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At least 19 recordsLinked to original sources
PubMed1976

Aggregation of acridine orange: crystal structure of acridine orange tetrachlorozincate 2C17H19N3-2HCl-ZnCl2-CH3COOH.

The crystal structure of the biological stain, "acridine orange," has been determined. This compound, when crystallized from ethanol, is shown to be a zinc chloride double salt of acridine orange, containing, in addition, acetic acid of crystallization. These additional components are residuals from the method of preparation of acridine orange. This complex, 2 acridine orange-2HCl-ZnCl2-CH3COOH, (2C17H19N3-2HCl-ZnCl2-CH3COOH) crystallizes in the monoclinic space group P21, a = 9.965 (2), b = 21.507 (6), c = 9.645 (2) A, beta = 113.98 degrees (2), V = 1888.7 (8) A3, FW = 800.0, Z = 2, DX = 1.41 g-cm-3, Dobs = 1.43 (9) g-cm-3. Three-dimensional diffraction data were collected with CuKalpha radiation, and the structure refined to R = 0.065 for 1885 observed reflections. In the crystal structure hydrogen bonds are formed, via the protonated nitrogen atom of the central rings of two acridine orange cations, to two chloride ions in a ZnCl42- tetrahedral grouping. These two acridine orange molecules are stacked in parallel planes, approximately 3.4 A apart, with the long axes of the ring systems inclined at 26.5 to each other. Thus an apparent dimerization of the acridine, orange is facilitated by the anions present, resulting in the complex studied. The two -N(CH3)2 groups of each acridine orange molecule are not protonated in this crystalline form. The mode of molecular packing found here may be relevant to models for the external stacking of acridine orange around a DNA molecule. The importance of removing any zinc salt from acridine orange preparations prior to aggregation studies is stressed.

Acridines↗
PubMed1988

Dissipation of pH Gradients in Tonoplast Vesicles and Liposomes by Mixtures of Acridine Orange and Anions: Implications for the Use of Acridine Orange as a pH Probe.

Acridine orange altered the response to anions of both ATP and in-organic pyrophosphate-dependent pH gradient formation in tonoplast vesicles isolated from oat (Avena sativa L.) roots and red beet (Beta vulgaris L.) storage tissue. When used as a fluorescent pH probe in the presence of I(-), ClO(3) (-), NO(3) (-), Br(-), or SCN(-), acridine orange reported lower pH gradients than either quinacrine or [(14)C]methylamine. Acridine orange, but not quinacrine, reduced [(14)C]methylamine accumulation when NO(3) (-) was present indicating that the effect was due to a real decrease in the size of the pH gradient, not a misreporting of the gradient by acridine orange. Other experiments indicated that acridine orange and NO(3) (-) increased the rate of pH gradient collapse both in tonoplast vesicles and in liposomes of phosphatidylcholine and that the effect in tonoplast vesicles was greater at 24 degrees C than at 12 degrees C. It is suggested that acridine orange and certain anions increase the permeability of membranes to H(+), possibly because protonated acridine orange and the anions form a lipophilic ion pair within the vesicle which diffuses across the membrane thus discharging the pH gradient. The results are discussed in relation to the use of acridine orange as a pH probe. It is concluded that the recently published evidence for a NO(3) (-)/H(+) symport involved in the export of NO(3) (-) from the vacuole is probably an artefact caused by acridine orange.

Journal Article↗
PubMed2000

Substituted benz[a]acridines and benz[c]acridines as mammalian topoisomerase poisons.

Coralyne and several other synthetic benzo[a,g]quinolizium derivatives related to protoberberine alkaloids have exhibited activity as topoisomerase poisons. These compounds are characterized by the presence of a positively charged iminium group, which has been postulated to be associated with their pharmacological properties. The objective of the present study was to devise stable noncharged bioisosteres of these compounds. Several similarly substituted benz[a]acridine and benz[c]acridine derivatives were synthesized and their relative activity as topoisomerase poisons was determined. While the benz[c]acridine derivatives evaluated as part of this study were devoid of topoisomerase poisoning activity, several dihydrobenz[a]acridines were able to enhance DNA cleavage in the presence of topo I. In contrast to certain protoberberine derivatives that did exhibit activity as topo II poisons, none of the benz[a]acridines derivatives enhanced DNA cleavage in the presence of topo II. Among the benz[a]acridines studied, 5,6-dihydro-3,4-methylenedioxy-9,10-dimethoxybenz[a]acridine, 13e, was the most potent topo I poison, with comparable potency to coralyne. These data suggest that heterocyclic compounds structurally related to coralyne can exhibit potent topo I poisoning activity despite the absence of an iminium cation within their structure. In comparison to coralyne or other protoberberine derivatives, these benz[a]acridine derivatives possess distinctly different physicochemical properties and represent a novel series of topo I poisons.

Acridines↗
PubMed2002

DNA-binding antitumor agents: from pyrimido[5,6,1-de]acridines to other intriguing classes of acridine derivatives.

In the field of antitumor DNA-binding agents, the class of acridine derivatives play an important role either as number of compounds or as importance of their anticancer properties. We have synthesized a number of acridine derivatives as potential antitumor drugs, in which the chromophore is fully or partially constituted by acridine or by 9-acridone ring systems: from the pyrimido[5,6,1-de]acridines, to the pyrimido[4,5,6-kl]acridines, the bis(amine-functionalized) 9-acridone-4-carboxamides, the bis(amine-functionalized) acridine-4-carboxamides, and the pyrazolo[3,4,5-kl]acridine-5-carboxamides. In the present revue we will describe the rational design, the synthesis, and the salient biological characteristics of these classes of acridine derivatives.

Acridines↗
PubMed1996

From amsacrine to DACA (N-[2-(dimethylamino)ethyl]acridine-4-carboxamide): selectivity for topoisomerases I and II among acridine derivatives.

A number of acridine derivatives, including the clinical antileukaemia agent amsacrine and the experimental agent DACA (N-[2-(dimethylamino)ethyl]acridine-4-carboxamide), target the enzyme topoisomerase II. We demonstrate here that DACA induces DNA cleavage in the presence of topoisomerase I as well as of topoisomerase II. We also investigate a series of acridine derivatives which link amsacrine to DACA in terms of DNA binding, topoisomerase poisoning and biological activity. The presence of an acridine 4-linked N-2-(dimethylamino)ethyl group provides both a pronounced G-C preference for DNA binding and activity towards topoisomerase I. The removal of the anilino side chain of amsacrine, in combination with the presence of the N-2-(dimethylamino)ethyl group, provides in vitro biological activity against "atypical" multidrug resistant leukaemia lines with low topoisomerase II activity. Among these compounds, suppression of the ionisation of the acridine nitrogen to produce the compound DACA is associated with experimental activity against solid tumours. The addition of an acridine 2-chloro substituent to DACA suppresses the stimulation of topoisomerase II-dependent DNA cleavage but increases stimulation of topoisomerase I cleavage. 2-Substitution also increases activity against the "atypical" multidrug resistant cell lines. Overall, the results suggest that augmentation of topoisomerase I-dependent activity in this series by appropriate chemical substitution in this series leads to circumvention of topoisomerase II-mediated multidrug resistance.

Acridines↗
PubMed2007

Differential selection of acridine resistance mutations in human DNA topoisomerase IIbeta is dependent on the acridine structure.

Type II DNA topoisomerases are targets of acridine drugs. Nine mutations conferring resistance to acridines were obtained by forced molecular evolution, using methyl N-(4'-(9-acridinylamino)-3-methoxy-phenyl) methane sulfonamide (mAMSA), methyl N-(4'-(9-acridinylamino)-2-methoxy-phenyl) carbamate hydrochloride (mAMCA), methyl N-(4'-(9-acridinylamino)-phenyl) carbamate hydrochloride (AMCA), and N-[2-(dimethylamino)ethyl]acridines-4-carboxamide (DACA) as selection agents. Mutations betaH514Y, betaE522K, betaG550R, betaA596T, betaY606C, betaR651C, and betaD661N were in the B' domain, and betaG465D and betaP732L were not. With AMCA, four mutations were selected (betaE522K, betaG550R, betaA596T, and betaD661N). Two mutations were selected with mAMCA (betaY606C and betaR651C) and two with mAMSA (betaG465D and betaP732L). It is interesting that there was no overlap between mutation selection with AMCA and mAMSA or mAMCA. AMCA lacks the methoxy substituent present in mAMCA and mAMSA, suggesting that this motif determines the mutations selected. With the fourth acridine DACA, five mutations were selected for resistance (betaG465D, betaH514Y, betaG550R, betaA596T, and betaD661N). betaG465D was selected with both DACA and mAMSA, and betaG550R, betaA596T, and betaD661N were selected with both DACA and AMCA. DACA lacks the anilino motif of the other three drugs but retains the acridine ring motif. The overlap in selection with DACA and mAMSA or AMCA suggests that altered recognition of the acridine moiety may be involved in these mutations. We used restriction fragment length polymorphisms and heteroduplex analysis to demonstrate that some mutations were selected multiple times (betaG465D, betaE522K, betaG550R, betaA596T, and betaD661N), whereas others were selected only once (betaH514Y, betaY606C, betaR651C, and betaP732L). Here, we compare the drug resistance profile of all nine mutations and report the biochemical characterization of three, betaG550R, betaY606C, and betaD661N.

Acridines↗
PubMed1993

[Quenching of ethidium-DNA fluorescence by novel acridines with antitumor activities. II. The structure-activity relationship in acridines with fluorescence quenching of ethidium-DNA].

In order to elucidate the structure-activity relationship between the antitumor activity and the molecular structure of novel DNA-intercalator acridine derivatives (1a-g and 2a-i in Chart 1), DNA-binding properties (intercalation) of these acridines were examined by quenching in the fluorescence of the ethidium-DNA complex. The mechanism of quenching is caused by the displacement of DNA-bound ethidium by a second DNA binding ligand, acridines. The concentration (C50 value) of acridine necessary to reduce the initial fluorescence of DNA-bound ethidium by 50% showed a good correlation with their antitumor activities. The quenching of fluorescence for acridines was examined using amsacrine (AMSA) as a typical standard of the second DNA-bound ligand, and calf thymus DNA with an apparent site size of two base pair. Some of the acridine derivatives showed more potent quenching of fluorescence than amsacrine (AMSA).

Acridines↗
PubMed1983

Synthesis and carcinogenic activity of oxidized benzacridines: potential metabolites of the strong carcinogen 7-methylbenz[c]acridine and of the inactive isomer 12-methylbenz[a]acridine.

The synthesis of 15 compounds related either to the benz[c]acridine or to the benz[a]acridine series is reported. Spectral data, i.e., NMR and EI fragmentation, are given. These compounds were tested for carcinogenic activity in mice of the XVIInc/Z strain by subcutaneous injection. Only three weak carcinogens were detected, 5,6-dihydro-5,6-dihydroxy-12-methylbenz[a]acridine, 3-methoxy-7-methylbenz[c]acridine, and 4-acetoxy-7-methylbenz[c]acridine. These results are discussed with consideration to the data previously obtained with other benzacridines and condensed quinolines.

Acridines↗
PubMed2004

Rational design, synthesis, and biological evaluation of bis(pyrimido[5,6,1-de]acridines) and bis(pyrazolo[3,4,5-kl]acridine-5-carboxamides) as new anticancer agents.

The good results obtained with pyrimido[5,6,1-de]acridines 7 and with pyrazolo[3,4,5-kl]acridinecarboxamides 8 prompted us to the synthesis of two new series of bis acridine derivatives: the bis(pyrimidoacridines) 5 and the bis(pyrazoloacridinecarboxamides) 6. Compounds 5 can be regarded also as cyclized derivatives of bis(acridine-4-carboxamides) 3 and compounds 6 as cyclized derivatives of bis(acridine-4-carboxamides) 4. The noncovalent DNA-binding properties of these compounds have been examined using fluorometric techniques. The results indicate that (i) the target compounds are excellent DNA ligands; (ii) the bis derivatives 5 and 6 are more DNA-affinic than corresponding monomers 7 and 8; (iii) the new bis 5 and 6 result always less efficient in binding than related bis(acridine-4-carboxamides) 3 and 4; and (iv) in both series 5 and 6 a clear, remarkable in some cases, preference for binding to AT rich duplexes can be noted. In vitro cytotoxic potency of these derivatives toward the human colon adenocarcinoma cell line (HT29) is described and compared to that of reference drugs. Structure-activity relationships are discussed. We could identify six very potent cytotoxic compounds for further in vitro studies: a cytotoxic screening against six human cancer cell lines and the National Cancer Institute (NCI) screening on 60 human tumor cell lines. Finally, compound 6a was selected for evaluation in a NCI in vivo hollow fiber assay.

Acridines↗
PubMed1997

Structure-activity relationships for acridine-substituted analogues of the mixed topoisomerase I/II inhibitor N-[2-(dimethylamino)ethyl]acridine-4-carboxamide.

The mixed topoisomerase I/II inhibitor N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) is currently in clinical trial as an anticancer drug. A series of acridine-substituted analogues were prepared, using a new synthetic route to substituted acridine-4-carboxylic acids (conversion of substituted diphenylamine diacid monoesters to the corresponding aldehydes and mild acid-catalyzed ring closure to form the acridines directly). The analogues were evaluated in a panel of cell lines which included wild-type (JLC) and mutant (JLA and JLD) forms of the human Jurkat leukemia line. The latter mutant lines are resistant to topoisomerase II targeted agents due to lower levels of the enzyme. Structure-activity studies suggest that the electronic properties of the substituents do not markedly affect cytotoxicity, but steric bulk is important, with larger groups leading to loss of activity. The compounds fell broadly into two categories. The majority had cytotoxicities similar to (or lower than) that of DACA itself and were equitoxic in all the Jurkat lines, suggesting a relatively greater effect on topoisomerase I compared with topoisomerase II. Most of the 5-substituted derivatives and the 7-Ph compound were more cytotoxic than DACA, but were less effective against JLA and JLD cell lines than in the wild-type JLC, suggesting a mode of cytotoxicity largely mediated by effects on topoisomerase II. Both DACA and selected acridine-substituted analogues were active in the relatively refractory subcutaneous colon 38 tumor model in vivo.

Acridines↗
PubMed1998

Antitumour polycyclic acridines. Part 2. Physicochemical studies on the interactions between DNA and novel polycyclic acridine derivatives.

The noncovalent interactions between a series of new polycyclic acridine derivatives (1-5) and salmon testes DNA have been studied using several physicochemical techniques. These include spectrophotometric analysis, fluorescence quenching, thermal denaturation, and circular and linear dichroism. In order to compare the extent of the DNA binding by compounds 1-5 in their neutral and cationic forms, all experiments have been conducted at pH 7.4 and at pH 5.0. Other polynucleotides, including [Poly(dA-dT)]2 and [Poly(dG-dC)]2, were used in order to study the DNA base-pair binding specificity of these novel annelated acridine derivatives. The results indicate that the new polycyclic acridines display the following properties: (i) they are strong DNA-binding ligands with affinities 10- to 400-fold greater than that of acridine, 3- to 100-fold greater than that of m-AMSA (6) and 1- to 23-fold greater than that of proflavine at physiological pH (7.4); (ii) they have stronger DNA-binding activity at pH 5.0 as a result of the N-protonation of the aromatic chromophore; (iii) they bind more selectively to [Poly(dA-dT)]2 polynucleotide than to [Poly(dG-dC)]2 polynucleotide; (iv) within the series compound 3 binds to DNA less than compounds 1, 2, 4 and 5 at both pH values studied; and (v) the polycyclic acridines form a molecular complex with DNA undergoing intercalation inside the duplex macromolecule, as shown by linear and circular dichroism. Nevertheless, circular dichroism studies reveal alternative binding modes at low DNA: drug ratios.

Acridines↗
PubMed1982

On the metabolic activation of benz[a]acridine and benz[c]acridine by rat liver and lung microsomes.

The metabolism of benz[a]- and benz[c]acridine by liver and lung microsomes from untreated, phenobarbital (PB)-treated and benzo[k]fluoranthene (BkF)-treated rats has been studied by gas chromatography/mass spectrometry (GC/MS). Epoxidation and hydrolysis of the epoxides to dihydrodiols were found to be the predominant pathways for all substrates. N-Oxidation is likely to occur in the case of benz[c]acridine. However, no unequivocal evidence could be obtained for the formation of the ultimate carcinogens--the t-3,4-dihydrodiol-1,2-epoxides--in case of both benz[a]- and benz[c]acridine. K-Region oxidation was induced by phenobarbital, whereas the formation of non-K-region metabolites increased after BkF treatment in the case of benz[c]acridine.

Acridines↗
PubMed2006

Fluorescence quenching method for the determination of sodium carboxymethyl cellulose with acridine yellow or acridine orange.

In near neutral to weak basic media, sodium carboxymethyl cellulose (NaCMC) will dissociate to become a macro polymeric anion, which can react with acridine yellow (AY) or acridine orange (AO) to form an ion-association complex resulting in fluorescence quenching of the acridine dyes. The maximum fluorescence quenching wavelength is 505 nm (lambda(ex)=440 nm) for AY system and 530 nm (lambda(ex)=493 nm) for AO system, respectively. The fluorescence quenching values (DeltaF) are directly proportional to the concentrations of NaCMC and the linear ranges are 20.0-4000 microg/L for AY system and 20.0-7000 microg/L for AO system, separately. This method has high sensitivity and the detection limits for NaCMC are 58.0 microg/L (AY system) and 157.2 microg/L (AO system). The effects of coexistent substance have been investigated, and the results show that this method has a relatively good selectivity. A fluorescence quenching method for the determination of NaCMC based on the ion-association reactions of CMC polymeric anion with a basic acridine dye was developed. The method is sensitive, simple and fast.

Acridine Orange↗
PubMed2003

A comparative study on the interaction of acridine and synthetic bis-acridine with G-quadruplex structure.

DNA from the telomeres contains a stretch of simple tandemly repeated sequences in which clusters of G residues alternate with clusters of T/A sequences along one DNA strand. Model telomeric G-clusters form four-stranded structures in presence of Na(I), K(I) and NH(4)(I) ions. Electrophoretic and spectroscopic studies were made with the telomeric related sequences d(T6G16) or d(G4T2G4T2G4T2G4). It was noticed earlier that G-quadruplex may either be inter-molecular, or intra-molecular, or a mixture of both. CD spectral characteristics of various G-quadruplex DNA suggests that the CD maximum at 293 nm corresponds to that of an intra-molecular G-quadruplex structure or hairpin dimers. Fluorescence titration studies also show that acridine and the bis-acridine are interacting with G-quadruplex DNA and destabilize the K(I)-quadruplex structure more efficiently than the quadruplex formed by NH(4)(I) ion. Among the two drugs studied, acridine is more capable of breaking the G-quadruplex structure than bis-acridine. This result is further confirmed by the CD experiments.

Acridines↗
PubMed1995

The stereochemistry of the major rat hepatic microsomal metabolites of 7,9-dimethylbenz[c]acridine and 7,10-dimethylbenz[c]acridine.

The monofunctionalized dihydrodiol metabolites of 7,9-dimethylbenz[c]acridine and 7,10-dimethylbenz[c]acridine formed in incubations with rat liver microsomes from untreated and phenobarbital and 3-methylcholanthrene-pretreated rats were isolated by reversed-phase high performance liquid chromatography. The relative amounts of each enantiomer were determined by HPLC of diastereoisomeric esters with (+)-(1R,2S,4S)-endo-1,4,5,6,7,7-hexachlorobicyclo-[2.2.1]hept-5 e ne-2- carboxylic acid (HCA). For the K-region dihydrodiols, absolute configurations were determined from their circular dichroic spectra using the empirical method. The absolute configuration of 3,4-dihydrodiol of 7,9-dimethylbenz[c]acridine was determined by the exciton chirality method from the CD spectrum of its bis-4-(dimethylamino)benzoate ester. For the 8,9-dihydrodiol of 7,10-dimethylbenz[c]acridine the absolute configurations were tentatively assigned by normal-phase HPLC comparison of the (+)-HCA esters with literature data. In every case the R,R-configuration predominated with optical purities > 86% for non-K-region dihydrodiols and 56-68% for the K-region dihydrodiols.

Acridines↗
PubMed2004

2-Ethylphenyl acridine-9-carboxylate and 2,5-dimethylphenyl acridine-9-carboxylate.

The title compounds, 2-ethylphenyl acridine-9-carboxylate, C22H17NO2, (I), and 2,5-dimethylphenyl acridine-9-carboxylate, C22H17NO2, (II), form triclinic and monoclinic crystals, respectively. Related by a centre of symmetry, adjacent molecules of (I) are linked in the lattice via a network of C-H...pi and non-specific dispersive interactions. As a result, acridine moieties and independent phenyl moieties of (I) are parallel in the lattice. The molecules of (II), arranged in a 'head-to-tail' manner and related by a centre of symmetry, form pairs stabilized via C-H...pi interactions. These are linked in the crystal via dispersive interactions. Acridine and independent phenyl moieties lie parallel within the pairs, while adjacent pairs are perpendicular, forming a herring-bone pattern.

Journal Article↗
PubMed1989

Induction of genetic duplications and frameshift mutations in Salmonella typhimurium by acridines and acridine mustards: dependence on covalent binding of the mutagen to DNA.

The aroC321 allele permits positive selection for the detection of a large genetic duplication that arises in the Salmonella typhimurium chromosome by homologous recombination. Strains that contain both aroC321 and the hisC3076 allele were constructed so that the induction of genetic duplications and frameshift mutations in a run of GC base pairs could be studied simultaneously by selecting for tryptophan and histidine prototrophy, respectively. Using these strains, we examined the ability of 9-aminoacridine, quinacrine, four acridine mustards (ICR-170, ICR-191, ICR-372, and quinacrine mustard) and the nitroacridine Entozon to induce genetic duplications and frameshift mutations. Although all these compounds induce reversion of hisC3076, only the four mustards and Entozon are effective as inducers of genetic duplications under identical treatment conditions. The induction of genetic duplications by acridine mustards, like the toxic and mutagenic effects of these compounds, is enhanced by a deficiency for excision repair caused by a deletion through the uvr B gene. The ineffectiveness of 9-aminoacridine and quinacrine in the test for genetic duplications indicates that simple intercalation is sufficient for the mutagenic effect measured with the hisC3076 allele but that the induction of duplications by the acridine mustards and Entozon requires covalent binding of the chemical to DNA.

Acridines↗
PubMed2006

Potent antitumor 9-anilinoacridines and acridines bearing an alkylating N-mustard residue on the acridine chromophore: synthesis and biological activity.

A series of 9-anilinoacridine and acridine derivatives bearing an alkylating N-mustard residue at C4 of the acridine chromophore were synthesized. The N-mustard pharmacophore was linked to the C4 of the acridine ring with an O-ethyl (O-C(2)), O-propyl (O-C(3)), or O-butyl (O-C(4)) spacer. It revealed that all newly synthesized compounds were very potent cytotoxic agents against human leukemia and various solid tumors in vitro. These agents did not exhibit cross-resistance against vinblastine-resistant (CCRF-CEM/VBL) or taxol-resistant (CCRF-CEM/taxol) cells. It also showed that these agents were DNA cross-linking agents rather than topoisomerase II inhibitors. Of these agents, compounds 27a and 27c were shown to have potent antitumor activity in nude mice bearing the human breast carcinoma MX-1 xenograft. The therapeutic efficacies of these two agents are comparable to that of taxol.

Acridines↗