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PubMed2003

Mechanisms of action of DNA intercalating acridine-based drugs: how important are contributions from electron transfer and oxidative stress?

Reactive oxygen species (ROS) are produced continuously in living cells as a by-product of respiration and other metabolic activity. Some ROS may react with DNA, and in some cases may abstract an electron from the double helix, leading to long range electron transfer (ET) reactions. Thus, the DNA of living cells may be in a continuous state of ET. We consider here whether acridine-based anticancer or antimicrobial drugs, which bind to DNA by intercalation, might either donate electrons to, or accept electrons from, the double helix, thus actively participating in ET reactions. We focus in particular on two acridine-based drugs that have been tested against human cancer in the clinic. Amsacrine is a 9-anilinoacridine derivative that appears to act as an electron donor in ET reactions on DNA, while N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) may act as an electron acceptor. Such reactions may make important contributions to the antitumor activity of these drugs.

Acridines↗
PubMed1990

Acridine orange fluorescence, Campylobacter pylori, and chronic gastritis.

Endoscopic gastric biopsy specimens from 230 consecutive patients in a North Liverpool District were histologically studied by routine light microscopy and ultraviolet fluorescence after acridine orange staining. Eighty patients with chronic gastritis were further studied with regard to type of gastritis and its activity, presence of Campylobacter pylori (CP), and degree of colonization of the gastric mucosa. Miscellaneous gastritis, gastric ulcers, erosions, neoplasms, and histologically normal specimens were excluded from the study. The results show statistically significant correlation between chronic gastritis and CP (P = 0.01, Mann-Whitney test). The activity of gastritis correlated well with CP, but there was no statistical significance between the density of neutrophils and degree of CP colonization (P greater than 0.5, Mann-Whitney test). In a small sample of CP-positive specimens acridine orange stain was compared with Warthin-Starry, Giemsa (modified), cresyl fast violet, and haematoxylin and eosin stains. Acridine orange stain in the histologic identification of CP has been used only once before in a large study.

Acridine Orange↗
PubMed1996

Highly selective acridine and ethidium staining of bacterial DNA and RNA.

The acridine dyes acridine orange (AO) and coriphosphine O (CPO) and ethidium bromide (EtBr) were used to stain bacterial digests after electrophoresis in native and denaturing (SDS) polyacrylamide gels and were shown to stain DNA and RNA preferentially over other subcellular components in the gels. Vegetative cell digests of Bacillus subtilis, Escherichia coli, Micrococcus luteus, and Staphylococcus aureus showed intense staining of DNA with AO and CPO near the top of the gel, but little or no staining of other cellular constituents. EtBr stained both DNA and RNA in the gels. Protein standards and non-nucleic acid cellular constituents stained faintly with high concentrations (> or = 100 microM) of AO, lower concentrations (13.9 microM) of CPO, and did not stain with 0.5 microgram/ml EtBr in denaturing gels. The complete set of cellular biochemicals was visualized by silver staining, while the protein subset was detected by Coomassie blue staining. The highest concentrations of AO (120 microM) and CPO (13.9 microM) were shown to detect purified DNA in gels with a sensitivity in the range of 25-50 ng per band. This work demonstrates the specificity of acridine and ethidium dyes for nucleic acids, while illustrating the level of non-nucleic acid-specific interactions with other cellular components by staining of electrophoretically separated cellular components in a gel matrix.

Acridine Orange↗
PubMed2000

Influence of fluorescence of bacteria stained with acridine orange on the enumeration of microorganisms in raw milk.

The staining of gram-positive and gram-negative cultures with acridine orange in metabolically active and inactive states was investigated using a Bactoscan, direct epifluorescent filter technique (DEFT), and standard plate count as the reference method. The evaluation of the bacterial cultures in the Bactoscan revealed a linear relationship between Bactoscan counts (pulses) and the quantity of pure culture suspension used. But the proper detection of bacteria with the fluorescence optic methods was dependent on the type of microorganism and the physiological state of the cells. The Bactoscan and DEFT underestimated the bacterial counts of gram-negative cultures as compared with standard plate counting. When stained with acridine orange, metabolically active bacteria showed more orange fluorescence and a lower percentage of green fluorescent cells as compared with inactive bacteria. Bactoscan pulse height analysis (PHA) diagrams, graphs of the detected pulses and their intensity, showed low pulses of inactive bacteria. Many of these weak pulses were eliminated from counting because of their faint fluorescent staining. In contrast, PHA diagrams of metabolically active microorganisms showed bright staining and, therefore, high pulses. A complete count of these bacteria was possible. These investigations point out that discrepancies between the fluorescence optical counting methods and the standard plate count depend strongly on the staining of the cultures with acridine orange and, therefore, on the type of microorganism and the metabolic state of the cells measured.

Acridine Orange↗
PubMed1975

[Teichoic acids as possible acridine orange acceptors on the surface of staphylococcal cell walls].

A study was made of acridine orange adsorption by the surface structures of intact Staphylococcus aureus (209-P strain) cells and their cellular walls. Acridine orange sorption by the cells and the cellular wall of staphylococcus depended on the content of teichoic acids in the object under study. A conclusion was drawn that teichoic acids of the cellular walls of Staph. aureus were responsible for the binding of the acridine orange stain.

Acridines↗
PubMed2002

The ability to overcome multidrug resistance of tumor cell lines by novel acridine cytostatics with condensed heterocyclic rings.

Two recently synthesized groups of acridine cytostatics containing fused heterocyclic ring(s): pyrazoloacridines (PAC) and pyrazolopyrimidoacridines (PPAC) were tested in regard to their in vitro cytotoxic activity towards a panel of sensitive and resistant human tumor cell lines. The obtained results corroborate our earlier hypothesis on the essential role of heterocyclic ring fused to the acridine moiety in the ability of acridine cytostatics to overcome multidrug resistance of tumor cells. The presence, location and kind of substituents considerably influenced both the cytotoxic activity of the derivatives and their ability to overcome multidrug resistance. The same factors also affected the cytostatics ability to differentiate between tumor cell lines with various types of drug exporting pumps.

Acridines↗
PubMed1975

Pharmacological studies on 1-nitro-9-alkyl acridine derivatives. I. Acute and subchronic action.

Preclinical pharmacologic studies of two further acridine derivatives, 1-nitro-9-(diethylaminopropylamino)-acridine (C-410) and 1-nitro-9-(diethylaminoethylamino)-acridine (C-516) are reported. Both compounds are characterized by high toxicity, especially when injected intravenously, poor absorption from the gastrointestinal tract, and local irritant action. Local irritation can be partly alleviated by using phosphate buffer of pH 7.0 as solvent. Both preparations caused hemodynamic changes (hypotension) due to stimulation of the parasympathetic system (in cats), and higher doses showed direct action on the myocardium. Both preparations acted directly on smooth muscles, predominantly spastically (blood vessels, intestines in vivo and in vitro), and spasmolytically only on the smooth muscle of the urinary bladder in cats. Compound C-410 is deprived of a central component, and compound C-516 in most tests exhibited sedative properties. Despite moderate impairment of spermato- and spermiogenesis, neither of the compounds depressed reproductivity of the animals and no teratogenic action was observed.

Acridines↗
PubMed1975

[The action of acridine derivatives on penicillinase production by staphylococcus aureus].

A study was made of a possibility of inhibition of biosynthesis of penicillinase in Staph. aureus by acridine derivatives. Acetone preparations of penicillinase were obtained from the cultures of staphylococcus strains 16/160 and 8325 (p11(147) pen 1220) grown in the presence of various subbacterial concentrations of acridine derivatives. The activity of the enzyme was studied in experiment and control by the microiodometric method. Acriflavine and proflavine inhibited the penicillinase biosynthesis from the 4th hour of growth, and rivanol, acrichine, acridines No. 27 and 37--from the 12th hour of the culture growth.

Acridines↗
PubMed2001

Linker length in podophyllotoxin-acridine conjugates determines potency in vivo and in vitro as well as specificity against MDR cell lines.

We have synthesized two podophyllotoxin-acridine conjugates-pACR6 and pACR8. In these compounds an 9-acridinyl moiety is beta linked to the C4 carbon of the four ring system in 4'-demethylepipodophyllotoxin (epiDPT) via eighter an N-6-aminohexanylamide linker (pACR6) or via an N-8-aminooctanylamide linker containing two more carbon atoms (pACR8). The acridine-linker moiety occupies the position where different glucoside moieties, dispensable for activity, are normally linked to epiDPT in the well known epipodophyllotoxins VP-16 and VM-26. As with VP-16 and VM-26, pACR6 and pACR8 show evidence of being topoisomerase II poisons as they stimulate topoisomerase II mediated DNA cleavage in vitro and induce DNA damage in vivo. This in vivo DNA damage, as well as pACR6/pACR8 mediated cytotoxicity, is antagonized by the catalytic topoisomerase II inhibitors ICRF-187 and aclarubicin, demonstrating that topoisomerase II is a functional biological target for these drugs. Despite their structural similarities, pACR6 was more potent than pACR8 in stimulating topoisomerase II mediated DNA cleavage in vitro as well as DNA damage in vivo and pACR6 was accordingly more cytotoxic towards various human and murine cell lines than pACR8. Further, marked cross-resistance to pACR6 was seen among a panel of multidrug-resistant (MDR) cell lines over-expressing the MDR1 (multidrug resistance protein 1) ABC drug transporter, while these cell lines remained sensitive towards pACR8. pACR8 was also capable of circumventing drug resistance among at-MDR (altered topoisomerase II MDR) cell lines not over-expressing drug transporters, while pACR6 was not. Two resistant cell lines, OC-NYH/pACR6 and OC-NYH/pACR8, were developed by exposure of small cell lung cancer (SCLC) OC-NYH cells to gradually increasing concentrations of pACR6 and pACR8, respectively. Here, OC-NYH/pACR6 cells were found to over-express MDR1 and, accordingly, displayed active transport of 3H-labeled vincristine, while OC-NYH/pACR8 cells did not, further suggesting that pACR6, but not pACR8, is a substrate for MDR1. Our results show that the spatial orientation of podophyllotoxin and acridine moieties in hybrid molecules determine target interaction as well as substrate specificity in active drug transport.

Aclarubicin↗
PubMed1999

[Study on high performance liquid chromatography/indirect photometric detection of fosfomycin with acridine as detection reagent].

Fosfomycin is a broad-spectrum antibacterial agent which has strong polarity and weak UV absorption. In this work, a method using standard ODS column and conventional UV detector set at 254 nm to analyse fosfomycin was investigated. Firstly, several UV detection reagents were tested and acridine(A) was found to give the highest indirect detection response and proper modification on retention of fosfomycin. With acridine as the UV detection reagent, the mobile phase parameters which affect retention and detection response of solute are discussed, e.g. pH, concentration of organic solvent and concentration of acridine. The mechanism is interpreted for each case. After optimization, we adopted mobile phase as V(CH3OH):V(H2O) = 50:50, pH 3.18, [HAc] = 2 mmol/L, [A] = 1 x 10(-5) mol/L. A new chromatographic system monitored by indirect photometry for detection of fosfomycin was established. This method was used for quantitative analysis, the minimum detectable level was 10 mumol/L, the relative deviation was 4.51%.

Acridines↗
PubMed2003

The role of ultraviolet-adaptation of a marine diatom in photoenhanced toxicity of acridine.

Cultures of the marine diatom Phaeodactylum tricornutum were grown under laboratory light with a different fraction of ultraviolet radiation (UV) to study the potential role of photoadaptation in determining the sensitivity to photoenhanced toxicity of acridine. In short-term experiments, a higher acridine concentration was needed to inhibit the photosynthetic electron flux, monitored with chlorophyll a fluorescence, in algae exposed to fluorescent light (low UV) than to mercury light (high UV), consistent with the expected role of UV. The two types of light in long-term exposures led to changes in the pigment composition and photosystem I (PS I) to photosystem II (PS II) stoichiometry to optimize the utilization of fluorescent and mercury light. Despite the adaptation of the photosynthetic apparatus to a small fraction of UV, long-term exposure to mercury light did show a constant sensitivity of the photosynthetic efficiency of P. tricornutum to the phototoxic acridine. It is concluded that the prime receptor of photoenhanced toxicity may be unrelated to the photosynthetic machinery.

Acridines↗
PubMedDate not supplied

Induction of anti-Escherichia coli activity in mice by phenothiazines, benzo[a]phenothiazines and benz[c]acridines.

The abilities of 14 phenothiazines, 8 benzo[a]phenothiazines and 12 benz[c]acridines to induce anti-Escherichia coli activity in mice were compared. Pretreatment with several benzo[a]phenothiazines or benz[c]acridines protected mice from lethal infection of Escherichia coli in a dose-dependent manner, whereas most of the phenothiazines induced much weaker anti-Escherichia coli activity. However, direct contact of Escherichia coli with these compounds or their administration just after bacterial inoculation were ineffective. These data suggest the immunopotentiation activity of benzo[a]phenothiazines and benz[c]acridines.

Acridines↗
PubMed1992

Morphological and histochemical study of supragingival human calculus and dental plaque using ruthenium hexammine trichloride and acridine orange.

Ruthenium hexammine trichloride (RHT) and acridine orange were used to preserve and visualize anionic groups in human plaque and dental calculus. RHT-reacting material was present on the membrane of micro-organisms and in intermicrobial spaces of the calcifying areas, and seems to correspond to, and derive from, acidic glyco- and phospholipids of the plasma membrane of the micro-organisms. However, the presence of acidic salivary peptidoglycans cannot be ruled out. Two types of calcification were found: extramicrobial and intramicrobial. The former consisted of calcified deposits irregularly scattered in the intermicrobial matrix. They were in close relationship with RHT-reacting material, or were placed inside vesicular structures delimited by a membrane. Intramicrobial calcification consisted of small aggregates of needle-shaped crystals and/or of granular deposits; in both cases, they either masked the whole cytoplasm of the micro-organisms, or were located only over the plasma membrane. These results suggest that mineral deposition occurs in connection with acidic components of intermicrobial matrix, microbial plasma membranes, and cytoplasms. The addition of RHT and acridine orange to fixing and decalcifying solutions yields satisfactory preservation of dental calculus and plaque, and apparently reduces loss of their anionic organic components and increases their electron density. However, these substances are not sufficient to preserve all ultrastructural details in decalcified areas, probably because the inorganic substance prevents reaction of acridine orange and RHT with the organic components of the calcified matrix.

Acridine Orange↗
PubMedDate not supplied

An acridine amino acid derivative for use in Fmoc peptide synthesis.

An acridine derivative of N-alpha-Fmoc-lysine has been prepared and used in solid phase peptide synthesis. The fluorescence properties of the acridine reporter group are retained throughout the peptide synthesis procedure. The utility of the acridine group was demonstrated by its use as an energy acceptor in a fluorescence energy-quenching assay with trypsin.

Acridines↗
PubMed1989

Mutagenicity of dihydrodiols and diol epoxides of dibenz[a, h]acridine in bacterial and mammalian cells.

Bay-region diol epoxides are ultimate carcinogenic metabolites of a number of polycyclic aromatic compounds. Dibenz[a, h]acridine can form two diastereomeric pairs of these diol epoxides which are not positionally equivalent as a result of the nitrogen atom at position 7. We have assessed the structure-activity relationships resulting from heterocyclic nitrogen substitution by examining the mutagenic activity of these four bay-region diol epoxides of dibenz[a,h]acridine in both bacterial and mammalian cells. In strains TA98 and TA100 of Salmonella typhimurium, the diastereomeric 10,11-diol-8,9-epoxides were 20 to 40 times more mutagenic than the corresponding 3,4-diol-1,2-epoxides. Furthermore, in strain TA100, dibenz[a,h]acridine 10,11-dihydrodiol, the expected metabolic precursor of the 10,11-diol-8,9-epoxide, was metabolically activated by rat hepatic microsomes up to a 12-fold greater extent than the 3,4-dihydrodiol. In Chinese hamster V79 cells, the 10,11-diol-8,9-epoxide diastereomers were 20 to 80 times more mutagenic than their 3,4-diol-1,2-epoxide counterparts. Quantum mechanical calculations of the predicted ease of benzylic carbocation formation at C-1 and C-8 from the diol epoxides indicate that the 3,4-diol-1,2-epoxides should be less reactive due to resonance destabilization of the C-1 carbocation as a result of the electronegative nitrogen atom. Decreased chemical reactivity of 3,4-diol-1,2-epoxides may explain their decreased mutagenic activity.

Acridines↗
PubMed1989

Binding of acridine orange to DNA in situ of cells from patients with acute leukemia.

Fluorescence flow cytometry was used to generate DNA histograms of acridine orange stained leukemic cell populations in G0-G1 phase of the cell cycle. Complexes of the intercalating agent, acridine orange, with double-stranded DNA in situ, emit green fluorescence upon excitation with blue laser light. The histograms were evaluated by first determining the standard deviation of the fluorescence intensity relative to the mean channel of fluorescence, i.e., the coefficient of variation, and then dividing the coefficient of variation of a patient's sample by that of a control sample (rCV). The mean rCV of cell populations of acute lymphoblastic leukemia (31 patients) differed significantly from that of nonlymphoblastic leukemia (21 patients). When cells were treated with a solution of citric acid and magnesium sulfate prior to their staining with acridine orange, the mean rCV of cell populations of acute lymphoblastic leukemia increased while that of acute nonlymphoblastic leukemia decreased compared to their respective pretreatment values. The mean difference of rCVs between untreated and treated cells (rCVD) within each disease category was statistically significant. A logistic regression model, based on rCVD, confirmed the conventional classification of acute lymphoblastic leukemia and acute nonlymphoblastic leukemia cells in 90% of the cases.

Acridine Orange↗
PubMedDate not supplied

[DNA interaction with the bifunctional acridine dye].

The comparative studies of the formation of DNA-complexes with the acridines containing one and two chromophores were accomplished. It was shown that both of acridines were bonded with DNA by means of intercalation irrespective of the ionic strength of medium (mu). When mu = 0.1 the diacridine (1,6-bis(9-acridylamino)-hexan) behaves as an mono-intercalator. Under these conditions both of the ligands exert equal influence of the molecular parameters of DNA. When mu = 0.001 the binding mode of the diacridine with DNA depends on its concentration in a complex. If a number of diacridine molecules on a pair of nucleotides (r) falls in a region 0 less than r less than 0.2 its binding with DNA is accomplished via the bis-intercalation mode and accompanied by the structure distortion of the monomer remnant of the macromolecule. As r increases from 0.2 to 0.4 the gradual change of the binding mode of the diacridine with DNA from bis-intercalation to mono-intercalation takes place. Moreover the structure of nucleotides is reduced. When mu = 0.001 the behaviour of DNA complexes with mono-acridine is analogous to the observed one when mu = 0.1.

Acridines↗
PubMed1986

High tumorigenicity of the 3,4-dihydrodiol of 7-methylbenz[c]acridine on mouse skin and in newborn mice.

The tumorigenicities of 7-methylbenz[c]acridine (7MB[c]ACR) and its five metabolically possible trans-dihydrodiols were determined in two mouse tumor models. In initiation-promotion studies on mouse skin, a single topical application of 0.15 to 0.75 mumol of compound was followed 9 days later by twice weekly applications of 12-O-tetradecanoylphorbol-13-acetate for 20 wk. Comparison of the average number of skin tumors per mouse indicated that 7MB[c]ACR 3,4-dihydrodiol, the metabolic precursor of a bay-region diol-epoxide, was 4- to 6-fold more active than the parent compound as a tumor initiator. The 1,2-, 5,6-, 8,9-, and 10,11-dihydrodiols of 7MB[c]ACR had no significant tumor-initiating activity at the doses tested. In newborn mice, a total dose of 0.35 mumol of compound was administered i.p. during the first 15 days of life, and tumorigenic activity was determined when the mice were 32 to 36 wk old. 7MB[c]ACR 3,4-dihydrodiol induced about 8-fold more pulmonary tumors per mouse and 9-fold more hepatic tumors per male mouse than the parent aza-substituted hydrocarbon. The other four dihydrodiols of 7MB[c]ACR had no significant tumorigenic activity. The high tumorigenic activity of 7MB[c]ACR 3,4-dihydrodiol in both tumor models suggests that a bay-region 3,4-diol-1,2-epoxide may be an ultimate carcinogenic metabolite of 7MB[c]ACR. 7MB[c]ACR was at least 5-fold more active as a tumor initiator on mouse skin than was the unsubstituted aza-aromatic compound, benz[c]acridine. This latter result indicates that substitution of a methyl group at position 7 of benz[c]acridine leads to enhanced tumor-initiating activity, as has been previously demonstrated for benz[a]anthracene and its 7-methyl derivative.

Acridines↗