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The title compound, [AuCl(3)(C(13)H(9)N)], is the first complex of gold and acridine to be reported. The coordination sphere of the Au atom is square planar. The crystal structure is built up of neutral complex molecules linked into chains by means of attractive pi--pi interactions between the parallel acridine ligands.
In highly humic water, acridine orange precipitated with dissolved humic matter, resulting in such bright background fluorescence that no bacteria could be seen. With bisbenzimide staining, a similar precipitate was nonfluorescent but obscured many cells. An acriflavine staining method proved useful and reproducible both in clear and in humic waters. Fading of fluorescence was not a problem, and stained samples could be stored after preparation. The fluorescence of cells stained with acriflavine was weaker than that with acridine orange, making counting extremely small cells slightly more difficult with the former stain.
It has been found that, like Atabrine, the phenothiazine tranquilizers promazine, chlorpromazine, promethazine, levopromethazine, and Stelazine; the antidepressants (dibenz-azepine and dibenzocycloheptene derivatives) Tofranil, Pertofrane, cyclobenzaprine, Elavil, protriptyline, and 3-chlorodibenzocycloheptene; and the acridine derivatives acridine orange, acriflavin, SKF no. 16214-A2, SKF no. 13231-A2, SKF no. 9200, and SKF no. 9836 are all to a greater or lesser extent than Atabrine, effective in preventing the emergence of resistant strains of Staphylococcus aureus and Escherichia coli in the presence of streptomycin, sulfathiazole, or chloramphenicol. The antimalarials chloroquine and hydroxychloroquine were also studied and found to be ineffective. The medical significance of these findings is discussed, as well as the effect of the structural variations of these compounds on their relative activities.
4'-(9-Acridinylamino)methanesulfon-m-anisidide (m-AMSA) is a DNA intercalating 9-aminoacridine with clinical activity in adult acute leukemia. m-AMSA has been shown to produce protein-linked DNA strand breaks in mammalian cells through an interaction with the nuclear enzyme DNA topoisomerase II. We have compared the effects of m-AMSA and several acridine analogues (9-aminoacridine; A, NSC 343499; B, SN 16507; C, NSC 140701; D, SN 13553) on DNA integrity and cell survival in L1210 leukemia in vitro. Cells (or isolated nuclei) were treated with drugs (0.1-50 microM) for 0.5-1.0 h and subsequently analyzed using the alkaline elution technique. All drugs, except Compound D, produced DNA-protein cross-links (DPC) in L1210 cells. At 1 microM, potency was in the order, C greater than m-AMSA greater than B greater than A much greater than 9-aminoacridine. In isolated nuclei, DPC and single-strand breaks were produced in essentially a 1:1 ratio, which is consistent with topoisomerase II-mediated protein-linked DNA breaks. Potency differences were less pronounced in nuclei than in cells. In isolated nuclei, Compound D produced extensive DPC not associated with single-strand breaks, which suggests a more complex activity for this compound. Colony formation assays demonstrated the cytotoxicity of most of these acridine analogues (C greater than B greater than A approximately equal to m-AMSA much greater than D = 9-aminoacridine). Correlation of DPC with cell kill gave similar curves for each compound. These results are evidence for a causal relationship between drug-induced topoisomerase II-mediated DNA breaks and cytotoxicity.
For the anticancerous derivative of acridine--Ledakrin C-283 [1-nitro-9-(3-dimethylaminopropylamino)-acridine . 2HCl-H2O] 1H and 13C NMR spectra were assigned and analysed with particular emphasis on pH effects. On pH increase in 2H2O, the deprotonation of N(10) in Ledakrin aromatic core causes a high and selective upfield shift of the resonances for aromatic protons and strong deshielding for aromatic carbons C(11)-C(14), especially those adjacent to N(10). The signals of remaining aromatic carbons are shifted upfield on increase of pH, whereas those of protons and carbons in aminoaliphatic chain at C(9) are only slightly affected by change of pH. The above NMR characteristics of Ledakrin may be useful in studies on mechanisms of its interaction with proteins and nucleic acids in aqueous solution at various pH values.
The influence of l-nitro-9-/2-dihydroxyethylamino-ethylamino-/-acridine (C-835) and l-nitro-9/3-izopropylaminopropylamino/-acridine (C-846) on the basic functions of animal organism in acute and subchronic experiments was studied. Both compounds displayed distinct all-biologic activity. Their toxicity (LD50) in mice was contained in milligramme interval (i.v.), while LD50 administered into the stomach was several dozen times higher. Even administration in protective phosphate buffer, which provides the most neutral pH, produced quite strong local irritant action. The range between LD50 and LD10 was relatively small, which proved relatively small tolerance factor. Both preparations injected intravenously in the doses starting from several mg/kg had hypotensic influence due to their affinity with the myocardium, the parasymphatetic system and the vascular system. The preparations acted spasmolytically on intestine muscles both in vivo and in vitro in a number of animal species. Central action showed clear stimulating component in a behavioric test. The effect of the compounds in interaction to hypnotic and convulsant drugs was equivocal and dependent on the dose and the reference-preparation. The examined compounds did not influence reproduction processes and did not display the teratogenic action. They impaired only the speed of growth of the newborns. The effect of both examined compounds was qualitatively and quantitatively similar.
3-amino-6-methoxy-9-(2-hydroxyethylamine) acridine (AMHA) is an acridine derivative, which is easily excited in near ultraviolet and which emits a bright green fluorescence. The dye was preferentially incorporated into nucleic structures as attested by microscopic and cytometric analyses after RNase and DNase treatments. The affinity for RNA seemed low and similar to that observed for propidium iodide. AMHA was quickly accumulated in fixed cells, and in appropriate concentrations (10-50 microM) was a DNA- and RNA-specific dye. AMHA probably exhibits an adenine-thymine specificity, as suggested by its quenching after bromodeoxyuridine uptake: the fluorescence quenching was similar to that obtained for Hoechst 33258. After cell treatment by RNase and in the presence of MgCl2, AMHA staining allowed flow cytometric analysis of the cell-cycle distribution. The resulting histograms were similar to those obtained with propidium iodide (CV near 3.5%, and similar cell cycle distribution). Thus, AMHA is a suitable fluorescent dye for efficient analysis of the cell cycle by flow cytometry.
Salmon DNA has been irradiated with visible light in the presence of acridine orange. If the dye is bound to the DNA, there results: (a) a decrease in sedimentation coefficient, (b) a lowering of viscosity, and (c) a decrease in the thermal denaturation temperature. CsCl banding experiments show that the first two effects reflect depolymerization of the DNA. Depolymerization apparently occurs by single-strand scission although some double-strand scission is not excluded. The destabilization of secondary structure results probably from chemical attack on the components of the individual strands.
Previous workers have reported that proflavine and acridine orange form various structurally different complexes with the dinucleoside phosphates rCpG and dCpG, with uniform C3'-endo and mixed C3'-endo (3'-5') C2'-endo sugar puckers being observed. We present theoretical calculations, based on the method of molecular mechanics, which support the experimental observations. The results suggest that the mixed C3'-edo (3'-5') C2'-endo pucker conformation isi intrinsically more stable than the uniform C3'-endo conformation, but that the additional stabilisation gained from specific, hydrogen bonding, interactions between nucleic acid and solvent, or intramolecularly within the nucleic acid, can lead to the adoption of the latter conformation, or of variants between the two. The role played by hydrogen bonding between amino-groups and nucleic acid phosphate appears more subtle than previously supposed.
Purple adenine (ad-3) mutants induced in Neurospora crassa by 2-methoxy-6-chloro-9-(3-[ethyl-2-chloroethyl] aminopropylamino) acridine dihydrochloride (ICR-170) result from intragenic alterations. They are further characterized by low frequencies of leakiness, allelic complementation, and nonpolarized complementation patterns. These characteristics distinguish them from ad-3 mutants induced by x-rays, nitrous acid, and 2-aminopurine.
Gregory, Kenneth F. (Ontario Agricultural College, Guelph, Ontario, Canada), and Jay C. C. Huang. Tyrosinase inheritance in Streptomyces scabies. II. Induction of tyrosinase deficiency by acridine dyes. J. Bacteriol. 87:1287-1294. 1964.-Growth in minimal medium containing 1 mug of acriflavine per ml resulted in a large increase (up to 62%) in the frequency of tyrosinase-deficient (tye(-)) mutants in all of ten strains of Streptomyces scabies and eight unidentified streptomycetes studied. This increased frequency did not result from the selection of preformed mutants, since tye(-) clones were usually inhibited by lower concentrations of acriflavine than were tyrosinase-producing (tye(+)) clones, and no significant difference in mycelial yields occurred between the two types growing in a 1 mug/ml concentration of the dye. The mutations induced by X rays and acriflavine were either allelic or closely linked. This tye(-) phenotype was not caused by the production of an enzyme inhibitor, lack of a cofactor, or defect in the conversion of a protyrosinase to tyrosinase. Tye(-) mutants formed no detectable tyrosinase under a variety of conditions, including the presence of possible inducers. Mutants were able to oxidize glucose and succinate. The S. scabies tyrosinase was heat-labile (half-life at 59 C = 1.6 min) and not particle-bound. We conclude that acriflavine induces the loss of, or alteration in, a structural gene for tyrosinase production present as an extrachromosomal factor.
BACKGROUND: We set out to develop an assay for the simultaneous analysis of mitochondrial membrane potential and mass using the probes 10-nonyl acridine orange (NAO), MitoFluor Green (MFG), and MitoTracker Green (MTG) in HL60 cells. However, in experiments in which NAO and MFG were combined with orange emitting mitochondrial membrane potential (DeltaPsi(m)) probes, we found clear responses to DeltaPsi(m) altering drugs for both probes. METHODS: The three probes were titrated to determine whether saturation played a role in the response to drugs. The effects of a variety of DeltaPsi(m) altering drugs were tested for MFG and MTG at probe concentrations of 20 nM and 200 nM and for NAO at 0.1 microM and 5 microM, using rhodamine 123 at 0.1 microM as a reference probe. RESULTS: Incubation of GM130, HL60, and U937 cells with 2,3-butanedione monoxime (BDM), nigericin, carbonyl cyanide 3-chlorophenylhydrazone (CCCP), carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone (FCCP), 2,4-dinitrophenol (DNP), gramicidin, ouabain, and valinomycin resulted in increases of the fluorescence intensity for MFG or MTG with only a few exceptions. The fluorescence intensity of cells stained with 0.1 microM NAO increased following incubation with BDM, nigericin, and decreased for FCCP, CCCP, DNP, gramicidin, and valinomycin. The results with 5 microM NAO were similar. CONCLUSIONS: MFG, MTG, and NAO appeared poor choices for the membrane potential independent analysis of mitochondrial membrane mass. Considering the molecular structure of these probes that favor accumulation in the mitochondrial membrane because of a positive charge, our results are not surprising. Cytometry 39:203-210, 2000. Published 2000 Wiley-Liss, Inc.
Analysis of cellular DNA and RNA contents of 249 bladder irrigation specimens from 129 patients with a history of transitional cell carcinoma (TCC) of the bladder was performed using acridine-orange flow cytometry (FCM). Washings from patients with prior intravesical chemotherapy or radiation therapy were compared to those from patients with no history of treatment other than tumor resection to evaluate the reliability of FCM for the detection of tumor and the influence of prior local therapy on that reliability. Five FCM patterns were defined on the basis of DNA and RNA indexes in relationship to peripheral blood lymphocytes. FCM results were compared to cytologic findings in 237 cases, cystoscopic findings in 230 cases, and histologic data in 99 cases. Presence of a single diploid stem line was associated with absence of bladder tumor in 71% of cases from patients treated with surgery alone or with radiation therapy, but there was residual tumor in 53% of patients exposed to prior local chemotherapy. An elevated RNA content in a diploid cell population did not provide additional diagnostic information. Presence of an aneuploid stem line was associated with tumor in 85% of cases, regardless of prior therapy. Aneuploidy predicted the appearance of tumor in four of six patients with a negative cystoscopy. Tetraploidy (greater than 10% of total cell population) was associated with tumor in 79% of patients treated with surgery alone, whereas no tumor was found in more than 50% of patients who had undergone prior chemotherapy or radiation therapy. This study stresses the importance of prior treatment history in evaluating the results of DNA-FCM for bladder cancer. It demonstrates the unreliability of FCM diploid and tetraploid cell populations in patients previously treated by local chemotherapy or radiation. However, it also supports prior observations that DNA-aneuploidy and DNA-tetraploidy are useful for detecting and predicting bladder cancer in patients submitted to surgery alone.
We have used an automated system to measure serial reticulocyte samples from phlebotomized rats and rats treated with the chemotherapeutic agent actinomycin-D. In performing the automated samples, we utilized two different methods. The first method employed a fluorescent dye, acridine orange, which stains RNA in a manner similar to supravital stains presently used in performing reticulocyte counts. The second method is unique in that we utilized an immunofluorescent assay with antitransferrin receptor antibody which identifies the transferrin receptor found on the cell surface of reticulocytes but not on mature red cells. Both methods gave reproducible values in estimating the increase in reticulocytes seen after phlebotomy and the initial reticulocytopenia followed by recovery of the peripheral blood reticulocyte count seen after treatment with actinomycin-D. Also, since the antitransferrin receptor antibody appears to recognize the more immature reticulocytes, both methods taken together may provide an estimate of the maturity of a population of reticulocytes.
Cytoplasmic RNA was demonstrated in neurons of the developing rat brain using acridine orange (AO) as a histochemical marker. Fetuses of 18 days and postnatal rats of 1, 7, 14, and 21 days as well as adults several months old were studied. Neuroblasts of the germinal matrix exhibited minimal or no orange-red AO-RNA fluorescence, but immature nerve cells in migration within the cerebral hemispheres of the rat showed a weak but definite orange colour. This finding contrasts with the absence of AO-RNA fluorescence in migrating human neuroblasts. Neurons of the neocortical plate showed uniformly strong fluorescence. In the hippocampus, the most pronounced increase in AO-demonstrated RNA was in pyramidal and granule cells during the first postnatal week. The cerebellum showed a paradoxically stronger fluorescence of granule cells in the 18-day fetus than at birth, and almost no AO-RNA fluorescence of granule cells at 21 days of age or in adults. Motor neurons showed the strongest fluorescence of all neurons. It is likely that the increase in cytoplasmic RNA in neurons corresponds to the onset of neurotransmitter biosynthesis, but transitory fetal neuropeptides may explain stronger fluorescence of some neurons in young individuals. The reliable and simple AO method provides a supplementary means of studying one aspect of neuronal maturation.
A threadlike structure in blood vessels that is considered part of the Bohghan duct system was first reported about 40 years ago. This structure has remained elusive since then due to the inability of other researchers to duplicate the original identification. In this study we identified the characteristic features of this threadlike structure in rats by the use of fluorescent microscope imaging of nuclei stained by acridine orange perfusion. The nuclei of the tissue that comprises the structure are rod-shaped, 10-20 microm long, and aligned in a broken-line striped fashion. The novel technique reported here can differentiate the intravascular threadlike structure from the fibrin strings that normally form during perfusion and can confound the observation procedure. The physiological function of the threadlike structure remains to be elucidated; however, further study may provide a new understanding of mammalian biology in general, and of acupuncture and Oriental medicine in particular.
The fluorescence of acridine orange (AO) is greatly quenched by the anionic surfactant sodium dodecyl benzene sulphonate (SDBS), but when protein is added into the AO-SDBS system, the fluorescence intensity of the latter is enhanced again. Based on this, a new fluorimetric method of determination of protein was developed. Under optimum conditions, the enhanced intensity of fluorescence is in proportion to the concentration of protein, such as bovine serum albumin (BSA), human serum albumin (HSA) and egg albumin (EA), over a wide range with detection limits at the 10(-9) g/mL level. This method has been satisfactorily used for the determination of protein in samples. We compared results using 280 nm and 490 nm excitation wavelengths and the mechanism of the assay.
The products of interaction between acridine orange (AO) and natural RNA, or the synthetic RNA homopolymers are precipitates insoluble over a wide range of ionic strength. These complexes have a composition of 1 AO molecule per 1 phosphate. The reaction is highly cooperative and the complex exhibits metachromatic luminescence. Significant differences in the luminescence spectra, related to base composition of RNA, characterize the insoluble complexes. This observation suggests that dye-base interactions take place in the AO-RNA complexes. During titration of poly(rA) with AO and simultaneous measurement of the luminescence and light scatter a two-step formation of the particles could be detected. The cooperative binding of the ligand at D/P less than 0.6 coincides with formation of small particles (molecular aggregates or micelles) and is followed at D/P greater than 0.6 by a cooperative agglomeration; the product of this agglomeration is particles of the size 0.35 micrometer and larger. Evidence is presented that suggests that the long wave length luminescence (approximately 650 nm) is a consequence of the solute-solid state transition of the AO-RNA interaction product rather than the classic dye-dye interactions previously visualized in the stacking model. Since these novel observations cannot be fully explained by the previously postulated molecular mechanisms of AO binding, an alternative model is advanced. Its implications in quantitative cytochemistry of nucleic acid as applied to flow cytometry are discussed.