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PubMed1975

[Factors influencing transduction of genetic determinants of penicillinase activity and pathogenicity in staphylococcus aureua. II. Antiphage activity of acridine derivatives].

Acridine dyes examined earlier (acrichine, acridine orange, proflavine and rivanol) and newly-synthesized preparations (acridines No. No. 37--40) were studied in the capacity of nonspecific agents influencing the lytic cycle in development of staphylococcus phages. Acrichine and acridine No. 37 failed to prevent lysis of the indicator staphylococcus cultures (strains 16/160 and 8325) by bacteriophages; proflavine, rivanol, acridines No. No. 39--40 produced a marked inhibitory effect; acridine orange and acridine No. 38 inhibited the staphylococcus lysis completely. Some preparations could be used to investigate the transduction phenomenon.

Acridines↗
PubMed1979

Relationship of carcinogenicity, mutagenicity, and K-region reactivity in benz[c]acridines.

Benz[c]acridine and its 10 methyl-substituted derivatives were examined for chemical reactivity with osmium tetroxide and mutagenic activity on Salmonella typhimurium, and the results were contrasted with the electronic charge in the K region and the carcinogenic activity of benz[c]acridines. The addition of osmium tetroxide took place at the K region of benz[c]acridines. A linear relationship was established between the charge in the K region and the rate constant of the second-order reaction between osmium tetroxide and benz[c]acridines except the 5,7-dimethyl derivative whose substituent in the 5-position sterically hindered the reaction. Benz[c]acridines showed mutagenic activity in the presence of S-9 Mix, but not in the absence of S-9 Mix. There was a corresponding relationship among the K-region reactivity, mutagenic activity, and carcinogenic activity in benz[c]acridines. The only exception for this was the 7,11-dimethyl derivative in which the 11-methyl group had a steric effect on the ring-nitrogen atom. It was suggested that a common mechanism with regard to the reactivity of the K region is working in both carcinogenesis and mutagenesis. It was concluded that benz[c]acridines are activated, before they display a carcinogenic or mutagenic activity, to a proximate form such as 5,6-epoxides, through a metabolic process in which the nucleophilic property of the K region to react with electrophilic reagents plays an important role.

Acridines↗
PubMedDate not supplied

Effects of acridines on bacterial plasmid replication and endotoxin.

Different amino- and imino-acridines were systematically synthesized. The antibacterial, antiplasmid, antimotility and endotoxin complexing effect of acridines were studied, when antibacterial effect of the compounds was compared on E. coli. Aminoderivatives were more active than imino-acridines. The N-heptyl-9-imino-acridine was able to select lon minus mutants in the E. coli culture, however, the other acridines tested were ineffective in this respect. The iminoacridines inhibited the motility of Proteus vulgaris more effectively than aminoderivatives. The antimotility action of the acridines was also dependent on the ionic content of the media. The antiplasmid effect was measured on an F-prime plasmid of E. coli LE140 strain. Iminoacridines had a more powerful antiplasmid effect than the amino-substituted derivatives. The majority of the compounds inhibited the intercellular plasmid transfer from E. coli. Kmr donor to a Na-azide resistant recipient. In this test the aminosubstituted derivatives were shown to be more effective inhibitors of conjugation than the imino-substituted compounds. Endotoxin formed complexes with N-butylamino. N-propy-lamino and imidoderivatives. However, complex formation of N-ethyl-, N-heptyl-, N-diethylaminoethyl- and N-diethylamino-propyl-acridines were different. Correlations between molecular orbitals and the antibacterial effects are also discussed.

Acridines↗
PubMed1985

Photodynamic mutagenic action of acridine compounds on yeast Saccharomyces cerevisiae.

The photodynamically produced mutagenicity and toxicity of 8 acridine compounds were compared in Saccharomyces cerevisiae under resting and growing conditions. Without irradiation none of the acridines induced respiratory-deficient ('petite') colonies, indicative of mitochondrial DNA damage, in resting cells; and only acriflavine and proflavine induced 'petites' in growing cells. Also, without irradiation none of the acridines were significantly toxic or mutagenic for nuclear DNA under resting or growing conditions. However, with irradiation, acriflavine, proflavine, acridine yellow and rivanol became effective 'petite'-inducing mutagens and highly toxic for resting cells, while acriflavine, proflavine, and acridine orange became effective nuclear mutagens for resting cells. Acridine, quinacrine and 9-aminoacridine were not at all biologically effective with irradiation for resting cells. The results presented here indicate that singlet oxygen is generated by a photodynamic mechanism when acriflavine is irradiated, and further, that acridine, quinacrine and 9-aminoacridine are ineffective photosensitizers, because they are incapable of generating singlet oxygen with irradiation.

Aminoacridines↗
PubMed2006

Acridin-9-yl exchange: a proposal for the action of some 9-aminoacridine drugs.

The finding that several derivatives of 9-aminoacridine were deacridinylated in the presence of primary aliphatic amines during the solid phase synthesis of acridine-peptide conjugates prompted us to investigate the acridin-9-yl moiety transfer from a relatively low-molecular acridine source to a high-molecular carrier. The hydrophobic polymer was used as a model of hydrophobic core of biologically active proteins. While the alpha-amino group in the peptide was found to play the role of weak acridine acceptor, the epsilon-amino group of lysine appeared to serve as a moderate acceptor of acridine moiety. The covalent modification of the lysine residues side chain in the hydrophobic core of prion protein aggregates could thus explain the discrepancy between the ability of the acridine drug quinacrine to reduce efficiently the incidence of prion protein in cell culture and its weak prion binding affinity.

Acridines↗
PubMed1998

A quantitative model for using acridine orange as a transmembrane pH gradient probe.

Monitoring the acidification of the internal space of membrane vesicles by proton pumps can be achieved easily with optical probes. Transmembrane pH gradients cause a blue-shift in the absorbance spectrum and the quenching of the fluorescence of the cationic dye acridine orange. It has been postulated that these changes are caused by accumulation and aggregation of the dye inside the vesicles. We tested this hypothesis using liposomes with transmembrane concentration gradients of ammonium sulfate as model system. Fluorescence intensity of acridine orange solutions incubated with liposomes was affected by magnitude of the gradient, volume trapped by vesicles, and temperature. These experimental data were compared to a theoretical model describing the accumulation of acridine orange monomers in the vesicles according to the inside-to-outside ratio of proton concentrations, and the intravesicular formation of sandwich-like piles of acridine orange cations. This theoretical model predicted quantitatively the relationship between the transmembrane pH gradients and spectral changes of acridine orange. Therefore, adequate characterization of aggregation of dye in the lumen of biological vesicles provides the theoretical basis for using acridine orange as an optical probe to quantify transmembrane pH gradients.

Acridine Orange↗
PubMed1984

Acridine orange stain in the early detection of bacteria in blood cultures.

A total of 1,592 blood cultures without macroscopic signs of bacterial growth in the first 12-24 h of incubation were processed for both acridine orange stain and blind subculture. One hundred and twenty-one (7.6%) blood cultures were positive by either method; of these, 105 (8.68%) were positive by both methods, 11 (9.1%) positive by acridine orange and negative by subculture, and 5 (4.1%) negative by acridine orange and positive by subculture. The difference between the 116 blood cultures positive by acridine orange and the 110 blood cultures positive by subculture was not statistically significant (p greater than 0.1). Gram stain performed on all acridine orange positive cultures failed to reveal bacteria in 14 cases. Acridine orange staining is a sensitive, rapid and reliable method for detecting bacteria in blood cultures early during incubation. The method is inexpensive and easy to perform and can be substituted for blind subcultures.

Acridine Orange↗
PubMed1988

Hotspot sites for acridine-induced frameshift mutations in bacteriophage T4 correspond to sites of action of the T4 type II topoisomerase.

The type II topoisomerase of bacteriophage T4 is a central determinant of the frequency and specificity of acridine-induced frameshift mutations. Acridine-induced frameshift mutagenesis is specifically reduced in a mutant defective in topoisomerase activity. The ability of an acridine to promote topoisomerase-dependent cleavage at specific DNA sites in vitro is correlated to its ability to produce frameshift mutations at those sites in vivo. The specific phosphodiester bonds cleaved in vitro are precisely those at which frameshifts are most strongly promoted by acridines in vivo. The cospecificity of in vitro cleavage and in vivo mutation implicate acridine-induced, topoisomerase-mediated DNA cleavages as intermediates of acridine-induced mutagenesis in T4.

Acridines↗
PubMed1981

Comparison of petite induction in yeast by acridines, ethidium and their photoaffinity probes.

The production of petite mutations by different acridine analogs was studied in Saccharomyces cerevisiae. Compounds with amino substituents at the 2 and 3 positions of the acridine nucleus and methylation at position 10 were effective for petite induction in growing cells but not in resting cells, while those with chloro, nitro and methoxy substituents were not effective in either resting or growing cells. Photosensitive azido derivatives of the acridines were tested to evaluate the role of covalent drug attachment for mutagenesis in resting cells. Photolysis of resting cells with 9-axido, 3-azido-6-amino-, 9-azido-10-methyl-, or 3-azido-6-amino-10-methyl-acridine was highly toxic. 3-Azido-6-amino-acridine, and especially 3-azido-10-methyl-, and 3-azido-6-amino-10-methyl-acridine, were effective petite inducers in resting cells. Thus, the photosensitive (azido) group at position 9 produced only cell killing while the azido group at position 3 and/or 6 led to effective petite induction in resting cells. In contrast, petite induction was observed only for growing cells, for dark control experiments with these compounds or with the monoazide precursor compounds.

Acridines↗
PubMed1992

Lysosomal storage of sulfated glycosaminoglycans in cultured fibroblasts exposed to immunostimulatory acridine derivatives.

The purpose of the present cytological and radiochemical study was to investigate whether the immunomodulatory agent 3,6-bis[2-(diethylamino)ethoxy]acridine (CL-90.100) and three congeners induce lysosomal storage of sulfated glycosaminoglycans (sGAG) in cultured rat corneal fibroblasts. The reason for asking this question was as follows: The four acridine derivatives have molecular similarities with the dicationic amphiphilic compound tilorone, which has previously been shown to cause sGAG storage in cultured cells and in intact rats. The cells were exposed to the drugs for 72 hr. Tilorone served as reference. All acridine derivatives caused cytological alterations which, on the basis of the cytochemical results, were indicative of lysosomal sGAG storage. The threshold concentrations ranged from 0.3 to 0.7 microM. Radiochemical experiments showed that CL-90.100 up to 10 microM induced [35S]GAG storage in a dose-dependent manner, with an EC50 of 2 microM. Concentrations above 10 microM were cytotoxic. Experiments with equimolar concentrations (3 microM) demonstrated that three of the acridine derivatives were more potent and one was less potent than tilorone. Additionally, CL-90.100 was tested on bovine corneal fibroblasts, with cytochemical and radiochemical results similar to those in rat cells. The present findings show that (a) the four acridine derivatives induce lysosomal sGAG storage; (b) the acridine ring, compared with the fenfluorenone ring (tilorone), enhances this potency; and (c) the substituents at the nitrogens can have some influence on the potency to induce sGAG storage.

Acridines↗
PubMed2005

Synthesis and antileishmanial activities of 4,5-di-substituted acridines as compared to their 4-mono-substituted homologues.

Newly synthesized 4,5-di-substituted acridines were assessed for in vitro antileishmanial activities as compared to those of their 4-mono-substituted homologues. Mono-substituted acridines exhibited a weak specificity for Leishmania parasites. Di-substituted acridines, on the contrary, displayed interesting amastigote-specific activities through a mechanism of action that might not involve intercalation to DNA. This antileishmanial property, associated with a low antiproliferative activity towards human cells, led to the identification of a new class of promising acridine derivatives such as 4,5-bis(hydroxymethyl)acridine with a nonclassical mechanism of action based on the inhibition of Leishmania internalization within macrophages. In the meantime, the effects of experimental lighting on the biological properties of acridines were assessed: experimental lighting did not significantly improve the antileishmanial activity of the compounds since it produced a greater toxicity against human cells.

Acridines↗
PubMed1998

Cytotoxic and DNA-damaging properties of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) and its analogues.

An antitumor drug N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) and its three close structural analogs N-[2-(hydroxyethylamino)ethyl]acridine-4-carboxamide (DACAH), N-[2-(dimethylamino)ethyl]-9-aminoacridine-4-carboxamide (amino-DACA), and N-[2-(hydroxyethylamino)ethyl]-9-aminoacridine-4-carboxamide (amino-DACAH) were studied for their ability to inhibit RNA synthesis in vitro and to form topoisomerase II-mediated DNA lesions in relation to cell-killing activity. All tested compounds induced chromatin lesions characteristic of topoisomerase II-blocking drugs (DNA breaks and DNA-protein cross-links) in treated cells, but were much less active than reference antileukemic acridine m-AMSA (4'-(9-acridinylamino)-methanesulfon-m-anisidide). The ability to form these lesions was dependent on the structure of the 4-carboxamide side-chain, which seems to be an important factor affecting the drug transport rate through cell membrane. A 4-carboxamide chain with an N-2-(dimethylamino)ethyl moiety resulted in more efficient transport through cell membranes, higher cytotoxicity, and DNA-damaging activity. The mode of action of acridine-4-carboxamides was further elucidated by their incubation with cells in the presence of antitopoisomerase II agents of a known mechanism of inhibition. These were: bisdioxopiperazine (ICRF-187), a catalytic inhibitor of topoisomerase II, and etoposide (VP-16), an inducer of a cleavable complex of the enzyme with DNA. The cytotoxicity of DACA and its analogs was not antagonized by preincubating cells with ICRF-187. All tested acridines protected cells against DNA breakage induced by VP-16, but the extent of protection varied significantly. Amino-DACA, which easily penetrates cell membrane, fully inhibited DNA break formation, whereas other analogs exhibited a low degree of protection when used at high concentration. Our results suggest that the acridine-4-carboxamides discussed here are poor topoisomerase II poisons and that this enzyme is not their main target.

Acridines↗
PubMed1995

Novel acridine-triazenes as prototype combilexins: synthesis, DNA binding, and biological activity.

A series of bifunctional ligands has been developed as prototype DNA-binding combilexins using a DNA template-directed approach. These novel agents contain a 1,3-diaryltriazene linker moiety, present in the established DNA minor groove-binder berenil [1,3-bis(4'-amidinophenyl)-triazene], which is attached to an intercalating acridine chromophore by a functionalized thiazole residue. This 9-arylacridine is predicted to confer rotational freedom to the hybrid molecule and thus facilitate bifunctional interaction with double-stranded DNA through a combination of 'classical' intercalation and minor groove-binding processes. The noncovalent DNA-binding properties of these acridine-triazene combilexins, together with the component molecular fragments, have been examined by fluorescence quenching and thermal denaturation studies with calf thymus DNA and two oligonucleotides, [poly(dA-dT)]2 and [poly(dG-dC)]2. In addition, the binding behaviors of these acridine compounds are compared to those of proflavine (3,6-diaminoacridine) and its 9-phenyl derivative. The results indicate that the hybrid agents (i) are more DNA-affinic than either molecular component, (ii) retain the AT-preferential binding properties of the parent difunctionalized 1,3-diaryltriazene residues, despite weak GC-preferential behavior associated with the acridine chromophore, and (iii) have a reduced binding affinity at pH 7 that reflects the protonation status of the acridine. In contrast, the more basic proflavines show much greater binding affinity and a marked preference for GC-rich DNA sequences. In vitro cytotoxicity data with L1210 mouse leukemia and A2780 human colon cancer cell lines show that the conjugate molecules are approximately 10-40-fold more potent than the acridine or triazene subunits and have activities that compare favorably with those of other reported synthetic combilexins. Intercalative binding modes with a model d(GATACGATAC).d(GTATCGTATC) target duplex have been investigated using molecular modeling techniques. These studies provide a rational basis for the binding properties and suggest that the prototype combilexins can bind in a bimodal manner that induces little distortion of the host DNA duplex. Energy-minimized models for the possible dual interactions are discussed.

Acridines↗
PubMed1999

Structure-activity relationships for substituted bis(acridine-4-carboxamides): a new class of anticancer agents.

A series of acridine-substituted bis(acridine-4-carboxamides) linked by a (CH2)3N(Me)(CH2)3 chain have been prepared by reaction of the isolated imidazolides of the substituted acridine-4-carboxylic acids with N,N-bis(3-aminopropyl)methylamine. These dimeric analogues of the mixed topoisomerase I/II inhibitor N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA), currently in clinical trial, show superior potencies to the corresponding monomeric DACA analogues in a panel of cell lines, including wild-type (JLC) and mutant (JLA and JLD) forms of human Jurkat leukemia. The latter mutant lines are resistant to topoisomerase II targeted agents because of lower levels of the enzyme. Analogues with small substituents (e.g., Me, Cl) at the acridine 5-position were clearly superior, with IC50's as low as 2 nM against the Lewis lung carcinoma and 11 nM against JLC. Larger substituents at any position caused a steady decrease in potency, likely due to lowering of DNA binding affinity. A small series of analogues of the most potent bis(5-methylDACA) compound, with second substituents (Me and Cl) in the 1- or 8- position had broadly similar potencies to the 5-Me compound, indicating that, while the 1- and 8-substituents are acceptable, they add little to the enhancing effect of the 5-methyl group. All of the compounds were at least equitoxic (some up to 4-fold more cytotoxic) against the mutant Jurkat lines than in the wild-type, consistent with a relatively greater effect on topoisomerase I compared with topoisomerase II. The bis(5-methylDACA) compound was found to inhibit the action of purified topoisomerase I in a cell-free assay. Compounds were on average 10-fold less cytotoxic in an MCF7 breast cancer line overexpressing P-glycoprotein than in the wild-type line and showed some selectivity for colon tumor lines in the NCI human tumor cell line panel. Several analogues produced significant growth delays in the relatively refractory subcutaneous colon 38 tumor model in vivo at substantially lower doses than DACA. The bis(acridine-4-carboxamides) represent a new and interesting class of potent topoisomerase inhibitors.

Acridines↗
PubMed1999

Ionization potentials and metabolic activations of carbazole and acridine derivatives.

7H-Dibenzo[c,g]carbazole (DBC) and dibenz[a,j]acridine (DBA) representing environmental nitrogen-heterocyclic aromatic (NHA) genotoxicants undergo differing metabolism and exhibit differing DNA binding patterns and carcinogenic activities. Two chemical oxidation-related parameters, anodic peak potentials (E(pa)) and maximum absorption energies (E(CT)) of the charge-transfer complexes, were measured for a series of 18 derivatives of carbazole and acridine. On the basis of the E(pa) and E(CT) values and the ionization potential (IP) data of the parent carbazole and acridine that are available in the literature, with linear regression analyses, IP values of the 18 carbazoles and acridines were reported for the first time. The two sets of IP values determined from either E(pa) or E(CT) agreed with one another for most of the compounds. Carbazoles possessed IP values (ranging from 7.2 to 7.6 eV) that are lower than those of acridines (i.e., 7.8-8.1 eV). These data are consistent with the potential activation of carbazole and/or acridine derivatives. For DBC having an IP of approximately 7.3 eV, both one-electron oxidation and monooxygenation pathways are involved in the metabolic activation. In contrast, DBA with a high IP of approximately 8.0 eV is activated through the monooxygenation pathway only. Therefore, just as it is known for carcinogenic PAHs, IP appears to be an important parameter in predicting the metabolic activation for genotoxic NHA in the environment.

Acridines↗
PubMed1995

The hepatic metabolism of two carcinogenic dimethylbenz[c]acridines in control and induced rats: the distribution and the mutagenicity of metabolites.

The major and minor metabolites of the potent polycyclic aza-aromatic carcinogens 7,9-dimethylbenz[c]acridine and 7,10-dimethylbenz[c]acridine, and the stereochemistry of the dihydrodiol metabolites have been previously described. The metabolite distributions produced in incubations of the aza-aromatic compounds with liver microsomes from phenobarbital- and 3-methylcholanthrene-pretreated and untreated rats, and the mutagenicity in the Ames test are described in this paper. The major metabolites of each were the alcohols produced by oxidation of the methyl group on the 8,9,10,11-ring for control and phenobarbital-induced preparations, while with 3-methylcholanthrene-induced preparations both the 7- and 9- (or 10-) monoalcohols were formed. Total monofunctionalized dihydrodiol metabolites, the 5,6- and 3,4-isomers for 7,9-dimethylbenz[c]acridine, and the 3,4-, 5,6- and 8,9-isomers for 7,10-dimethylbenz[c]acridine, constituted approximately 10% of total metabolites. As well, the K-region arene oxide was formed in substantial amounts with both compounds, accompanied in the case of 7,10-dimethylbenz[c]acridine with some 8,9-oxide. When incubations were carried out in the presence of the epoxide hydrase inhibitor 3,3,3-trichloropropane-1,2-oxide, dihydrodiol formation was almost completely inhibited and relative amounts of both phenols and oxides increased. Secondary metabolites were also formed to approximately 10% of the total products. The mutagenicity of synthetic alcohols and isolated purified metabolites was determined in the Salmonella mammalian microsome plate assay (Ames test) with strain TA100. Limited amounts of metabolites isolated precluded extensive testing, but high mutagenicities were noted for all 3,4-dihydrodiol derivatives isolated. These exceeded those of the parent aza-aromatic hydrocarbons. Alcohols were also active but less so than the parent compounds. The activation of these two dimethylbenz[c]acridines to mutagens appears to be through bay-region diolepoxides following patterns seen in other aza-aromatic compounds and the polycyclic aromatic hydrocarbons.

Acridines↗
PubMed1992

10N-nonyl acridine orange interacts with cardiolipin and allows the quantification of this phospholipid in isolated mitochondria.

The acridine orange derivative, 10N-nonyl acridine orange, is an appropriate marker of the inner mitochondrial membrane in whole cells. We use membrane model systems to demonstrate that 10N-nonyl acridine orange binds to negatively charged phospholipids (cardiolipin, phosphatidylinositol and phosphatidylserine). The stoichiometry has been found to be 2 mol 10N-nonyl acridine orange/mol cardiolipin and 1 mol dye/mol phosphatidylserine or phosphatidylinositol, while, with zwitterionic phospholipids, significant binding could not be detected. The affinity constants were 2 x 10(6) M-1 for cardiolipin-10N-nonyl-acridine-orange association and only 7 x 10(4) M-1 for that of phosphatidylserine and phosphatidylinositol association. The high affinity of the dye for cardiolipin may be explained by two essential interactions; firstly an electrostatic interaction between the quaternary ammonium of nonyl acridine orange and the ionized phosphate residues of cardiolipin and secondly, hydrophobic interactions between adjacent chromophores. A linear relationship was demonstrated between the cardiolipin content of model membranes and the incorporated dye. Consequently, a convenient and rapid method for cardiolipin quantification in membranes was established and applied to the cardiolipin-containing organelle, the mitochondrion.

Acridine Orange↗
PubMed1980

Evaluation of acridine orange stain for detection of microorganisms in blood cultures.

A pH 4.0 buffered solution of the fluorochrome acridine orange was used to stain samples of 2,704 blood cultures that failed to yield visible evidence of growth after 1 day of incubation. Results obtained by the staining method were compared with those obtained by aerobic and anaerobic subcultures simultaneously performed upon the same cultures. Of the 109 culture-positive blood specimens initially detected by the acridine orange and the subculture methods, 85 (78%) were detected by both acridine orange and subcultures techniques, 14 (12.8%) were detected by subculture alone, and 10 (9.2%) were detected by acridine orange alone. The differences between the subculture and acridine orange methods were not found to be statistically significant (P less than 0.1). The acridine orange method represents a rapid and inexpensive alternative to conventional subculture techniques for the detection of bacteria in blood cultures that fail to yield visible evidence of growth after 1 day of incubation.

Acridine Orange↗