying the binding and biological effects of acridines, appeared to be due to a photodynamic action analogous to that of acriflavine. Sodium azide or anaerobiosis prevented the light-activated effects of 3-azido-10-methylacridinium chloride despite the fact that the initial chemical breakdown of the azido derivative induced by light was not affected. Cells suspended in D2O demonstrated an enhanced response to 3-azido-10-methylacridinium chloride with irradiation. These results indicate that singlet oxygen mediates the light-activated biological effects of both acriflavine and 3-azido-10-methylacridinium chloride.

Acridines↗
PubMed1984

Identification of an acridine photoaffinity probe for trypanocidal action.

Twenty-four acridine derivatives were screened for trypanocidal activity in Trypanosoma brucei in order to determine which structural features of the acridine molecule confer maximal antiparasitic activity. The synthesis of several new azidoacridine derivatives are also reported as well as an assessment of their value as possible photoaffinity probes for the study of acridine trypanocidal action. The most effective and selective acridine trypanocides, with and without irradiation, were the 3-amino-10-methylacridinium salt derivatives. With brief irradiation, one azidoacridine, 3-amino-6-azido-10-methylacridinium chloride, showed considerable trypanocidal activity at very limiting drug concentrations (10(-7)M) and warrants consideration as a possible photoaffinity probe.

Acridines↗
PubMed1980

Structure-function characterization for ethidium photoaffinity labels as mutagens in Salmonella.

The development of photoaffinity probes to characterize the binding process and subsequent biological activity of a drug has recently been emphasized by the synthesis of two ethidium azide analogs. The initial finding showed that one of the azido analogs, the 8-azido-3-amino derivative, was at least 40-fold more mutagenic and toxic in Salmonella tester strain TA1538 than the other analog, the 3.8-diazido derivative. These observations suggested the need to examine the structural requirements of ethidium photoaffinity labels for frameshift mutagenic activity in Salmonella. Thus, the isomer of the monoazide, the 3-azido-8-amino derivative, and two deaminated monoazide derivatives were synthesized and all of the ethidium analogs were screened in two Salmonella frameshift tester strains, TA1537 and TA1538, and in their excision-repair positive isogenic strains. The results presented in this paper demonstrate that two substituents are needed to produce significant mutagenicity and toxicity by the compound. One substituent, usually the amino group, is required for mutagenic activity, perhaps by orienting the phenanthridinium ring into its mutagenic configuration. The other substituent, the azido group, is required for covalent attachment, a requisite for mutagenic activity. Thus, photoaffinity labeling has provided a means of comparing structure with mutagenic activity for ethidium compounds.

Affinity Labels↗
PubMed1980

Acridine structure correlated with mutagenic activity in Salmonella.

The structural basis for direct mutagenicity of acridines was studied by testing 50 different analogs in the Ames Salmonella tester strains without the addition of mammalian activating enzymes. These experiments showed that the single most effective substituent for frameshift mutagenesis in strain TA1537 is an amino group at the "9" position, while an amino group at either the "3" or "1" position is less effective. Other substitutions at the "9" position demonstrate decreased frameshifting activity compared to 9-aminoacridine. Furthermore, all substituents in combination with the amino group of 9-aminoacridine also decrease frameshifting activity, except for the addition of another amino group at the "1" position or a methyl at the ring nitrogen. Nitro substituents at the "1" and "3" positions enhance 9-aminoacridine toxocity. All nitro substituents decrease typical acridine-frameshift mutagenesis for strain TA1537, but they induce mutagenic activity either in the other type of frameshift strain, TA1538, or in the base-pair substitution strain TA1535. These studies have provided important structure-function relationships for acridine mutagenicity and toxicity in Salmonella. Consequently, this biological system has provided a sensitive means for determining the structural requirements for mutagenic mechanisms.

Acridines↗
PubMed1980

Petite induction in Saccharomyces cerevisiae by ethidium analogs: distinction between resting and growing cells.

The importance of specific substituents, especially amino azide groups, for ethidium induction of petites was evaluated in resting and dividing cells of Saccharomyces cerevisiae through the study of a series of ethidium analogs. The structural requirements in resting and growing cells were found to be different, suggesting that at least two mechanisms are responsible for induction. The significance of particular substituents in the induction processes were recognized by: (1) a dependence upon the ethyl substituent at the ring nitrogen in both actively growing and in resting cells; and (2) the implication that amino substituents are important for the effect in dividing cells and especially in resting cells. Photolytic enhancement of petite induction (via a nitrene which forms a covalent linkage to a biological site) was observed for 3 of the azide analogs, which emphasizes the likelihood that metabolic activation of ethidium to a covalent complex is responsible for its effectiveness. Furthermore, these studies indicate that these monoazide analogs should be ideal probes for examining the mitochondrial mutagenic processes.

Ethidium↗