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PubMed1991

Cytosol mediated metabolism of the experimental antitumor agent acridine carboxamide to the 9-acridone derivative.

The acridine antitumor agent N-[2'-(dimethylamino)ethyl]acridine-4-carboxamide (AC; NSC 601316; acridine carboxamide) is oxidized efficiently in vitro by rat and mouse hepatic cytosolic fractions. Under these conditions the oxidase activity has an apparent Km of 11 microM towards AC. A single product is formed which has been identified as the corresponding 9(10H)-acridone carboxamide by 1H-NMR and mass spectrometry. Inhibition with menadione and amsacrine, but not allopurinol, indicates that this reaction is most likely to be catalysed by aldehyde oxidase (EC 1.2.3.1). Several AC analogues with modifications to the side chain (the N-oxide, N-monomethyl-, and amino-derivatives) are also metabolized to the equivalent acridone product but the 7-hydroxylated and 4-carboxylic acid acridine derivatives are not.

Acridines↗
PubMed1989

Acridine orange, an inhibitor of protein kinase C, abolishes insulin and growth hormone stimulation of lipogenesis in rat adipocytes.

To determine whether protein kinase C plays a role in the actions of insulin and growth hormone in rat adipocytes, we tested the effect of acridine orange, a potent inhibitor of kinase C, on the lipogenic activity of both hormones. This compound completely inhibited the effects of insulin, growth hormone and phorbol ester 12-myristate 13-acetate, whereas 9-acridine carboxylic acid, an analog of acridine orange which does not inhibit kinase C, had no effect. Acridine orange did not act through inhibition of hormone binding. These data are consistent with the involvement of kinase C in the action of insulin and growth hormone on lipogenesis in rat fat cells.

Acridine Orange↗
PubMed1983

In vitro effects of acridine intercalation on RNA polymerase interactions with supercoiled DNA.

In vitro transcription of supercoiled DNA by purified E. coli RNA polymerase was inhibited by Acridine Orange in a bimodal manner while N-10 benzyl substituted Acridine Orange is about one-third as inhibitory and effects monophasic inhibition. The inhibition correlates with the supercoil unwinding abilities of these two intercalators with Acridine Orange unwinding supercoiled DNA at 1/3 the concentration required for the substituted acridine orange. Direct visualization of DNA-RNA polymerase complex on agarose gels showed that these intercalators directly interfere with this association and the more effective the drug is in unwinding DNA supercoils the more effective it is in interfering with the DNA-enzyme complex. In addition, specific intercalators differentially affect the stability of DNA-RNA polymerase-RNA ternary complexes.

Acridine Orange↗
PubMed1984

DNA injection proteins are targets of acridine-sensitized photoinactivation of bacteriophage P22.

Viruses and other nucleoprotein complexes are inactivated on exposure to white light in the presence of acridine and related dyes. The mechanism is thought to involve generation of singlet oxygen or related species, but the actual molecular targets of the inactivating event have not been well defined. We have re-examined the mechanism of dye-sensitized photoinactivation taking advantage of the well characterized bacteriophage P22. Though the inactivated phage absorb to their host cells, the cells are not killed and genetic markers cannot be rescued from the inactivated phage. These observations indicate that the chromosome is not injected into the host cell. However, the DNA of the damaged particles shows no evidence of double-stranded breaks or crosslinking. The DNA injection process of P22 requires three particle-associated proteins, the products of genes 7, 16 and 20. Gp16, which can act in trans during injection, is inactivated in the killed particles. Sodium dodecyl sulfate/polyacrylamide gel analysis reveals that gp16, gp7 and gp20 are progressively covalently damaged during photoinactivation. However, this damage does not occur in particles lacking DNA, indicating that it is DNA-mediated. Similar findings were obtained with acridine orange, acridine yellow, proflavin and acriflavin. These results indicate that the actual targets for inactivation are the DNA injection proteins, and that the lethal events represent absorption of photons by acridine molecules stacked in a region of DNA closely associated with the injection proteins.

Acridines↗
PubMed1984

Induction of cytoplasmically inherited respiration-deficient ('petite') mutants by photodynamic action of acridine compounds.

All acridines used (acriflavine, proflavine, acridine orange and 3-azido-10-methylacridinium chloride) produced killing in yeast cells when activated with visible light. Acriflavine, proflavine and 3-azido-10-methylacridinium chloride, but not acridine orange, produced petite and sectored colonies. Both cell killing and petite induction by light activation of acriflavine resulted apparently from photodynamic action mediated by singlet oxygen (1O2) since the effect were prevented by either sodium azide or anaerobiosis. The biological effects of 3-azido-10-methylacridinium chloride, which was developed as a potential photoaffinity probe for studying the binding and biological effects of acridines, appeared to be due to a photodynamic action analogous to that of acriflavine. Sodium azide or anaerobiosis prevented the light-activated effects of 3-azido-10-methylacridinium chloride despite the fact that the initial chemical breakdown of the azido derivative induced by light was not affected. Cells suspended in D2O demonstrated an enhanced response to 3-azido-10-methylacridinium chloride with irradiation. These results indicate that singlet oxygen mediates the light-activated biological effects of both acriflavine and 3-azido-10-methylacridinium chloride.

Acridines↗
PubMed1989

5-bromodeoxyuridine (BUdR) quenching of acridine orange fluorescence distinguishes cycling and non-cycling normal and malignant bone marrow cells in vitro.

Suppression of the green fluorescence of acridine orange by 5-bromodeoxyuridine incorporation into cellular DNA was measured by flow cytometry. Bone marrow cells from normal volunteers and patients with chronic myelogenous leukemia acute lymphocytic leukemia acute myelogenous leukemia and multiple myeloma were incubated with BUdR in vitro. By 24 h acridine orange stained cycling cells that had synthesized DNA in the presence of BUdR were differentiated from quiescent cells as a second peak with quenched green fluorescence (DNA). After 72 h in culture 11-65% of the G0/G1 cells from normal bone marrows and bone marrows with myeloid leukemia were identified as cycling in culture by the presence of a second peak with quenched green fluorescence. A greater percentage of cells with BUdR quenched AO fluorescence was associated of acridine orange was higher in the cycling cells that had synthesized DNA in the presence of BUdR than in the non-cycling G0/G1 cells. In one patient with AML there was quenching of the DNA fluorescence of the aneuploid population but not the diploid population indicating that the aneuploid leukemia cells were proliferating. In contrast in patients with multiple myeloma, the quenched fluorescence of the diploid cell population and not the aneuploid cells, indicated that the diploid cells were proliferating. The cells from patients with untreated ALL failed to proliferation prohibiting an in vivo assessment of growth. Although measurements of proliferation obtained by this method are clearly influenced by the cell's adaptation to culture, measurement of BUdR quenching of acridine orange fluorescence is technically feasible and can identify and allow characterization of the cycling population of cells.

Acridine Orange↗
PubMed1979

Genetic effects of acridine compounds.

Acridines and a very large number of acridine derivatives are used in enormous quantities both in medicine and industry. The mutagenic action of these compounds has been demonstrated in a wide variety of organisms and is known to occur both in the dark as well as in the presence of light (photodynamic action). At the molecular level, acridines have been shown to cause frameshift mutations of both the addition and deletion types, a characteristic which has been of tremendous help in elucidating the nature of the genetic code. These and various other biological effects of acridines, such as inhibition of DNA repair, curing of plasmids and cell-growth inhibition, are examined in this review.

Acridines↗
PubMed1994

DNase I footprinting of triple helix formation at polypurine tracts by acridine-linked oligopyrimidines: stringency, structural changes and interaction with minor groove binding ligands.

We have investigated the binding of short (10 base) acridine-linked triplex-forming oligonucleotides to the target sequence A6G6.C6T6 by DNase I footprinting. Specific binding is detected at low pH (< 6.0) for 5'-Acr-T5C5 and 5'-Acr-5BrU5(5Me)C5. The sequence T5C5, lacking the acridine modification, binds less strongly, though specific binding is still evident. 5'-Acr-T5C5 produces footprints at slightly lower concentrations than 5'-Acr-5BrU5(5Me)C5. All three oligonucleotides produce enhanced DNase I digestion at the 3'-end of the target purine strand, suggesting that there is a DNA structural change at the triplex-duplex boundary. Target sequences AnG4A and TAC3Tn, containing one and two triplex mismatches, show no interaction with the acridine-free oligonucleotide, but bind the acridine-linked oligonucleotides. In these secondary binding modes the third strand is positioned so that the mismatches are located at the 3'-end of the oligonucleotide. Mithramycin and distamycin, binding in the minor groove to GC- and AT-rich sequences respectively, abolish triple helix formation.

Acridines↗
PubMed1995

The effect of carbamazepine and its reactive metabolite, 9-acridine carboxaldehyde, on immune cell function in vitro.

Carbamazepine, a widely used anticonvulsant, is associated with a wide range of adverse reactions including agranulocytosis, aplastic anemia and drug-induced lupus. It has also been reported to alter immune function in a variety of ways. We had previously demonstrated that carbamazepine is oxidized by activated neutrophils to several metabolites and this leads to covalent binding of the drug to the cells. It appears that the major metabolite responsible for this binding is 9-acridine carboxyaldehyde. In this study the effects on leukocyte function of carbamazepine and its leukocyte-generated metabolites were compared. Incubation of lymphocytes with 100 microM 9-acridine carboxaldehyde resulted in 40% cell death while carbamazepine at this concentration had no effect on viability. The effect on the immune cell function was investigated using the autologous mixed lymphocyte reaction (AMLR), allogeneic mixed lymphocyte reaction (MLR), lymphocyte transformation test (LTT) and mitogenesis assays. Alteration of immune cell function by the reactive metabolite, 9-acridine carboxyaldehyde, was demonstrated by an increased proliferation at low concentrations (0.08-1.0 microM) and inhibition at high concentrations (20-100 microM) in the allogeneic MLRs. Carbamazepine had no measurable effect. 9-Acridine appears to have more of an effect on B-cells since this augmentation-suppression phenomenon was also observed in mitogenesis assays with Staphylococcus aureus, a B-cell mitogen, in contrast to mostly inhibition observed in the mitogenesis assay with phytohemagglutinin, a T-cell mitogen. Again, carbamazepine had no measurable effects at comparable concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Acridines↗
PubMed1984

Destruction of implanted gastric tumors in rats by acridine orange photoactivation with an argon laser.

The phototoxicity of acridine orange and argon laser irradiation on Walker carcinosarcoma 256 stomach tumors was studied. Wistar strain rats bearing stomach tumors 4-6 mm in diameter 5-10 days after their implantation were injected intraperitoneally with 40 mg/kg of acridine orange 2 hr before irradiation. Then the forestomach was opened and the tumors were exposed to the argon laser at 488 nm at an intensity of 15 mW/cm2 for 20 min. Tumors in rats treated with acridine orange were brightly fluorescent during irradiation. No marked temperature rise was detected during irradiation. Argon irradiation significantly prolonged the survival of rats treated with acridine orange. Histologically, complete or partial tumor necrosis was observed, with sparing of surrounding mucosa, in rats treated by the combination therapy. Phase-contrast and electron microscopy showed that cytotoxicity was mediated by changes in the cell, nuclear and lysosomal membranes. Neither the dye nor laser alone had any effect.

Acridine Orange↗
PubMed1987

An acridine-linked oligodeoxynucleotide targeted to the common 5' end of trypanosome mRNAs kills cultured parasites.

Anti-messenger oligodeoxynucleotides covalently linked to an intercalating agent were tested for their ability to inhibit translation of Trypanosoma brucei mRNAs in a cell-free system. The sequence of these oligodeoxynucleotides was complementary to part of the 35-nucleotide (nt) sequence which is present at the 5' end of all trypanosome mRNAs (the so-called mini-exon sequence). In a rabbit reticulocyte lysate, a nonadeoxynucleotide linked to an acridine derivative, specifically inhibited protein synthesis from T. brucei mRNAs much more efficiently than unmodified oligodeoxynucleotides of similar length. These oligodeoxynucleotides were tested on cultured trypanosomes. The acridine-linked nonadeoxynucleotide had a lethal effect on the parasites. No effect was observed with the homologous unmodified 9-mer nor with those 9-mers linked to the acridine derivative which were not complementary to the mini-exon sequence. These effects are probably a result of hybrid formation between the anti-messenger and mini-exon sequence. Trypanocidal activity of the acridine-modified nonadeoxynucleotide is most likely due to (i) increased affinity for its target, (ii) improved resistance to 3' exonucleases, and (iii) promoted membrane penetration of living parasites.

Acridines↗
PubMed1988

Phosphorothioate and normal oligodeoxyribonucleotides with 5'-linked acridine: characterization and preliminary kinetics of cellular uptake.

Certain phosphorothioate oligodeoxynucleotide (S-oligo) analogs, unlike their normal congeners, have been found to exhibit significant anti-HIV activity [Matsukura et al., Proc. Natl. Acad. Sci. USA 84 (1987) 7706-7710]. Here we report melting temperatures (Tm) of a series of S-oligos compared with those of the corresponding normal oligomers. The Tm's for AT base pairs of S-oligos are significantly depressed relative to normal oligos, while GC-containing S-oligos show much less Tm depression. The Tm's of S-dT oligomers with poly(rA) are reduced relative to the duplexes with normal dA oligomers. These results provide a rational basis for the S-d(CG) sequences as anti-message inhibitors of gene expression. We also describe an automated synthesis of 5'-acridine linked oligothymidylates using phosphoramidite-linked acridine. During this synthesis we noted the replacement of thiophenol for the 6-chloro substituent on acridine. We have measured the Tm's of the compounds with 3 and 5 methylene groups linked to normal and phosphorothioate dTn (with n = 3-40) on duplex formation with the equivalent dAn, and have found small increases of Tm for the 5-methylene-linked acridine derivative. We have monitored the uptake of these fluorescently labeled oligos into HL60 cells, and found that the shorter oligos are more rapidly taken up than the longer, and the normal oligos faster than the S-oligos. The temperature dependence of the cellular uptake suggests an energy-dependent process, and a possible membrane receptor for oligos. These results have significance for the potential use of such compounds as inhibitors of gene expression.

Acridines↗
PubMed1994

Subcultures of BACTEC-positive but gram or acridine orange stain-negative NR 6A and 7A blood culture bottles are unnecessary.

A prospective study was done to assess the comparative use of acridine orange and Gram stains for detecting false-positive BACTEC blood culture bottles, thereby eliminating unnecessary subcultures. A total of 1049 NR 6A and 7A bottles that were instrument-positive in the BACTEC 660 nonradiometric system, but were Gram stain-negative, had aerobic and anaerobic subcultures as well as an acridine orange stain performed. Only five of 1049 (0.5%) instrument-positive, Gram stain-negative bottles grew microorganisms on subculture. Of these five microorganisms, acridine orange stain detected two. All five microorganisms were assessed not to be clinically significant based on review of the patients' charts. Our data showed that the Gram stain and the acridine orange stain are comparable for detecting false-positive NR 6A and 7A bottles. We conclude that subculture of BACTEC-positive, Gram stain-negative NR 6A and 7A bottles is not necessary.

Acridine Orange↗
PubMed2006

Synthesis and evaluation of acridine- and acridone-based anti-herpes agents with topoisomerase activity.

The discovery of new non-nucleoside antiviral compounds is of significant and growing interest for treating herpes virus infections due to the emergence of nucleoside-resistant strains. Using a whole cell virus-induced cytopathogenic assay, we tested a series of substituted triaryl heterocyclic compounds including acridones, xanthones, and acridines. The compounds which showed activity against Herpes Simplex-1 and/or Herpes Simplex-2 were further assayed for inhibition of topoisomerase activity to gain insight into the mechanism of action. The results indicate that the acridine analogs bearing substituted carboxamides and bulky 9-amino functionalities are able to inhibit herpes infections as well as inhibit topoisomerase II relaxation of supercoiled DNA. Given the mechanism of action of amsacrine (a closely related, well-studied 9-amino substituted acridine), the compounds were further tested in a DNA topoisomerase II cleavage assay to determine if the compounds function as poisons. The results show that the acridines synthesized in this study function through a different mechanism to that of amsacrine, most likely by blocking topoisomerase binding to DNA (akin to that of aclarubicin). This not only suggests a unique mechanism of action in treating herpes virus infections, but also may be of great interest in the development of anticancer agents that target topoisomerase II activity.

Acridines↗
PubMedDate not supplied

Synthesis of twisted intercalating nucleic acids possessing acridine derivatives. Thermal stability studies.

Twisted intercalating nucleic acids (TINA) possessing acridine derivatives have been synthesized via the postsynthetic modifications of oligonucleotides possessing insertions of (R)-1-O-(4-iodobenzyl)glycerol (8) or (R)-1-O-(4-ethynylbenzyl)glycerol (9) at the 5'-end or in the middle as a bulge. In the first postsynthetic step, oligonucleotides 8 and 9 on the CPG support were treated with a Sonogashira coupling reaction mixture containing 9-chloro-2-ethynylacridine or 9-chloro-2-iodoacridine, respectively. After the postsynthetic step, treatment of the oligonucleotides with 32% aq ammonia or 50% ethanolic solution of tris(2-aminoethyl)amine led to the substitution of chloride on acridine concurrent with deprotection of the bases and cleavage of the oligonucleotides from CPG. Molecular modeling of the parallel triplex with a bulged insertion of the monomer (R)-3-O-[4-(9-aminoacridin-2-ylethynyl)benzyl]glycerol in the triplex-forming oligonucleotide (TFO) showed that the acridine moiety was stacking between the bases of the duplex, while phenyl was placed between the bases of the TFO. Thermal denaturation studies and fluorescence properties of TINA-acridine oligonucleotide duplexes and triplexes are discussed.

Acridines↗
PubMedDate not supplied

Synthesis and properties of an oligonucleotide modified with an acridine derivative at the artificial abasic site.

The synthesis of an oligodeoxynucleotide (ODN) modified with 2-methoxy-6-chloro-9-aminoacridine (Acr) at an abasic site is described. A stereochemically defined aminodiol, L-threoninol, was used to serve as artificial abasic nucleoside. The molecule was modified so as to be suitable for the standard phosphoramidite method and was incorporated into the interior of an ODN. In addition, N-hydroxysuccinimidyl N-[9-(6-chloro-2-methoxy)acridinyl]-6-aminocaproate has been synthesized for postsynthetic modification of the amino substrate of the L-threoninol moiety in the ODN. By using absorption spectroscopy, it is shown that oligo(dA) conjugated with acridine binds with complementary strand in a 1:1 ratio. The melting temperature showed that the nonmodified (abasic) duplex is destabilized as a result of lacking in base at the abasic site, but the covalently linked acridine ring compensates for the destabilization effect. The fluorescence quantum yield of the acridine ring was enhanced by connection to oligo(dA) and, further, by formation of a double-strand with the complementary ODN. The quantum yield is larger than that of intermolecular intercalation. The excitation spectra of Acr-ODN in the duplex is quite similar to the absorption spectra. The results indicate that the covalently linked acridine ring is selectively intercalated into the adjacent abasic site.

Acridines↗
PubMed1995

Interactions of acridine antitumor agents with DNA: binding energies and groove preferences.

Absorbance spectroscopy is used to examine the thermodynamic properties associated with the interaction of the experimental antitumor agents N-[2-(dimethylamino)ethyl]-9-aminoacridine-4-carboxamide (AAC) and N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) with nucleic acids. Placement of the amino substituent at the C9 position on the acridine ring results in marked changes to the acridine chromophore's electronic properties, with the overall charge of AAC increasing to +2 in comparison to DACA's charge of +1 at neutral pH. In comparative DNA binding studies, we examine the influence that the electrostatic properties of these ligands have on the binding energies as well as their effects on enthalpy and entropy contributions. These studies show that placement of the amino moiety at C9 results in 6 times greater DNA binding affinity as compared the deamino analog (DACA). Comparisons of ionic strength dependence for these two analogs reveal a difference in the binding energies of the compounds which can be attributed to electrostatic effects. Further dissection of the enthalpy and entropy components of the binding energy reveals the enhanced electrostatic effects are related to an increased entropy contribution upon formation of the AAC-DNA complex. Groove selectivity of these acridine analogs was probed by examining the binding profiles to native and groove-modified DNAs which included glycosylated T4 DNA and the distamycin-DNA complex. These studies are indicative of minor groove interactions for both compounds with DNA.

Acridines↗
PubMed1982

Interactions of some novel amide-linked bis(acridines) with deoxyribonucleic acid.

A novel series of bis(acridines) has been synthesized in which the two potential intercalating chromophores are separated by symmetrical amide-linked chains varying in both length and conformational flexibility. By comparison to a monointercalating adduct, mono- vs. bis-intercalative behavior has been established for the bis(acridines). Spectrophotometric (visible, circular dichroism, and fluorescence) and viscometric (linear sonicated and closed circular superhelical DNA) experiments indicate that a highly rigid 8.8 A separated bis(acridine) monointercalates, whereas the longer and more flexible bis(acridines) are capable of bis-intercalation. In addition, spectrophotometric studies suggest a correlation between the tendency of intramolecular association and the ability to bis-intercalate. The results are in agreement with predictions based on the neighbor-exclusion principle and indicate that connecting chain rigidity is capable of playing a determining role in the mono- vs. bis-intercalation mechanism.

Acridines↗