Acridine Dimers Research Articles

Aggregation of N-Heteropolycyclic Aromatic Molecules: The Acridine Dimer and Trimer.

Polycyclic aromatic hydrocarbons and their nitrogen-substituted analogues are of great interest for various applications in organic electronics. The performance of such devices is determined not only by the properties of the single molecules, but also by the structure of their aggregates, which often form via self-aggregation. Gaining insight into such aggregation processes is a challenging task, but crucial for a fine-tuning of the materials properties. In this work, an efficient approach for the generation and characterisation of aggregates is described, based on matrix-isolation experiments and quantum-chemical calculations. This approach is exemplified for aggregation of acridine. The acridine dimer and trimer are thoroughly analysed on the basis of experimental and calculated UV and IR absorption spectra, which agree well with each other. Thereby a novel structure of the acridine dimer is found, which disagrees with a previously reported one. The calculations also show the changes from excitonic coupling towards orbital interactions between two molecules with decreasing distance to each other. In addition, a structure of the trimer is determined. Finally, an outlook is given on how even higher aggregates can be made accessible through experiment.

Transcriptional regulation of telomeric repeat-containing RNA by acridine derivatives

ABSTRACT Telomere is a specialized DNA–protein complex that plays an important role in maintaining chromosomal integrity. Shelterin is a protein complex formed by six different proteins, with telomeric repeat factors 1 (TRF1) and 2 (TRF2) binding to double-strand telomeric DNA. Telomeric DNA consists of complementary G-rich and C-rich repeats, which could form G-quadruplex and intercalated motif (i-motif), respectively, during cell cycle. Its G-rich transcription product, telomeric repeat-containing RNA (TERRA), is essential for telomere stability and heterochromatin formation. After extensive screening, we found that acridine derivative 2c and acridine dimer DI26 could selectively interact with TRF1 and telomeric i-motif, respectively. Compound 2c blocked the binding of TRF1 with telomeric duplex DNA, resulting in up-regulation of TERRA. Accumulated TERRA could bind with TRF1 at its allosteric site and further destabilize its binding with telomeric DNA. In contrast, DI26 could destabilize telomeric i-motif, resulting in down-regulation of TERRA. Both compounds exhibited anti-tumour activity for A549 cells, but induced different DNA damage pathways. Compound 2c significantly suppressed tumour growth in A549 xenograft mouse model. The function of telomeric i-motif structure was first studied with a selective binding ligand, which could play an important role in regulating TERRA transcription. Our results showed that appropriate level of TERRA transcript could be important for stability of telomere, and acridine derivatives could be further developed as anti-cancer agents targeting telomere. This research increased understanding for biological roles of telomeric i-motif, TRF1 and TERRA, as potential anti-cancer drug targets.

Synthesis of Small Molecules Targeting Multiple DNA Structures using Click Chemistry

The ability of small molecules to target DNA forms the basis of many clinically used antitumour agents. This study examines the effects of novel 9-aminoacridine carboxamides, synthesised by click chemistry based upon the reactions of either 9-(2-azidoethyl)amino or 9-propargylaminoacridine compounds, on various types of DNA tertiary structures. This gave either monomeric or dimeric compounds, the dimeric derivatives being the first unsymmetrical acridine dimers to be described. The compounds were assayed for duplex DNA, quadruplex DNA and four-way junction DNA binding. Their antiproliferative activity in the Human promyelocytic leukaemia cell line, HL60, was also assessed. Although for some of the compounds, notably the acridine 4-carboxamides, activity correlated with DNA binding affinity, for others it did not, with the rigidly linked dimers in particular showing a complicated relationship between 3- and 4-carboxamide structure and biological activity. The monomeric 3-carboxamides were more effective at stabilising G-quadruplex structures and also gave more hits in the four-way junction stabilisation assay. There is clear evidence from the binding of the 3-carboxamides that these compounds destabilise the open X form of the junction at lower concentrations and stabilise the X-stacked at higher concentrations. This might have implications for the biological activity of these compounds against proteins that bind to the Holliday junction (HJ).

Increasing antitumor activity in vivo by enhancing acridine dimer solubility with salt preparations

The potent activities of many anticancer agents have been demonstrated by in vitro assays. However, their poor solubility may result in diminishing anticancer activities in vivo. Previously, we synthesized a series of bisacridine derivatives shown to be potent in cytotoxicity and DNA intercalating activity in vitro. Initially, the compound 1, (N-(6-chloro-2-methoxy-acridin-9-yl)-N′-[3-(6-chloro-2-methoxy-acridin-9-ylamino)-propyl]-propane-1,3-diamine), is insoluble in polar solvent and does not reveal antihuman COLO 205 solid-tumor activity in vivo. To enhance its solubility, three salt forms (CH3COOH, CH3SO3H, and CF3COOH) of compound 1 were synthesized and their solubility was found to be greatly improved compared with that of the free base. Among these salts, the compound 1 · (tris)acetate salt has shown good solubility in H2O and 2.5% Cremophor (v/v) and demonstrated anti-COLO205 solid-tumor activity in vivo.

BRACO19 analog dimers with improved inhibition of telomerase and hPot 1

Human chromosomes terminate with telomeres, which contain double-stranded G-rich, repetitive DNA followed by a single-stranded overhang of the G-rich sequence. Single-stranded oligonucleotides containing G-rich telomeric repeats have been observed in vitro to fold into a variety of G-quadruplex topologies depending on the solution conditions. G-quadruplex structures are notable in part because G-quadruplex ligands inhibit both the enzyme telomerase and other telomere-binding proteins. Because telomerase is required for growth by the majority of cancers, G-quadruplex-stabilizing ligands have become an attractive platform for anticancer drug discovery. Here, we present the preparation and biochemical activities of a novel series of 3,6-disubstituted acridine dimers modeled after the known G-quadruplex ligand BRACO19. These BRACO19 Analog Dimer (BAD) ligands were shown to bind to human telomeric DNA and promote the formation of intramolecular G-quadruplexes in the absence of monovalent cations. As expected, the BAD ligands bound to telomeric DNA with a 1:1 stoichiometry, whereas the parent compound BRACO19, a monomer, bound with a 2:1 stoichiometry. The BAD ligands exhibited potent inhibition of human telomerase with IC 50 values similar to or lower than those of BRACO19. Furthermore, the BAD ligands displayed greater potency in the inhibition of hPot1 and increased selectivity for G-quadruplex DNA when compared to BRACO19. Collectively, these experiments support the hypothesis that there is an increased potency and selectivity to be gained in the design of G-quadruplex-stabilizing agents that incorporate multiple interactions.

Identification of Trinucleotide Repeat Ligands with a FRET Melting Assay

DNA hairpin structures formed within a repeated tract might be a causative factor for triplet expansion observed in several debilitating diseases. We have designed and used a fluorescence resonance energy transfer (FRET) melting assay to screen for ligands that bind specifically to the CNG triplet repeats. Using this assay, we screened a panel of 33 chemicals that were previously designed to bind DNA or RNA secondary structures. Remarkably, we found that macrocyclic compounds, such as acridine dimers and trimers, exhibit interesting affinities and specificities for this motif.

Linker-modified triamine-linked acridine dimers: Synthesis and cytotoxicity properties in vitro and in vivo

The preparation and cytotoxicity properties of a series of N ε-substituted triamine-linked acridine dimers are described. Most acridine dimer derivatives reveal highly potent in vitro cytotoxicity properties and DNA binding activity. Several acridine dimers were selected to study their action in vivo. These acridine dimers have demonstrated a narrow safe margin, as has adriamycin, but higher maximum tolerate dose (MTD) in comparison with that of adriamycin in ICR mice. The acridine dimers also demonstrated various anit-COLO 205 solid tumor activities in vivo. Compound 1 has shown the most potent solid tumor inhibition.

Neutral and Ionic Supramolecular Structures of Unsaturated Dicarboxylic Acids and Acridine: Significance of Molecular Geometry and Proton Transfer

AbstractSix supramolecular structures exhibiting distinct architectures have been prepared from acridine and different dicarboxylic acids. The co‐crystallization of acridine (1) and configurational isomers of dicarboxylic acids such as cis,trans‐muconic (a) and trans,trans‐muconic acid (b), or fumaric (c) and maleic acid (d) provided strikingly different packing motifs and properties. The supramolecular structures have been rationalized based on the molecular geometry and the constituent synthons. Co‐crystallization of acridine and b, c, or terephthalic acid (e) gave neutral assemblies stabilized by the O‐H···N hydrogen‐bond synthon I. Acridine was found to undergo proton transfer with a, d, and acetylenedicarboxylic acid (f) to form ionic supramolecular structures exhibiting synthon II, i.e. charge‐assisted carboxylate‐acridinium O−···H−N+‐hydrogen bonding. The packing mode of 1+·a− has been inferred from the corresponding acridine‐isophthalic acid analog based on the superimposable structure of the acids and the common charge‐assisted hydrogen bonding motif. Acetylenedicarboxylic and cis,trans‐muconic acid favor the formation of antiparallel acridinium π‐stacks stabilized by alternating hydrogen bonds with two infinite anionic chains of dicarboxylic acids that also undergo head‐to‐tail hydrogen bonding. Because of their different structure and geometry, b, c, d, and e form less uniform packing arrangements with 1. Fumaric and trans,trans‐muconic acid afford 2:1 neutral co‐crystals with parallel acridine rings that are stabilized by π−π‐interactions, whereas terephthalic acid favors association of antiparallel acridine dimers to adopt a different one‐dimensional network. By contrast, d undergoes intramolecular hydrogen bonding which leaves only one carboxyl group available to form a 1:1 ionic supramolecular structure with 1. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

Analysis of the Origin Band of Acridine Dimer Fluorescence Excitation Spectrum - Conformations of Jet-Cooled Acridine Dimer

The analysis of rotational band contour for the origin transition of fluorescence excitation spectrum of acridine dimer, earlier observed under conditions of jet-cooling in supersonic helium expansion, has been performed.An optimized ground-state equilibrium structure of acridine dimer fits the approximation of asymmetric top rigid rotor. In this approximation rotational constants were determined and an A-type rotational band was computed. It has turned out that the computed rotational band contour is much narrower than the experimental one. In search for the reasons of this discrepancy between calculations and experiment, an analysis of relative rotational motion of acridine moieties of the dimer was carried out. It was found that minima of potential energy curves for rotational motion, although very flat, under conditions of supersonic expansion can acquire (in their shallow local minima) non-vanishing population of slightly different conformations of the dimer. It was shown that in terms of non-statistical distribution of such populations, the origin bands of individual conformations may contribute to the experimental band contour.

Interaction of an Acridine Dimer with DNA Quadruplex Structures

The reactivation of telomerase activity in most cancer cells supports the concept that telomerase is a relevant target in oncology, and telomerase inhibitors have been proposed as new potential anticancer agents. The telomeric G-rich single-stranded DNA can adopt an intramolecular G-quadruplex structure in vitro, which has been shown to inhibit telomerase activity. The C-rich sequence can also adopt a quadruplex (intercalated) structure (i-DNA). Two acridine derivatives were shown to increase the melting temperature of the G-quadruplex and the C-quadruplex at 1 μM dye concentration. The increase in Tm value of the G- quadruplex was associated with telomerase inhibition in vitro. The most active compound, “BisA”. showed an IC50 value of 0.75 μM in a standard TRAP assay.

An Acid‐Catalyzed Fragmentation Reaction of a Triamine‐Linked Acridine Dimer

AbstractAn acid‐catalyzed cleavage of the C‐Nϵ bond from Nϵ‐(2,3,4,5‐tetrahydroxyvaleryl) substituted side chain and/or its acetonide form of a triamine‐linked acridine dimer is de scribed. An envisaged multi‐neighboring group‐assisted solvolysis reaction mechanism is proposed.

New Polyacridine Compounds: Synthesis of Acridine Dimers and Tetramers

A series of 7,9-disubstituted acridine dimers and tetramers have been synthesized from nucleophilic attack of 2-bromomethyl-9-chloro-7-methoxy acridine 5 by different alkyl diamines.

Laser-induced emission spectroscopy of acridine cooled in a supersonic jet: the role of dimers and hydrogen-bonding in photophysics of acridine

The formation of acridine (ACD) dimers under supersonic jet-cooling conditions has been established by the observations of laser-induced fluorescence and fluorescence excitation spectra. The structure of ACD dimers predicted by using the semi-empirical AM1 parametric method suggests the possibility of the formation of hydrogen bonds between ACD moieties in the dimers. This possibility is verified with use the of the PM3 parametric method. The configuration interaction calculations performed for optimized dimer structures gives clear insights into the physical mechanism of the enhancement of the radiative processes in dimers (which, however, seems to be limited to specific conditions of supersonic expansions). The well-known role of hydrogen-bonding in the photophysics of ACD in protic liquid solutions is also supported by the results of preliminary observations under supersonic jet-cooling.

Normal Mode Analysis of Vibrations of Jet-Cooled Acridine Dimer

Normal Mode Analysis of Vibrations of Jet-Cooled Acridine Dimer

Fluorescence excitation and fluorescence spectra of jet-cooled acridine molecules: acridine dimer formation and structure

The fluorescence excitation and fluorescence spectra from a supersonic helium jet seeded with acridine molecules have been obtained. The presence of low-frequency vibrational transitions in the fluorescence excitation spectrum, which can be assigned as intermolecular vibrational modes, clearly indicates that acridine dimers are formed under jet-cooling conditions. The acridine dimer ground-state geometry determined by AM1 calculations is a head-to-tail-like structure with an almost collinear arrangement of the short molecular axes of both molecular components. The results of calculations of spectral characteristics predict a large enhancement of the oscillator strength for the transition from the ground to first excited singlet state of the dimer (as compared to acridine molecule). Such enhancement is entirely connected with structure of the dimer (which presumably is also stabilized by the formation of a hydrogen bond).

ChemInform Abstract: Synthesis of New Mono‐ and Bibridged Acridine Dimers.

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Synthesis of New Mono- and Bi-bridged Acridine Dimers

Synthesis of New Mono- and Bi-bridged Acridine Dimers

Emission of Acridine and its Aggregates Isolated in the Neon Matrix

The results of experimental studies of fluorescence and phosphorescence of acridine in the low-temperature inert neon matrix, at 7 K, are reported. It is found that the low-temperature inert matrix of neon affects the energy levels of acridine molecules very weakly even as compared. with nonpolar (aprotic) and non-reactive solvent (e.g. hexane) and that there are different sites for acridine molecules in the neon matrix. However, the observed fluorescence spectra are strongly dependent on the excitation wavelength and besides the different (monomer) sites other emitting species are also contributing to the observed fluorescence emission of acridine in the neon matrix. Clear-cut evidence of the formation of singlet excimers of acridine in the neon matrix demonstrates itself as a very broad and structureless fluorescence spectrum with a relatively large shift from the origin of monomer (site) fluorescence which is characterized by a very distinct vibrational structure. The phosphorescence emission was observed only for the monomers. The observed differences in the low-energy part of excitation spectra of phosphorescence and fluorescence are discussed in terms of the close-lying excited singlet states of n, π* and π, r* character (mixed by the vibronic coupling) and tentatively interpreted as dne to the formation of resonance acridine dimers. Their fluorescence spectrum is slightly shifted toward lower energies from the origin of monomer (site) fluorescence.

Synthesis and preliminary cytotoxic activity of dimethoxy‐acridines and dimethoxynitroacridines

AbstractThe preparation of a series of dimethoxy and dimethoxynitroacridines and their activity in oxic and hypoxic cells is reported. Anthranilic acids 1,4,14 were prepared according to the Ullmann condensation. 9‐chloroacridines were obtained from anthranilic acids by refluxing in phosphorus oxychloride. The synthesis of two new acridine dimers 9,10 is described. Nitration of 9‐chloro‐2,4‐dimethoxyacridine 15 gave 3‐nitro isomer 19. By phenol‐mediated coupling reaction from all the 9‐chloroacridines, the respective 9‐(alkylamino)acridines were obtained. By nitration of 17 a new 2,4‐dimethoxy‐3,7‐dinitroacridine 21 was prepared

Aggregation-controlled fluorescence of acridine in a crystalline matrix of anthracene

The results of experimental studies of the fluorescence of chemically mixed crystals of anthracene with large acridine concentrations (⩾ 1 mol%) at 4.2 K are reported. Excitation of fluorescence, carried out with excitation energies lower than the energy of the bottom of the singlet excitonic band, has revealed the formation of acridine dimers (resonance pairs) in the case of crystals with 1 mol% concentration of acridine. An aggregation-controlled spacing between nearly degenerate (in an isolated molecule) singlet 1(π, π*) and 1(n, π*) states of acridine is proposed as an explanation of the fluorescence properties of acridine dimers