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PubMed1986

7-Methylbenz[c]acridine: mutagenicity of some of its metabolites and derivatives, and the identification of trans-7-methylbenz[c]-acridine-3,4-dihydrodiol as a microsomal metabolite.

The presence of the proposed proximate carcinogen, trans-3,4-dihydro-3,4-dihydroxy-7-methylbenz[c]acridine (7MBAC-3,4-DHD) among the liver microsomal metabolites of 7-methylbenz[c]acridine (7MBAC) has been demonstrated using gas chromatography mass spectrometry (GCMS) and by co-chromatography with synthetic standards on reverse and normal phase h.p.l.c. 7MBAC-3,4-DHD represented 2.2-3.4% of the total ethyl acetate-extractable metabolites formed from 7MBAC by liver microsomes prepared from untreated and induced rats. About 2.3-2.7% of metabolites formed by lung microsomes was identified as 7MBAC-3,4-DHD. Mutagenicity studies with 7MBAC-3,4-DHD have been carried out in bacterial and mammalian systems using S9 fractions derived from rats pre-treated with Aroclor and guinea pigs pre-treated with 3-methylcholanthrene. Comparative data with other 7MBAC derivatives are also reported. The 7MBAC-3,4-DHD and the analogous dihydro derivative of 7MBAC were the most potent mutagens of those compounds requiring metabolic activation. The data imply that the 3,4-dihydrodiol is metabolised to a bay region diol epoxide as the ultimate carcinogen. In support of this anti-1,2-epoxy-trans-3,4-dihydroxy-7-methyl-1,2,3,4- tetrahydrobenz[c]acridine was a potent mutagen in the Ames and V79 cell systems without activation. The syn-isomer was less active.

Acridines↗
PubMed1963

DYNAMICS OF ACRIDINE ORANGE-CELL INTERACTION. I. INTERRELATIONSHIPS OF ACRIDINE ORANGE PARTICLES AND CYTOPLASMIC REDDENING.

The in vitro localization of acridine orange (AO) in living cells was monitored by means of fluorescence microscopy, quantitative cell viability studies, and photofluorimetric measurements following dye-cell interaction. The parameters, pH, time, dye concentration, and the metabolic state of the cell were found to exert a profound influence on the time course and distribution of staining. The parameters studied are mutually interdependent, and intracellular dye localization may be predictably altered by their appropriate manipulation. Conditions are defined whereby two morphologically distinct but physiologically interrelated reactions, namely, acridine orange particle (AOP) formation and cytoplasmic reddening (CR) may be caused, prevented, reversed, or modified. These results are explained in terms of the facilitation or inhibition of an intracytoplasmic dye-segregating mechanism, in turn affected by the rate of dye ingress and the physiological state of the cell. Whereas the accumulation of AO in AOP is compatible with cell viability, the appearance of CR is correlated with cell death. It is pointed out that meaningful interpretation of vital staining requires precise regulation of many parameters in the extracellular milieu. A scheme of cell compartmentalization with respect to AO is proposed to satisfactorily account for the effects of environmental variations on the distribution and ultimate fate of intracellular dye. The AOP are viewed as normally present acid phosphatase-positive multivesicular bodies.

Acridine Orange↗
PubMed1964

DYNAMICS OF ACRIDINE ORANGE-CELL INTERACTION. II. DYE-INDUCED ULTRASTRUCTURAL CHANGES IN MULTIVESICULAR BODIES (ACRIDINE ORANGE PARTICLES).

The brilliantly fluorescent cytoplasmic particles that accumulate in HeLa cells treated with acridine orange, previously referred to as acridine orange particles, are shown to represent acid phosphatase positive multivesicular bodies (MVB). Dynamic changes in the ultrastructure of these organelles may be induced by varying the concentration of extracellular dye and the length of exposure to the dye. Low concentrations of dye for long intervals of time lead to marked hypertrophy of the MVB and accumulation of myelin figures within them, the acid phosphatase activity being retained. High concentrations of dye for short time intervals lead initially to a diffuse distribution of dye through out the cytoplasm (cytoplasmic reddening) as viewed in the fluorescence microscope. When cells are stained in this way and incubated in a dye-free medium, the diffusely distributed dye is segregated into MVB within 1 hour. Ultrastructurally, these MVB show dilatation but no myelin figures. The process of dye segregation is energy dependent and will not occur in starved cells. This energy dependence and the occurrence of segregation via dilatation of the MVB rather than ultrastructural transformation, i.e. formation of new binding sites, suggests that the process involves an active transport mechanism. Of the various energy sources supplied to starved cells, only glucose, mannose, and pyruvate are fully effective in supporting dye segregation. Blockage of the tricarboxylic acid cycle with malonate inhibits the effects of pyruvate but not of glucose, demonstrating the efficacy of both the tricarboxylic acid and glycolytic cycles in supplying energy for the process.

Acid Phosphatase↗
PubMed2003

Excited state characteristics of acridine dyes: acriflavine and acridine orange.

The magnitude of the Stokes shift (frequency shifts in absorption and fluorescence spectra) is observed on changing the solvents and further has been used to calculate experimentally the dipole moments (ground state and excited state) of acriflavine and acridine orange dye molecules. Theoretically, dipole moments are calculated using PM 3 Model. The dipole moments of excited states, for both molecules investigated here, are higher than the corresponding values in the ground states. The increase in the dipole moment has been explained in terms of the nature of the excited state. Acriflavine dye overcomes the non-lasing behaviour of acridine orange due to quaternization of the central nitrogen atom.

Acridine Orange↗
PubMed1995

Identification of hepatic metabolites of two highly carcinogenic polycyclic aza-aromatic compounds, 7,9-dimethylbenz[c]acridine and 7,10-dimethylbenz[c]acridine.

The hepatic microsomal metabolites of the highly carcinogenic dimethylbenzacridines, 7,9-dimethylbenz[c]acridine (7,9-DMBAC), and 7,10-dimethylbenz[c]acridine (7,10-DMBAC) were obtained with preparations from 3-methylcholanthrene-pretreated rats. Metabolites were separated by reversed-phase HPLC and characterized using UV spectral data and chemical ionization-mass spectrometry after trimethylsilylation and GC. Comparisons with products formed in the presence of the epoxide hydrolase inhibitor, 1,1,1-trichloropropane 2,3-oxide and with those formed from the three synthetic alcohol derivatives of each parent compound, aided the assignment of firm or tentative structures to 16 products from 7,9-DMBAC found in 22 reversed-phase chromatographic peaks, and for 17 products of 7,10-DMBAC found in 19 chromatographic peaks. The more abundant metabolites were derived from oxidation of the methyl groups. Other metabolites were dihydrodiols, epoxides, phenols and secondary metabolites. The 9-methyl group prevented dihydrodiol formation at the 8,9-position from 7,9-DMBAC, and for each carcinogen, the 3,4-dihydrodiol was formed. As well, 3,4-dihydrodiols of methyl oxidized compounds were found.

Acridines↗
PubMedDate not supplied

Quantitative analysis of structure-activity relationship in the acridine serie. Part 1: Antiparasitic 9-thioaryl-acridine derivatives.

Synthesis and antiparasitic activity vs T. cruzi and L. donovani of a series of 9-thioaryl acridines are reported. A convenient correlation between molecular structure and biological activity is proposed. Results not only agree with the classical interactions of acridines with DNA but also suggest possible role of charge transfer complexes.

Acridines↗
PubMed2005

Antitumor polycyclic acridines. Part 16. Triplex DNA as a target for DNA-binding polycyclic acridine derivatives.

Triple-stranded DNA structures have been implicated in a number of major biological processes, including the transcription and translation of a number of genes, as well as in the interaction of DNA with a number of proteins. Furthermore, antigene therapies under development are based on the recognition and binding of a single oligonucleotide strand to a double-stranded sequence, thus forming a triple helix. Triplex DNA formation is a relatively weak and temporary phenomenon; therefore, molecules that selectively bind to and stabilize triple helices may show a variety of novel biological effects. The biophysical and biological characterization of a series of antitumor polycyclic acridines that bind to triplex DNA is reported. These compounds, whose synthesis has been previously reported, have been tested for their interaction with both purine and pyrimidine type triple helices and compared with the relevant double-stranded DNA. As a pyrimidine triplex model we have used the T*AT sequence, which we have compared with the AT duplex, whereas the purine triplex oligonucleotide d[G3A4G3]*d[G3A4G3].d[C3T4C3] has been compared with the duplex d[G3A4G3].d[C3T4C3]. The compounds demonstrate various degrees of preferential binding to triplex DNA over normal duplex DNA, as measured by UV, fluorescence, circular dichroism, and thermal denaturation. Tri-substituted acridine derivatives demonstrated the highest affinity and ability to stabilize triplex DNA structures. Furthermore, structure/affinity analysis gives insights into the structural features that optimize affinity and selectivity for triplex DNA, and may play a role in their profile of antitumor activity.

Acridines↗
PubMed1998

Antitumour polycyclic acridines. Part 4. Physico-chemical studies on the interactions between DNA and novel tetracyclic acridine derivatives.

The non-covalent interactions between a series of new tetracyclic acridine derivatives (5-11) and DNA have been studied by spectrophotometric analysis, fluorescences quenching, thermal denaturation, and circular and linear dichroism. In order to compare the extent of the DNA binding by compounds 5-11 in their neutral and cationic forms, all experiments were conducted at pH 7.4 (physiological pH) and 5.0. The results indicated that compounds 5-11 are strong DNA-binding ligands with DNA affinities comparable to that of m-AMSA (1) or even higher. They showed a stronger DNA binding activity at pH 5.0 as a result of the N-protonation of the pyridoacridine aromatic chromophore. Ethidium-DNA fluorescence assays showed an A-T base pair preference of the binding distinguishing these novel compounds from simple acridines which show a slight G-C base pair preference. Circular and linear dichroism studies indicated that the drugs bind to DNA by undergoing intercalation inside the duplex macromolecule at high DNA:drug ratios and revealed alternative binding modes at low DNA:drug ratios.

Acridines↗
PubMed1983

Interactions of acridine orange with nucleic acids. Properties of complexes of acridine orange with single stranded ribonucleic acid.

Interactions between acridine orange (AO) and nucleic acids (calf thymus DNA, and homoribo- and homodeoxyribo-polynucleotides) were studied in solutions containing ethanol as a cosolvent. Light absorption, scattering and luminescence were measured as a function of AO concentration at different dye/phosphate (D/P) ratios, and the data were analyzed using the McGhee-von Hippel probabilistic model of the polymer-ligand interactions. The absorption spectra of AO complexes with four homoribopolymers are presented. The intrinsic association constants and cooperativity coefficients of the formation of the complexes were calculated. The effects of ethanol (up to 35%, v/v) on these interactions were concentration dependent and may be extrapolated to zero concentration of this cosolvent. The possibility of destabilization of the double helix of nucleic acids by AO at high D/P ratios is discussed in light of the available thermodynamic data.

Acridine Orange↗
PubMed2006

Study on the formation and depolymerization of acridine orange dimer in acridine orange-sodium dodecyl benzene sulfonate-protein system.

Experiment indicates that the fluorescence of acridine orange (AO) can be greatly quenched by anionic surfactant sodium dodecyl benzene sulfonate (SDBS), but when protein is added into the AO-SDBS system, the fluorescence intensity of the latter is enhanced. It is considered that SDBS can promote the formation of AO dimer, resulting in the quenching of the fluorescence of AO. When bovine serum albumin (BSA) is added into AO-SDBS system, BSA and SDBS can interact and form negative micelle-like cluster complex with "aromatic ring stacking," which destroys the formation conditions of AO dimer and makes some AO dimers turn into monomer, resulting in the fluorescence enhancement of AO-SDBS system. Whereas the positive AO and residual AO dimer are dissolved in the negative BSA-SDBS cluster through electrostatic and hydrophobic forces and form a large association. Here, the fluorescence enhancement of AO-SDBS is considered to originate from the hydrophobic microenvironment provided by BSA and SDBS, the depolymerization of AO dimer and intermolecular energy transfer between BSA and AO.

Acridine Orange↗
PubMed2000

Antitumor polycyclic acridines. 7. Synthesis and biological properties of DNA affinic tetra- and pentacyclic acridines.

New synthetic routes to a series of tetra- and pentacyclic acridines related in structure to marine natural products are reported. The novel water-soluble agent dihydroindolizino[7,6,5-kl]acridinium chloride 14 has inhibitory activity in a panel of non-small-cell lung and breast tumor cell lines exceeding that of m-AMSA. The salt inhibited the release of minicircle products of kDNA confirming that disorganization of topoisomerase II partly underlies the activity of the compound. COMPARE analysis of the NCI mean graph profile of compound 14 at the GI(50) level corroborates this conclusion with Pearson correlation coefficients (>0.6) to clinical agents of the topoisomerase II class: however, this correlation was not seen at the LC(50) level. The inhibitory action of 14 on Saccharomyces cerevisiae transfected with human topoisomerase II isoforms showed a 3-fold selectivity against the IIalpha isoform over the IIbeta isoform. Unlike m-AMSA, 14 is not susceptible to P-glycoprotein-mediated drug efflux and retains activity in lung cells with derived resistance to the topoisomerase II inhibitor etoposide.

Acridines↗
PubMed2001

trans-3,4-dihydroxy-anti-1,2-epoxy-1,2,3,4-tetrahydrodi- benz[a,j]acridine involvement in dibenz[a,j]acridine DNA adduct formation in mouse skin consistent with Ha-ras mutation patterns in tumors.

Dibenz[a,j]acridine (DBA), is a N-heteropolycyclic aromatic environmental carcinogen found in complex combustion mixtures. The major route of DBA metabolic activation is reportedly through the trans-3,4-dihydroxy-3,4-dihydroDBA (DBA-3,4-DHD). The present studies were undertaken to determine the role of trans-3,4-dihydroxy-anti-1,2-epoxy-1,2,3,4-tetrahydroDBA (DBADE) in DBA activation pathway(s), the DNA bases involved in the binding of DBA to DNA, and whether the adducts produced are consistent with the mutation pattern in the Ha-ras gene. DBA (300 microg) or 50 microg synthesized (+/-)-DBADE was applied to the back of female Hsd:ICR(Br) mice. The mice were sacrificed 48 h later, and skin DNA was isolated, hydrolyzed, and analyzed with (32)P-postlabeling. Of the four adducts produced in vivo, adduct 1 was the major adduct for DBA (>50%) and adduct 2 was the major adduct for DBADE (89%). After the reaction of (+/-)-DBADE with purine nucleotides or calf thymus (CT) DNA in vitro, 100% of the DBADE-2'-dAMP adducts and 94% of DBADE-CT DNA adducts were chromatographically identical on TLC with adduct 2 and 86% of the DBADE-2'-dGMP adducts were chromatographically consistent with adduct 1 by (32)P-postlabeling. Papillomas were induced on the backs of mice by a single application of 0.2 micromol of DBA followed by twice-weekly application of 12-o-tetra-decanoylphorbol-13-acetate (TPA, 2 microg) for 24-26 weeks. Skin carcinomas were induced by twice weekly applications of DBA (0.1 micromol) on the backs of mice. A to T and G to T transversions were found in codons 12, 13, and 61 of the Ha-ras gene in the treated mouse skin carcinoma and papilloma DNA. The mutational spectra in the Ha-ras gene are consistent with the DNA binding of DBA to dG or dA in vivo. Thus, this research has indicated that DBADE plays an important role in DBA metabolic activation and DNA binding in mouse skin, and an alternative pathway through a bis-dihydrodiol-epoxide of DBA may also be involved.

Acridines↗
PubMed2003

Antitumour polycyclic acridines. Palladium(0) mediated syntheses of quino[4,3,2-kl]acridines bearing peripheral substituents as potential telomere maintenance inhibitors.

Pd(0) mediated couplings between substituted 2-(pivaloylamino)benzeneboronic acids and 3,6-disubstituted-10-methylacridones 13 bearing a bromo or trifluoromethylsulfonyloxy substituent in the 1-position yield intermediate 1-arylacridones 16 which can be can be cyclised to new 8-methylquino[4,3,2-kl]acridines 17 with phosphorus oxychloride or 6 M HCI in EtOH. Heck reactions between triflate-substituted substrates 17 and acrylic acid derivatives afforded quinoacridines with unsaturated side-chains in the 6-position. Alkylboranes, prepared by interaction of 9-borabicyclo[3,3,1]nonane (9-BBN) and allyl acetate or N-allyltrifluoroacetamide, participated in Suzuki-Miyaura reactions with chloro-substituted 8-methylquinoacridines to form derivatives bearing functionalised propyl groups in the 6- and 10-positions. Representative 8-methylquinoacridines were methylated with methyl iodide to yield telomerase-inhibitory 8,13-dimethylquinoacridinium iodides 24.

Acridines↗
PubMed1987

The role of inhibitors in the fluorescent staining of benign naevus and malignant melanoma cells with 9-amino acridine and acridine orange.

Guanidinobenzoatase is a trypsin-like protease capable of degrading fibronectin. An inactive form of guanidinobenzoatase is present on the surface of benign naevus cells and these cells stain very weakly with 9-aminoacridine, a known competitive inhibitor of guanidinobenzoatase. Malignant melanoma and metastatic malignant melanoma cells exhibit strong surface staining with 9-aminoacridine and also exhibit strong staining of cytoplasmic RNA with acridine orange. These simple fluorescent techniques have been used to distinguish benign naevus cells from malignant melanoma cells in human skin sections. This difference in cell surface staining with 9-aminoacridine has been demonstrated to be caused by the presence or absence of an inhibitor. The inhibitor can be displaced from the cell surface enzyme and then replaced by an affinity purified inhibitor obtained from fresh liver homogenates. It is proposed that the inhibition or control of cell surface guanidinobenzoatase may be one of the regulatory mechanisms by which benign naevus cells are prevented from developing into malignant melanoma cells.

Acridine Orange↗