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PubMed1975

An acridine probe into the physiological state of the cell.

Acridine orange was used as a probe to look into the physiological state of the yeast cell, particularly as regards the change in the properties of the membrane (which acts as a barrier against the incoming acridine orange) and the availability of binding sites for acridine orange in chromosomal DNA during growth. After acridine orange had been introduced into the cell, the genetic change at a specific locus with incubation time was measured photodynamically. A three-fold increase in the rate of penetration of acridine orange into the cell was observed, for instance, in going from the resting phase to the dividing phase. A five-fold increase was observed in the number of binding sites in chromosomal DNA under the same transition of the cell. These two parameters may be useful as a measure of the physiological changes in the cell. Some environmental factors such as pH and temperature were also demonstrated to affect the parameters.

Acridines↗
PubMed1984

Rapid screening of urine for significant bacteriuria by Gram stain, acridine orange stain, and the Autobac MTS system.

Urine specimens submitted for microbiologic examination were screened for evidence of bacteriuria by three rapid methods: Gram staining, acridine orange staining, and the Autobac MTS system. The screening results were compared with those obtained by semiquantitative colony counts on agar plates. In this comparative study 1055 urine specimens were examined, of which 146 (13.8%) had colony counts of greater than or equal to 1 X 10(5)/ml. All three urine screening methods detected this level of bacteriuria at a sensitivity of 98% and a specificity of 55.2% (acridine orange), 66.0% (Gram stain), and 83.2% (Autobac), respectively. Of the 1055 urine specimens examined, 185 (17.5%) had colony counts of greater than or equal to 1 X 10(4)/ml, at which level the sensitivity of the three methods was 93% and the specificity was 56.7% (acridine orange), 68.0% (Gram stain), and 86.0% (Autobac), respectively. For any level of sensitivity, the Autobac urine screen was shown to be more specific than either the Gram stain or the acridine orange method. The acridine orange stain was the least specific urine screen, especially at the upper limits of sensitivity.

Acridine Orange↗
PubMed2006

Linker-modified triamine-linked acridine dimers: synthesis and cytotoxicity properties in vitro and in vivo.

The preparation and cytotoxicity properties of a series of N(epsilon)-substituted triamine-linked acridine dimers are described. Most acridine dimer derivatives reveal highly potent in vitro cytotoxicity properties and DNA binding activity. Several acridine dimers were selected to study their action in vivo. These acridine dimers have demonstrated a narrow safe margin, as has adriamycin, but higher maximum tolerate dose (MTD) in comparison with that of adriamycin in ICR mice. The acridine dimers also demonstrated various anit-COLO 205 solid tumor activities in vivo. Compound 1 has shown the most potent solid tumor inhibition.

Acridines↗
PubMed1982

Thin-layer chromatographic and high-performance liquid chromatographic separation of metabolites of the weak carcinogen, 7-methylbenz[c]acridine.

The metabolism of [14C]7-methylbenz[c]acridine, a weakly carcinogenic polycyclic aza aromatic hydrocarbon, was studied in rates in vivo, and in rat hepatocytes and hepatic microsomes. Evidence for oxidation of the methyl group and excretion of 7-hydroxymethylbenz[c]acridine and benz[c]acridine-7-carboxylic acid in rat bile was obtained by thin-layer chromatography. A reversed-phase high-performance liquid chromatographic separation of metabolites was developed and chromatographic profiles of metabolites found in vivo and formed in vitro are presented. Several synthetic potential oxidation products were used to characterise the chromatographic profiles and evidence for the in vitro formation of 7-hydroxymethylbenz[c]acridine and 5,6-dihydro-5,6-dihydroxy-7-methylbenz[c]acridine was obtained.

Acridines↗
PubMed2003

RNA-ligand interactions: affinity and specificity of aminoglycoside dimers and acridine conjugates to the HIV-1 Rev response element.

Semisynthetic aminoglycoside derivatives may provide a means to selectively target viral RNA sites, including the HIV-1 Rev response element (RRE). The design, synthesis, and evaluation of derivatives based upon neomycin B, kanamycin A, and tobramycin conjugates of 9-aminoacridine are presented. To evaluate the importance of the acridine moiety, a series of dimeric aminoglycosides as well as unmodified "monomeric" aminoglycosides have also been evaluated for their nucleic acid affinity and specificity. Fluorescence-based binding assays that use ethidium bromide or Rev peptide displacement are used to quantify the affinities of these compounds to various nucleic acids, including the RRE, tRNA, and duplex DNA. All the modified aminoglycosides exhibit a high affinity for the Rev binding site on the RRE (K(d) <or= 10 nM), but few compounds have a high specificity for the RRE. Compared to the acridine conjugates, the dimeric and unmodified aminoglycosides exhibit good RNA over DNA selectivity, but show little differentiation between different RNA molecules. Neomycin-based derivatives consistently have the highest RNA and DNA affinities, but the lowest RRE specificity. To optimize these derivatives for RRE specificity, a series of neomycin-acridine conjugates with variable linker lengths were synthesized and evaluated. The neo-acridine conjugate with the shortest linker length has the optimal RRE specificity. Duplex DNA, on the other hand, prefers the acridine conjugate with the longest linker length, and duplex RNA (poly r[A]-r[U]) has the highest affinity for the conjugate with an intermediate linker length. Compared to neomycin B, the derivatives based upon tobramycin and kanamycin A have slightly lower RRE affinities, but better RRE specificities. These results illustrate how the binding affinity and specificity of aminoglycoside intercalator conjugates can be tuned by optimizing the linker length and by changing the identity of the aminoglycoside moiety. These results also indicate that many aminoglycoside-based ligands are capable of high-affinity binding of RNA, but achieving high site specificity remains a challenging objective.

Acridines↗
PubMed1995

9-substituted acridine derivatives with long half-life and potent antitumor activity: synthesis and structure-activity relationships.

A series of DNA-intercalating 9-anilinoacridines, namely 9-phenoxyacridines, 9-(phenylthio)acridines, and 9-(3',5'-disubstituted anilino)acridines, were synthesized as potential antitumor agents with inhibitory effects on DNA topoisomerase II. Unlike amsacrine (m-AMSA), these agents were designed to avoid the oxidative metabolic pathway. These acridine derivatives were, therefore, expected to have long half-life in plasma. Both 9-phenoxyacridines and 9-(phenylthio)acridines were found to have moderate cytotoxicity against mouse leukemia L1210 and human leukemic HL-60 cell growth in culture. Among 9-(3',5'-disubstituted anilino)acridines, 3-(9-acridinylamino)-5-(hydroxymethyl)aniline (AHMA) was found to be a potent topoisomerase II inhibitor and exhibited significant antitumor efficacy both in vitro and in vivo. Chemotherapy of solid-tumor-bearing mice with 10, 10, and 5 mg/kg (QD x 4, ip) AHMA, VP-16, and m-AMSA, respectively, resulted in more tumor volume reduction by AHMA than by VP-16 or m-AMSA for E0771 mammary adenocarcinoma and B-16 melanoma. For Lewis lung carcinoma, AHMA was as potent as VP-16 but more active than m-AMSA. Structure-activity relationships of AHMA derivatives are discussed.

Acridines↗
PubMedDate not supplied

Stereochemistry of the major rat liver microsomal metabolites of the carcinogen 7-methylbenz[c]acridine.

The major metabolites of the carcinogen 7-methylbenz[c]acridine (7MBAC), trans-5,6-dihydro-5,6-dihydroxy-7-methylbenz[c]acridine (7MBAC-5,6-DHD), and trans-8,9-dihydro-8,9-dihydroxy-7-methylbenz[c]acridine (7MBAC-8,9-DHD) were characterized as their enantiomers after separation of their bis-(+)-(1R,2S,4S)-endo-1,4,5,6,7,7-hexachlorobicyclo[2.2.1]hept-5 -ene-2-carboxylic acid [(+)-HCA] esters and hydrolysis. The synthetic precursor, trans-3,4-dihydroxy-7-methyl-1,2,3,4-tetrahydrobenz[c]acridine (7MBAC-3,4-THD), was similarly separated into enantiomers, and the dihydrodiol trans-3(S),4(S)-dihydro-3,4-dihydroxy-7-methylbenz[c]acridine (7MBAC-3,4-DHD) was prepared from 7MBAC-3(S),4(S)-THD. Absolute configurations were assigned by the chiral exciton coupling of the bis-p-(dimethylamino)benzoate of 7MBAC-3(R),4(R)-THD, and by the semiempirical methods based on the biaryl chromophores of the enantiomers of 7MBAC-5,6-DHD and of the methanolysis products of the 5,6-oxide of 7MBAC which were resolved as their (+)-HCA esters. X-ray crystallography was used for 7MBAC-8(S),9(S)-DHD bis-(+)-HCA ester, and assignments were correlated with chiral exciton coupling of the bis-4-(dimethylamino)cinnamates of 7MBAC-5(R),6(R)-DHD and 7MBAC-8(S),9(S)-DHD. The stereochemical compositions of four metabolites (three dihydrodiols and 7MBAC-5,6-oxide) formed in incubations with rat liver microsomes from control and induced liver were determined by normal-phase separations of bis-(+)-HCA esters, and by chiral stationary-phase separation of the 5,6-oxide methanolysis products. The 3(R),4(R)-enantiomer of 7MBAC-3,4-dihydrodiol predominated, 74-98% enantiomeric purity, and purity for the oxide varied from about 71% 5(R),6(S)-oxide for control microsomes to about 28% 5(R),6(S)-oxide for liver microsomes obtained from 3-methylcholanthrene-pretreated rats.

Acridines↗
PubMedDate not supplied

Identification of the major lesion from the reaction of an acridine-targeted aniline mustard with DNA as an adenine N1 adduct.

DNA adducts of two acridine-linked aniline half-mustards have been isolated and identified. The compound where the half-mustard is attached to the DNA-targeting acridine moiety by a short linker chain alkylates both double- and single-stranded DNA exclusively at guanine N7, as do the majority of known aromatic and aliphatic nitrogen mustards. The longer-chain analogue, also containing a more reactive half-mustard, shows a strikingly different pattern, alkylating double-stranded DNA to yield primarily (> 90%) the adenine N1 adduct, together with < 10% of the adenine N3 adduct and only trace amounts of the guanine N7 adduct. In the presence of MgCl2 (which is known not to inhibit the interaction of drugs at minor groove sites), the adenine N3 adduct is the major product. The latter compound is the first known aniline mustard (and apparently the first known alkylating agent of any type) to preferentially alkylate adenine at the N1 position in duplex DNA. These results are consistent with previous work [Prakash et al. (1990) Biochemistry 29, 9799-9807], which showed that the preferred site of DNA alkylation by the corresponding long-chain acridine-linked aniline bis-mustards in general was at major groove sites of adenines and identifies the major site of alkylation as adenine N1 and not N7. This selectivity for adenine N1 alkylation is suggested to result from a preference for the acridine mustard side chain of these compounds to project into the major groove following intercalation of the acridine, coupled with structural distortion of the DNA helix to make the N1 positions of adenines adjacent to the intercalation sites more accessible.

Acridines↗
PubMed1978

The effects of acridine orange on deoxyribonucleic acid in Escherichia coli.

1. Acridine Orange inhibits growth of Escherichia coli K12 when incubated at pH 7.9, but not at pH 7.4.2. At a non-permissive temperature for DNA polymerase I, Acridine Orange inhibits growth of a temperature-sensitive strain and also increases the rate of elimination of the F'-Lac plasmid. 3. DNA isolated from cells treated with Acridine Orange under conditions that inhibit growth contains material of low molecular weight, which is absent from DNA isolated from cells treated under conditions in which growth is not impaired. 4. Cells incubated with Acridine Orange at both pH 7.4 and 7.9 suffer degradation of DNA, as shown by loss of labelled DNA from the acid-insoluble fraction, which is not observed with untreated cells at either pH. 5. The results suggest that elimination of the F'-Lac plasmid by Acridine Orange requires inactivation of repair processes.

Acridines↗
PubMed1999

Use of acridine orange to evaluate chromatin integrity of human spermatozoa in different groups of infertile men.

To study the sperm chromatin compactness various methods, such as acidic aniline blue or acridine orange staining, have been applied. Due to its metachromatic properties, acridine orange dye fluoresces green with double- and red with single-stranded DNA. Samples (n = 181) were evaluated and grouped as follows: group I, normal recently fertile; group II, male having female partner with repeated early pregnancy loss; group III, male with varicocele; and group IV in-vitro fertilization and intrauterine insemination failures. Routine semen analyses were carried out in all the cases. Amorphous particulate matter as observed under phase contrast microscope was graded on the scale of nil to +4. Fixed smears were stained with an aqueous solution of acridine orange and viewed under a fluorescence microscope. Two hundred cells were counted and the percentage of fluorescence calculated. Groups II, III and IV exhibited significantly low green fluorescence compared with the control group. The study also indicates that increased amorphous particulate matter (indicating infection) might be one of the contributing factors to lower acridine orange stainability. Thus acridine orange staining can be used to evaluate the integrity of the nucleus, disorders of which can cause unexplained infertility or lower fertilization potential that may go undetected by routine analysis.

Acridine Orange↗
PubMed1994

Interaction of two peptide-acridine conjugates containing the SPKK peptide motif with DNA and chromatin.

The interaction between DNA and two peptide-acridine conjugates containing one (1) or two (2) moieties of the Ser-Pro-Lys-Lys (SPKK) minor groove-binding peptide motif has been studied by a combination of hydrodynamic, biochemical and spectroscopic methods including diffusion-enhanced luminescence energy transfer (DELET) measurements with a Tb(III) lanthanide chelate as donor. Viscometric titrations do not reveal any significant difference between the two hybrid molecules which both unwind (by about 15 degrees) and extend the DNA similarly. DELET measurements show that the acridinyl chromophore of compounds 1 and 2 is much more accessible than that of a simple monointercalating drug such as acridine orange or ethidium. The accessibility factor increases proportionally with the peptide length, reflecting the extent of perturbation imposed upon the intercalating chromophore by the binding to DNA of the peptide moiety of the hybrids. Experiments with the osmium tetroxide-bispyridine reagent indicate that the two hybrid compounds both affect the local conformation of DNA rendering certain thymine residues conspicuously accessible to the probe. The drug-induced sites of hyperreactivity towards OsO4 in DNA are very similar with the exception of a short run of three T residues which is attacked more strongly in the presence of tetrapeptide-acridine conjugate 1 than with the octapeptide-acridine conjugate 2. These results are fully in agreement with previous footprinting studies and support the view that a minimum of two SPKK motifs is required to mimic the AT-specific minor groove binding antibiotic netropsin. On the basis of the DNA-binding properties of these two peptide-acridine hybrids, we present DNA-binding models in which the acridinyl moiety of compound 1 protrudes slightly outside the double helix but remains more or less parallel to the plane of the base-pairs. In contrast, with compound 2, where the octapeptide SPKKSPKK is bound to the minor groove, we postulate that the chromophore lies only partially overlapped with the base pairs in the intercalation site and, in addition, the heterocyclic chromophore is significantly tilted with respect to the double helix axis. Electric linear dichroism and DELET measurements with chromatin reveal that the presence of histone proteins affects the intercalative binding of compound 2 while it has practically no effect on the binding of compound 1.

Acridines↗
PubMed2003

Oligoamine-acridine conjugates for promotion of gap-selective DNA hydrolysis by Ce(IV)/EDTA complex.

Oligoamines (spermidine, dipropylenetriamine and propylenediamine) were covalently attached to acridine via a hexamethylene linker. These oligoamine-acridine conjugates were efficiently bound to gap sites in substrate DNA, and promoted the DNA hydrolysis by a homogeneous Ce(IV)/ethylenediamine-N,N,N',N'-tetraacetate (EDTA) complex at these sites. In contrast, the hydrolysis of the double-stranded portion in the DNA was little affected by these conjugates, although they were strongly bound thereto by the intercalation of their acridine moieties. As a result, the gap site was selectively and efficiently hydrolyzed by combining the Ce(IV)/EDTA complex with the oligoamine--acridine conjugate. Either the oligoamine or the acridine was only poorly active for the purpose, substantiating the essential role of cooperation between them. The promotion of gap-selective DNA hydrolysis by the conjugates has been ascribed to electrostatic stabilization of a negatively charged transition state by their positive charges.

Acridines↗
PubMed1968

Acridine binding by Escherichia coli: pH dependency and strain differences.

Acridine dye binding by cells of Escherichia coli has been characterized in terms of a number of parameters. There is a temperature-dependent, readily reversible binding of acriflavine which occurs to a greater extent with acridine-sensitive mutants of E. coli K-12 than with wild-type E. coli B or K-12. There is an essentially irreversible internal binding of acriflavine which occurs when the cellular permeability barriers are destroyed or altered by heat-treatment, elevated pH, treatment with toluene or phenethyl alcohol, or infection with bacteriophage T2 or T4. Both the reversible and the irreversible binding of acridines occurs more effectively with the acridine dye acriflavine than with the related dye proflavine, and still less effectively with 9-aminoacridine and quinacrine. These properties of acridine binding can be correlated with various inhibitory effects of the dyes on the cells.

Acridines↗
PubMed1981

Comparison of acridine orange and Gram stains for detection of microorganisms in cerebrospinal fluid and other clinical specimens.

Acridine orange, a fluorochrome strain, is potentially superior to the Gram stain in the direct microscopic examination of clinical specimens because it gives striking differential staining between bacteria and background cells and debris. Its value in clinical laboratories was evaluated by testing 209 cerebrospinal fluids and 288 other body fluids, tissues, and exudates by both techniques. Smears were made in duplicate, fixed with methanol, stained, and examined without knowledge of the result of the companion smear or culture. Overall, acridine orange was slightly more sensitive than the Gram stain (acridine orange, 59.9%; Gram stain, 55.8%) and equally specific in detecting microorganisms. One smear was falsely positive by the Gram stain; none was falsely positive by the acridine orange stain. We conclude that acridine orange staining is a sensitive method for screening clinical specimens and reviewing selected specimens that are purulent, but negative by the Gram stain. Bloody fluids, thick exudates, and other normally difficult-to-read specimens were easily and quickly examined. We recommend, however, that positive smears be reexamined with the Gram stain to confirm the result and determine the Gram reaction of the microorganisms.

Acridine Orange↗
PubMed1975

The influence of acridine dyes and caffeine on recovery from ultraviolet damage in Eudorina elegans.

Caffeine and the acridine dyes, acridine orange and acriflavine, were used to examine the repair potential in Eudorina elegans following ultraviolet irradiation. Acridines blocked photoreactivation primarily as a result of absorption of photoreactivating wavelengths, but acridines did not influence dark survival. Therefore, an acridine-sensitive excision-resynthesis-repair process is absent in Eudorina. Caffeine decreased both dark and light survival, the latter only after relatively high doses of ultraviolet light were used for inactivation. The caffeine-sensitive repair process appears to function most actively when the organisms are engaged in DNA synthesis, indicating that a postreplication-repair system exists in Eudorina. However, the data suggest that a repair system not associated with the DNA synthetic phases may also exist.

Acridines↗
PubMed1991

Comparison of acridine orange stain with culture and gram stain of needle aspirate in experimental Pseudomonas pneumonia.

The sensitivity and specificity of culture, acridine orange stain, and Gram stain were determined using needle aspiration (NA) material obtained from 82 rats with acute Pseudomonas aeruginosa pneumonia and 18 control rats. Lungs were then processed for either bacterial quantitation or histopathologic examination. NA culture proved to be the most sensitive and specific (55 and 100%, respectively). Sensitivity of acridine orange stain was 40%, whereas Gram stain was only 29%. The specificity of each stain was at least 94%. Lung bacterial concentrations influenced the sensitivities of all three techniques, with better sensitivity found in NA samples obtained from lung with bacterial concentration of at least 10(4) colony-forming units (cfu) of P. aeruginosa. Acridine orange and Gram stain results were similar except in NA samples from lung with bacterial concentration of less than 10(4) cfu in which acridine orange stain was more sensitive. The presence of stains identifying bacteria collected from animals with sterile NA culture was found in a small but significant number of samples, suggesting the presence of nonviable though stainable organisms. Use of all three techniques (culture, acridine orange stain, and Gram stain) increased sensitivity to approximately 70% with minimal decrease of specificity.

Acridine Orange↗
PubMed1987

Microspectrofluorometric comparison of benzo(a)pyrene and dibenzo(c,h)acridine metabolism in single living 3T3 fibroblasts.

The purpose of this study was to determine if dibenzo(c,h)acridine could be used as a probe for the N-heterocyclic aromatic compound detoxification system. The determination was achieved by cell population studies (histograms) using microspectrofluorimetry on single living cells. The results show a similar metabolic distribution pattern between dibenzo(c,h)acridine and benzo(a)pyrene, whereas important differences appear between 6-aminochrysene and dibenzo(c,h)acridine, respectively amine aromatic and N-heterocyclic aromatic compounds. No differences were observed in the metabolism of benzo(a)pyrene in untreated cells and those treated with constant concentrations of dibenzo(c,h)acridine. However, inhibition of dibenzo(c,h)acridine metabolism was observed in the presence of benzo(a)pyrene, indicating that this compound should be a preferential substrate for a cell detoxification system.

Acridines↗
PubMed1988

Analysis of commercial samples of acridine orange using high-performance liquid chromatography.

We analyzed commercial samples of acridine orange using reverse-phase high-performance liquid chromatography. The mobile phase of 90:10:2.5 acetonitrile:de-ionized water:pentane sulfonic acid gave baseline separations of components of acridine orange samples in 15 min. Many of the samples were fairly homogeneous; the absorbance due to the acridine orange component ranged from 83-97%. Among the 11 samples tested, one was not acridine orange, reputedly different samples were identical, and the principal component of one sample was not acridine orange.

Acetonitriles↗