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PubMed2000

Synthesis of [1]benzopyrano[2,3,4-kl]acridin-3-ol and its analogues as pentacyclic compounds.

A new heterocyclic compound, [1]benzopyrano[2,3,4-kl]acridin-3-ol was synthesized by cyclization of xanthone derivatives. The key compound, 1-(3'-methoxyanilino)-xanthone, was prepared from 1-aminoxanthone. [1]benzopyrano[2,3,4-kl]acridin-3-ol analogues, [1]benzothiopyrano[2,3,4-kl]acridin-3-ol, pyrido[3',2':5,6]pyrano[2,3,4-kl]acridin-3-ol and pyrido[3',2':5,6]thiopyrano[2,3,4-kl]acridin-3-ol were synthesized by the same method.

Acridines↗
PubMed1999

5,7-Disubstituted analogues of the mixed topoisomerase I/II poison N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA): DNA binding and patterns of cytotoxicity.

DACA is a DNA-intercalating agent and dual topoisomerase (topo) I/II inhibitor currently in clinical trial as an anticancer drug. Substitutions in the acridine ring of DACA have significant effects on biological activity, with 5-substituted analogues being more potent but relatively less active against cell lines that underexpress topo II, and the converse for 7-substituted analogues. A small series of 5,7-disubstituted analogues was therefore prepared and evaluated. The compounds were prepared by CDI-assisted coupling of the appropriate acridine acids. When these contained no or only one halogen atom, they could be prepared by Al/Hg amalgam reduction of the corresponding acridine acids. However, this method could not be used to prepare dihalogen-substituted acridine acids due to substantial dehalogenation, and these intermediates were synthesized via cyclization of the appropriate aldehydes to give the acridines directly. These compounds showed enhanced DNA binding compared with the parent DACA, indicating that the known favourable influence of 5-substituents on DNA binding is retained. Cell line studies showed that the 5,7-disubstituted compounds retained both the broad-spectrum effectiveness of the 7-monosubstituted analogues and the higher cytotoxic potency of the 5-monosubstituted analogues. The 7-chloro-5-methyl and 5-chloro-7-methyl analogues showed comparable in vivo antitumour activity to DACA in the subcutaneous colon 38 model, but were substantially more potent (optimal doses of 60 mg/kg compared with 200 mg/kg for DACA).

Acridines↗
PubMed1999

Acridine orange stained blood wet mounts for fluorescent detection of malaria.

The age old Romanowsky stained thick blood smear examination for malarial parasites may fail to reveal the low parasitaemia. The commercial 'QBC' like acridine orange stained capillary tube preparation has a limitation of precise species identification and the detection of extra-erythrocytic parasites. Hence, the present study was aimed to improve malarial parasite detection by using acridine orange to stain large blood drops in the form of wet coverglass mounts. The acridine orange stained blood wet mounts over 2420 suspected malaria cases from Indore city were examined under fluorescent microscope and the results compared with the Leishman's stained thick blood smears in a blind study. The positivity of malarial parasites reported by the modified acridine orange staining was 248 against 109 by Leishman's stained thick blood smears. The modified acridine orange stained method is simple, instant and more efficient, requires less scanning time and skill, allows scanning of larger blood volume (75 ul) at lower magnification and the morphological details at higher magnification helps to make the precise species identification.

Acridine Orange↗
PubMed1990

[The effect of endothelial interaction on the binding capacity of DNA acridine orange in hypertension].

Interaction of monocytes and endothelial cells were examined by acridine orange reaction in arteries of normotensive and hypertonic rats. The method is suitable for electron microscope study of DNA template activity. Activity of gen was compared in surface bound and subendothelial and in nonadhesive endothelial cells bound to monocyte. Acridine orange positivity, indicative of genic activity, was not found in few monocytes adhered in arteries of normotensive animals, while 62% of adhesive monocytes of hypertonic and 86% of ones accessed to endothelial space contained the products of acridine-orange-chromatin reaction in its nuclear, showing with it the gene derepression quickly ensuing in acute hypertensive vascular lesions. Only 2% of endothelial cells of pseudo-operated normotensive animals showed acridine orange positivity, while 17% of endothelial cells of hypertonic animals were positive. In the latter animals, 57% of endothelial cells showed acridine orange positivity, if monocytes adhered to their surface. In 84% of monocyte-endothelial pairs connected to each other, the nuclei have activity of same sign. Results show intensive activation of genes of monocytes in relation with adhesion and migration to vascular wall. Presumably, both hypertonia and monocyte adhesion have contributed to the increase of template activity of endothelial cells.

Acridine Orange↗
PubMed1978

Formation of free radicals from carcinogenic benz[c]acridines in the presence of proteins.

Formation of a free radical from carcinogenic and noncarcinogenic benz[c]acridine derivatives in the presence of proteins was examined. When aqueous mixture of benz[c]acridine and protein was stirred for a long period, shielded from light, benz[c]acridines were converted into free radicals. Albumin had the greatest effect in accelerating the free radical formation, and the effect was smaller in globulin, histone, and deoxyribonuclease. The g-value of the free radicals thus obtained was 2.005. Intensity of the electron spin resonance (ESR) signals of the free radical from carcinogenic derivatives was higher than those of the free radical from noncarcinogenic derivatives. There was a corresponding correlation among the ESR signal intensity of the free radical formed from the mixed system of benz[c]acridine and protein, charge of the K-region or ring nitrogen of the compound, and carcinogenicity of benz[c]acridines.

Acridines↗
PubMedDate not supplied

Effects of amino and imino acridines on tumor necrosis factor production by human leukocytes.

Tumor necrosis factor (TNF) is a multifunctional cytokine with diverse effects on different cells and tissues. The biological activity of TNF is described on the basis of its cytotoxic action in vivo and in vitro. Different acridines were systematically synthesized and their effects were tested on endotoxin and Staphylococcus aureus-induced TNF production by human leukocytes. 9-aminobutylacridine and 9-ethylaminoacridine totally abrogated the TNF production of leucocytes at a concentration of 3.5 microM, whereas 9-imino -10-butylacridine and 9-imino-10-ethylacridine exerted only a 50% inhibition in the same concentration. Derivatives designated as 9-amino-(2-dimethylamino-ethyl)-acridine and 9-imino-10-(2-dimethylamino-ethyl)-acridine in a concentration of 7 microM exerted only a 30% and a 10% inhibition respectively. A significant modulation of TNF production was not observed when other alkylated derivatives in this series were applied. The TNF-mediated cytotoxic effect of monocytes against WEHI cells was also reduced by the most effective compounds. The acridines did not interfere with the expression of CD 14 molecules on monocytes. The exact mechanism of the suppression of TNF synthesis by acridines remains to be elucidated, but might be useful in the screening and evaluation of their anticancer properties and antimalarial effects.

Acridines↗
PubMed1997

Biological variation in sensitivity to N-heterocyclic PAHs; effects of acridine on seven species of micro-algae.

The toxicity of the nitrogen (N) heterocyclic polyaromatic hydrocarbon (PAH) acridine was tested for seven species of microalgae: Scenedesmus acuminatus, Selenastrum capricornutum, Chlamydomonas eugametos, Staurastrum chaetoceras, Staurastrum manfeldtii, Navicula salinarum and Nitzschia sigma. The effect of acridine on the algae was studied in a 96-h growth test, in which growth rates were determined using cell numbers and biovolume. The obtained EC50 values (for growth rates based on cell numbers) ranged from 0.08 mg litre(-1) for N. sigma to 0.78 mg litre(-1) for C. eugametos and N. salinarum. Effect concentrations based on biovolume were slightly higher for most species. Metabolism of acridine was observed for one species (S. capricornutum), but this capacity did not result in a very different tolerance. Acridine toxicity was neither related to taxonomical background (green algae versus diatoms) nor to original habitat of the species (planktonic or benthic, eutrophic or oligo-mesotrophic). The presence of near-UV radiation during the incubation might explain the higher toxicity of acridine than is expected on basis of QSAR derived narcotic toxicity.

Journal Article↗
PubMed2006

Silver(I) complexes in coordination supramolecular system with bulky acridine-based ligands: syntheses, crystal structures, and theoretical investigations on C-H...Ag close interaction.

In our efforts to investigate the coordination architectures of transition metals and organic ligands with tailored structures, we have prepared two structurally related rigid bulky acridine-based ligands, 9-[3-(2-pyridyl)pyrazol-1-yl]- acridine (L(1)) and 9-(1-imidazolyl)acridine (L2), and synthesized and characterized four of their Ag(I) complexes, {[AgL1](ClO4)}2 (1), {[AgL1](NO3)}2 (2), [AgL2(2)](ClO4) (3), and {[(Ag3L2(3))(NO3)](NO3)2(H2O)}(infinity) (4). The single-crystal X-ray diffraction analysis shows that the structures of 1 and 2 are similar to each other, with the two intramolecular Ag(I) centers of each complex being encircled by two L1 ligands; this forms a unique boxlike cyclic dimer, which is further linked to form one-dimensional (1D) chains of 1 and a two-dimensional (2D) network of 2 by intermolecular face-to-face pi...pi stacking and/or weak C-H...O hydrogen-bonding interactions, respectively. 3 has a mononuclear structure, which is further assembled into a 2D network via intermolecular Ag...O and pi...pi stacking weak interactions. 4 possesses two different 1D motifs that are further interlinked through interlayer face-to-face pi...pi stacking and Ag...O weak interactions, resulting in a 2D network. It is worth noting that one of the interesting structural features of 1, 2, and 4 is the presence of obvious C-H...M hydrogen-bonding interactions between the Ag centers and some acridine ring H atoms identified by X-ray diffraction on the basis of the van der Waals radii. Furthermore, as a representative example, full geometry optimization on the basis of the experimental structure, the natural bond orbital (NBO), and topological analysis of 1 were carried out by DFT and AIM (Atoms in Molecules) calculations. The total C-H...Ag interaction energy in 1 is estimated to be about 14 kJ/mol. Therefore, this work offers three new rare examples (1, 2, and 4) that exhibit C-H...Ag weak interactions, in which the N donors of the acridine rings coordinate to Ag(I) ions. Also, these results strongly support the existence of C-H...Ag close interactions and allow us to have a better understanding of the nature of such interactions in the coordination supramolecular systems.

Journal Article↗
PubMed1987

Potential antitumor agents. 50. In vivo solid-tumor activity of derivatives of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide.

The synthesis, physicochemical properties, and antitumor activity of a series of N-[2-(dialkylamino)alkyl]-acridine-4-carboxamides are reported. The compounds bind to DNA by intercalation, but exist under physiological conditions as monocations due to the weakly basic acridine chromophore (pKa = 3.5-4.5). The acridine-4-carboxamides show very broad structure-activity relationships (SAR) for antileukemic activity, with substituents at nearly all acridine positions proving acceptable. The compounds also show remarkable activity against the Lewis lung solid tumor in vivo, with several analogues capable of effecting 100% cures of the advanced disease. The broad SAR and high solid-tumor activity of the 9-acridine-4-carboxamides imply they should be considered as a completely new class of antitumor agent.

Aminoacridines↗
PubMed1989

Effect of temperature on the plasma membrane and tonoplast ATPases of barley roots : comparison of results obtained with acridine orange and quinacrine.

The effect of temperature on the rate of proton transport and ATP hydrolysis by plasma membrane (PM) and tonoplast (TN) ATPases from barley (Hordeum vulgare L. cv CM 72) roots were compared. Rates of proton transport were estimated using the fluorescent amine dyes quinacrine and acridine orange. The ratio between rate of transport and ATP hydrolysis was found to depend on the dye, the temperature, and the type of membrane. The PM ATPase had an estimated Arrhenius energy of activation (Ea) of approximately 18 kilocalories per mole for ATP hydrolysis, and the Ea for proton transport was best estimated with acridine orange, which gave an Ea of 19 kilocalories per mole. The TN ATPase had an Ea for ATP hydrolysis of approximately 10 kilocalories per mole and the Ea for proton transport was best estimated with quinacrine, which gave an Ea of 10 kilocalories per mole. Acridine orange did not give an accurate estimate of Ea for the TN ATPase, nor did quinacrine for the PM ATPase. Reasons for the differences are discussed. Because it was suggested (AJ Pope, RA Leigh [1988] Plant Physiol 86: 1315-1322) that acridine orange interacts with anions to dissipate the pH gradient in TN vesicles, the complex effects of NO(3) (-) on the TN ATPase were also examined using acridine orange and quinacrine and membranes from oats and barley. Fluorescent amine dyes can be used to evaluate the effects of ions, substrates, inhibitors, and temperature on transport but caution is required in using rates of quench to make quantitative estimates of proton fluxes.

Journal Article↗
PubMed1997

Photochemical and photobiological studies with acridine and phenanthridine hydroperoxides in cell-free DNA.

The acridine and phenanthridine hydroperoxides 3 and 7 were synthesized as photochemical hydroxyl radical sources for oxidative DNA damage studies. The generation of hydroxyl radicals upon UVA irradiation (lambda = 350 nm) was verified by trapping experiments with 5,5-dimethyl-1-pyrroline N-oxide and benzene. The enzymatic assays of the damage in cell-free DNA from bacteriophage PM2 caused by the acridine and phenanthridine hydroperoxides 3 and 7 under near-UVA irradiation revealed a wide range of DNA modifications. Particularly, extensive single-strand break formation and DNA base modifications sensitive to formamidopyrimidine DNA glycosylase (Fpg protein) were observed. In the photooxidation of calf thymus DNA, up to 0.69 +/- 0.03% 8-oxo-7,8-dihydroguanine was formed by the hydroperoxides 3 and 7 on irradiation, whose yield was reduced up to 40% in the presence of the hydroxyl radical scavengers mannitol and tert-butanol. The acridine and phenanthridine hydroperoxides 3 and 7 also induce DNA damage through the type I photooxidation process, for which photoinduced electron transfer from 2'-deoxyguanosine to the singlet states of 3 and 7 was estimated by the Rehm-Weller equation to possess a negative Gibb's free energy of ca -5 kcal/ mol. Control experiments with the sensitizers acridine 1 and the acridine alcohol 4 in calf thymus and PM2 DNA confirmed the photosensitizing propensity of the UVA-absorbing chromophores. The present study emphasizes that for the development of selective and efficient photochemical hydroxyl radical sources, chromophores with low photosensitizing ability must be chosen to avoid type I and type II photooxidation processes.

Cell-Free System↗
PubMed2003

Design of photoactivated DNA oxidizing agents: synthesis and study of photophysical properties and DNA interactions of novel viologen-linked acridines.

A new series of photoactivated DNA oxidizing agents in which an acridine moiety is covalently linked to viologen by an alkylidene spacer was synthesized, and their photophysical properties and interactions with DNA, including DNA cleaving properties, were investigated. The fluorescence quantum yields of the viologen-linked acridines were found to be lower than that of the model compound 9-methylacridine (MA). The changes in free energy for the electron transfer reactions were found to be favorable, and the fluorescence quenching observed in these systems is explained by an electron transfer mechanism. Intramolecular electron transfer rate constants were calculated from the observed fluorescence quantum yields and singlet lifetime of MA and are in the range from 1.06x10(10) s(-1) for 1 a (n=1) to 6x10(8) s(-1) for 1 c (n=11), that is, the rate decreases with increasing spacer length. Nanosecond laser flash photolysis of these systems in aqueous solutions showed no transient absorption, but in the presence of guanosine or calf thymus DNA, transient absorption due to the reduced viologen radical cation was observed. Studies on DNA binding demonstrated that the viologen-linked acridines bind effectively to DNA in both intercalative and electrostatic modes. Results of PM2 DNA cleavage studies indicate that, on photoexcitation, these molecules induce DNA damage that is sensitive to formamidopyrimidine DNA glycosylase. These viologen-linked acridines are quite stable in aqueous solutions and oxidize DNA efficiently and hence can be useful as photoactivated DNA-cleaving agents which function purely by the co-sensitization mechanism.

Acridines↗
PubMed1981

Metal mutagens and carcinogens effectively displace acridine orange from DNA as measured by fluorescence polarization.

Several metals are known mutagens and carcinogens. These metals effectively displace acridine orange from DNA when measured by fluorescence polarization. Displacement of 50% of the acridine orange is obtained with less than 0.5 mM concentrations of lead, manganese, cobalt, zinc, cadmium, nickel, iron, copper, and cis-platinum. In contrast, greater than 80 mM concentrations of lithium, sodium, and potassium are required to displace an equivalent amount of acridine orange from calf thymus DNA. Although cis-platinum shows the best DNA reactivity in this assay, the interaction between this metal and DNA does not occur immediately, as it does for the other metals tested. These results indicate the acridine orange displacement assay provides a relative measure of the interaction of metals with DNA, and this DNA reactivity shows a positive correlation with mutagenic/carcinogenic potential.

Acridine Orange↗
PubMed1980

Specific fluorescent bands on chromosomes produced by acridine orange after prestaining with base specific non-fluorescent DNA ligands.

Metaphase chromosomes stained with acridine orange exhibit uniform yellow-green fluorescence. Chromosome preparations treated with the non-fluorescent A-T specific antibiotic distamycinA prior to acridine orange staining exhibit longitudinal fluorescent banding patterns similar to those produced by a number of fluorescent R-band techniques. Similarly, chromosome preparations treated with the non-fluorescent G-C specific antibiotic actinomycin D followed by acridine orange staining exhibit "Hoechst-type" banding patterns. Interactions of various ligand-DNA combinations in solution indicate that the base pair specific antibiotics induce banding patterns by selectively altering acridine orange binding sites in chromosomal regions rich in the particular base pair for which the antibiotic exhibits specificity.

Acridine Orange↗
PubMed1981

Acridine orange stabilization of glycosaminoglycans in beginning endochondral ossification. A comparative light and electron microscopic study.

This study indicated that acridine orange, when combined with the initial fixative stabilized soluble matrix glycosaminoglycan in situ in areas where considerable glycosaminoglycan extraction is known to occur. Acridine orange was able to diffuse through bone into areas of undecalcified mineralizing cartilage and to bind with the glycosaminoglycans in these areas equally well as in growth plate cartilage matrix. Matrix staining was visible by light microscopy without further staining and was seen to vary territorially in intensity; although cellular definition was poor. This deficiency was overcome by the additional application of p phenylenediamine which stained the cells intensely. At the ultrastructure level, glycosaminoglycan was present as electron dense structures in the cartilage matrix. Preliminary X-ray microanalysis studies confirmed that the acridine orange stained structures contain sulphur; this finding extends the use of acridine orange further to quantitative analysis of glycosaminoglycan.

Acridine Orange↗
PubMed1992

Comparison of the blood-brain barrier and liver penetration of acridine antitumor drugs.

The blood-brain barrier penetration of amsacrine and its analogs 9-([2-methoxy-4-[(methylsulfonyl)-amino]phenyl]amino)-,5-dimethyl- 4-acridine carboxamide (CI-921) and M-[2-(dimethylamino)ethyl]-acridine-4-carboxamide (AC) was measured in the barbiturate-anesthetized mouse. After intracarotid administration, AC was almost completely extracted (90%) in a single transit through the brain capillaries, whereas CI-921 (20%) and amsacrine (15%) were moderately extracted. AC is retained in the brain; no loss of AC from the brain was apparent at 1, 2, 4, or 8 min after injection. In contrast, after intraportal administration, 75% of the AC, 94% of the CI-921, and 57% of the amsacrine was extracted in a single transit through the hepatic vasculature. Rather than being retained in the mouse liver, these acridine antitumor agents show time-dependent loss (t1/2 = 10 min for amsacrine and AC, 24 min for CI-921). We conclude that unlike most antitumor agents, these acridine drugs appear to penetrate the blood-brain barrier readily.

Acridines↗
PubMed1989

Acridine orange-mediated photodamage of microsomal- and lysosomal fractions.

Irradiation of microsomes with visible light in the presence of externally-added acridine orange results in O2 uptake, malondialdehyde accumulation, and inactivation of the microsomal drug-metabolizing system. The latter effect is reflected by a decrease in NADPH-cytochrome P450- and NADH-cytochrome b5 reductase activities and cytochromes P450 and b5 content by 88-, 85-, 60-, and 34%, respectively, after 5-min irradiation. Anoxia prevented inactivation of both reductases by 70-90%, whereas it prevented completely cytochrome b5 destruction. The presence of reducing equivalents, at the expense of NADPH and NADH, exert a partial protection (40-54% residual activities) against photosensitization damage on both reductase activities, whereas it almost fully protected cytochrome b5. Photosensitization of lipid peroxidation, as well as inactivation of the microsomal drug-metabolizing system, appears to involve both a type I and type II process. Products of lipid peroxidation might also play a role in enzyme inactivation and cytochrome destruction, as suggested by kinetic and time course studies and the redox state of microsomes. The uptake of acridine orange by isolated lysosomes is linearly dependent on the concentration of added dye and the distribution between extra- and intralysosomal acridine orange is strongly dependent on the amount of lysosomes. Irradiation of acridine orange-loaded lysosomes (light intensity at the sample position approximately 320 mW/cm2) produces an impairment of the membrane which leads to a rapid release of enzyme (N-acetyl-beta-glucosaminidase activity) into the medium, accompanied by a loss of activity in the lysosome-containing pellet and a partial photodamage of the enzyme. Concomitantly, thiobarbituric acid-reactive material accumulation increases in the reaction mixture with increasing irradiation time. When light intensity at the position was reduced to approximately 3.6 mW/cm2, photodamage of lysosomes was of a lesser magnitude, allowing the demonstration of a lag phase, which decreased with irradiation time, probably reflecting the so-called first-stage activation of lysosomes, preceding the release of lysosomal enzymes.

Acridine Orange↗
PubMed1988

Comparison of acridine orange and Gram stains in bacterial keratitis.

We assessed the comparative sensitivities of acridine orange and Gram stains in the examination of corneal scrapings using an experimental model of Pseudomonas aeruginosa keratitis. Acridine orange was more sensitive than Gram stain, requiring concentrations of about 10(4) colony-forming units/mg of corneal tissue compared to approximately 10(5) colony-forming units/mg. Our clinical experience with 21 consecutive cases of suspected microbial keratitis showed a similar diagnostic accuracy of acridine orange and Gram stain. Acridine orange accurately predicted culture results in 15 of 21 specimens (71%) compared to a diagnostic accuracy of 62% (13 of 21 specimens) for Gram stain.

Acridine Orange↗