Acridine Molecule Research Articles

Interactions between DNA and the acridine intercalator: A computational study

Cancer is a global public health problem characterized by deviations in the mechanisms that control cell proliferation, resulting in mutations and variations in the structure of DNA. The mechanisms of action of chemotherapeutic drugs are related to their interactions and binding with DNA; consequently, the development of antineoplastic agents that target DNA has extensively focused on use of acridine, a heterocyclic molecule that binds to deoxyribonucleic acid via intercalation, a process that modifies DNA and makes replication impossible. In this context, this study aimed to computationally investigate how acridine intercalators interact with DNA by evaluating the mechanism of interactions, binding, and interaction energies using quantum mechanics calculations. Molecular electrostatic potential (MEP) analysis revealed that acridine has well- distributed negative charges in the center of the molecule, indicative of a dominant electron-rich region. Acridine exhibits well-defined π orbitals (HOMO and LUMO) on the aromatic rings, suggesting that charge transfer occurs within the molecule and may be responsible for the pharmacological activity of the compound. Structural analysis revealed that acridine interacts with DNA mainly through hydrogen bonds between HAcridine… ODNA with bond lengths ranging from 2.370 Å to 3.472 Å. The Binding energy (ΔEBind) showed that acridine interacts with DNA effectively for all complexes and the electronic energy results (E+ZPE) for complexes revealed that the complexes are more stable when the DNA-centered acridine molecule. The Laplacian-analysis topological QTAIM parameter (∇2ρ(r)) and total energy (H(r)) categorized the interactions as being non-covalent in nature. The RGD peak distribution in the NCI analysis reveals the presence of van der Waals interactions, predominantly between the intercalator and DNA. Accordingly, we confirm that acridine/DNA interactions are relevant for understanding how the intercalator acts within nucleic acids.

An overview of pharmacological activities of acridine derivatives

The derivatives of acridine can be served as a lead molecule of an antibacterial, anti-viral antiprotozoal, anti-viral, antitubercular, anti-fungal, anti-malarial and anti-cancer agents. Even though the usage of acridine becomes limited due to its side effects, so many potent and safe compounds can be derived through molecular modification in the acridine ring. Since the resistance of pathogens and tumour cells has become more common nowadays, it necessitates the search of new drug candidates. Since the treatment and management of Alzheimer's disease is such a complicated and proper drug regimen is not designed so far, The cholinesterase activity of acridines can be used to derive novel compounds from treating Alzheimer's disease. The mosquito larvicidal activity of acridines is considered as an advantage as vector control to reduce the spreading rate of malaria. Unfortunately, the versatility of the acridine molecule is not entirely explored still. If new approaches may overcome the drawbacks of the acridines such as resistance of pathogens and tumour cells in synthesis and formulation acridine analogues will become a useful drug candidate for the treatment of diseases mentioned above. So this article aims to seek the attention of researchers in the acridine to utilise it’s a wide range of biological activities in the development of novel drug molecules for the various diseases in the future.

Improvement of Solid‐State Excimer Emission of the Aryl–Ethynyl‐o‐Carborane Skeleton by Acridine Introduction

We report highly‐efficient and solid‐state excimer emission based on the acridine–o‐carborane dyad possessing the ethynyl spacer. The previous pyrene‐modified o‐carborane showed excimer emission only at 77 K in the crystalline state, meanwhile, the current acridine‐modified molecule presented excimer emission with high efficiency (ΦPL = 0.23) in the crystalline state at room temperature. From single‐crystal X‐ray crystallography, it was indicated that two acridine moieties were stacked and the third acridine molecule was out of alignment. Such a packing mode could restrict exciton splitting over the columnar packing structure. Moreover, molecular interactions through the nitrogen atom in the acridine moiety and the hydrogen atom in the o‐carborane unit contribute to suppression of molecular motions. As a consequence, an improved emission efficiency was obtained. This study demonstrates that the ethynyl–o‐carborane skeleton should work as the excimer‐inducible component in the solid state.

Catalyst Design for Oxygen Reduction Reaction Using Pyridinic Nitrogen-Doped Carbon Materials

Nitrogen-doped graphitic carbons as non-Pt catalysts for oxygen reduction reaction (ORR) have been paid much attention in recent years because commercialization of fuel cells requires less expensive and abundant catalytic materials. Identification of the active site of nitrogen-doped carbon materials for ORR is thus urgently required, but still under debate. Currently, the debate focuses on whether the active site is created by pyridinic N (N bonded to two carbon atoms) or graphitic N (N bonded to three carbon atoms, also called substituted N or quaternary N). To determine the active site conclusively, we prepared model catalysts of highly oriented pyrolytic graphite (HOPG) with pyridinic N (pyri-HOPG) or graphitic N (grap-HOPG). The active sites and adsorption properties were examined by ORR and post-ORR X-ray photoelectron spectroscopy (XPS). We have thus determined the active nitrogen species in carbon [1].The graphitic-N doping was performed by mild bombardment with a nitrogen ion beam. To prepare the pyri-HOPG samples, edge patterning was first performed by bombarding the sample with an Ar+ ion beam through a slit-patterned Ni mask as shown in Fig.1 A-D. The edged HOPG samples were then exposed to NH3 at 973 K. The catalytic performances of the model catalysts were measured by cyclic voltammetry (CV) in acidic electrolyte (0.1 M H2SO4). It was found that the pyri-HOPG model catalyst shows high activity at high voltages, compared to the very low ORR activities of the N-free model catalysts (Fig.1 E, F). The pyri-HOPG sample with lower N concentration (N: 0.60 at%) is much more active than the grap-HOPG sample with higher N concentration (N: 0.73 at%). Since the pyri-HOPG sample is nearly free of graphitic N, the ORR results indicate that it is pyridinic N rather than the graphitic N that reduces the ORR overpotential and creates the active site. It is thus concluded that the ORR active sites in nitrogen-doped carbon materials are created by pyridinic N. Based on the model catalyst study, we then try to prepare catalytically active carbon surfaces covered with pyridinic nitrogen-containing aromatic molecules. That is, bottom-up preparation of catalysts using HOPG electrode covered with pyridinic nitrogen-containing aromatic molecules (dibenz[a,c] acridine (DA) molecule). The DA molecules were deposited on HOPG with different coverage by simply dropping solutions of the DA molecules at room temperature. Scanning tunneling microscopy (STM) measurements revealed that a well-ordered two-dimensional structure of DA monolayer is formed on HOPG surfaces with high densities via π-π interaction, rather than aggregates to form three-dimensional clusters. The nitrogen concentration of the DA-covered HOPG surfaces was estimated to be 0.5~1.5 at.% by XPS. The DA-covered HOPG model catalysts reveled activities of ORR. The specific activity per pyridinic nitrogen atom was estimated to be 0.08 (e sec-1 pyriN-1) at 0.3 eV, which is comparable to that for pyridinic nitrogen incorporated graphene sheets (0.07 ~ 0.14 (e sec-1 pyriN-1))[1]. The current densities at 0.1, 0.2, and 0.3 V vs RHE were in proportional to the surface coverage of DA molecules, indicating that the ORR active site was created by DA molecule adsorbed on HOPG. The present studies clearly show that fixing nitrogen-containing aromatic molecules on graphitic carbon materials is one of the promising approaches to prepare active ORR carbon catalysts. Acknowledgement: This study is supported by JST PRESTO and NEDO project. REFERENCES [1] D. Guo, R. Shibuyaa, C. Akiba, S. Saji, T. Kondo, J. Nakamura, Science, 351 (2016) 361. Figure 1

OXIDATIVE S N H AMIDATION OF ACRIDINE AND TAUTOMERISM OF N -(ACRIDIN-9-YL)BENZAMIDES

Direct oxidative nucleophilic substitution of hydrogen atom in acridine molecule was used to synthesize 9-acylaminoacridines. The prototropic amine-imine tautomerism of these compounds was studied. How to Cite Demidov, O. P.; Borovlev, I. V.; Amangasieva, G. A.; Avakyan, E. K. Chem. Heterocycl. Compd. 2016 , 52 , 104. [ Khim. Geterotsikl. Soedin. 2016 , 52 , 104.] For this article in the English edition see DOI 10.1007/s10593-016-1841-7

Oxidative SNH amidation of acridine and tautomerism of N-(acridin-9-yl)benzamides

Direct oxidative nucleophilic substitution of hydrogen atom in acridine molecule was used to synthesize 9-acylaminoacridines. The prototropic amine-imine tautomerism of these compounds was studied.

Enzyme inhibiting action of tetrahydroaminoacridine and its structural fragments.

Abstract Tetrahydro-5-aminoacridine and four compounds representing its structural fragments have been compared as inhibitors of acetylcholinesterase and of monoamine oxidase. The entire structure of tetrahydro-5-aminoacridine appears to be essential for optimal inhibition of the esterase, less than 10−6 m concentration showing a 50 per cent inhibition of the enzyme, with the inhibition constant Ki as 1 × 10−4. For optimum inhibition of monoamine oxidase, the 4-aminoquinoline part of the acridine molecule appears to be a structural requirement. 4-Arninoquinoline shows a stronger monoamine oxidase inhibition than any known therapeutically used inhibitor. It gives a 50 per cent inhibition of the oxidase in 10−6 m concentration, with ki as 1.1 × 10−5.

Diacridinium tetrakis(thiocyanato-κS)platinate(II)

The asymmetric unit of the title compound, (C13H10N)2[Pt(NCS)4], contains a protonated acridine molecule and one half of a [Pt(NCS)4]2− anion. In the complex anion, the PtII ion is located on an inversion centre and is four-coordinated in a slightly distorted square-planar environment by four S atoms from four thio­cyanate ligands. The compound displays numerous inter­molecular π–π inter­actions between six-membered rings, with a shortest centroid–centroid distance of 3.682 (3) Å. The component ions inter­act by means of inter­molecular N—H⋯N hydrogen bonds.

The role of intermolecular vibrations and reorganization of a reaction system in tunneling reactions with H atom transfer. A Debye model for the medium

Mechanisms of temperature dependence of the rate constants for two types of solid-state tunneling chemical reactions, namely, transfer of an H atom between two molecules and intramolecular transfer, are analyzed. To this end, an analytical expression for the rate constant for tunneling atom transfer in solids is derived in the framework of a modified theory of nonradiative transitions. The mechanisms of the temperature dependence of the rate constant considered in this work include oscillations of the potential barrier to chemical reaction in intermolecular fluctuations and reorganization of the medium. The effect of pressure on the distance between reactants and on the frequency of intermolecular vibrations is taken into account. The theory developed is used to interpret experimental data on tunneling transfer of an H atom in two reactions: a) intramolecular hydrogen transfer in a matrix-isolated formic acid molecule entrapped in an argon crystal and b) H atom transfer from a fluorene molecule to an excited acridine molecule in a fluorene crystal.

Acridine derivatives inhibit lysozyme aggregation

We have screened a library of structurally distinct acridine derivatives (19 compounds) for their ability to inhibit lysozyme amyloid aggregation in vitro. Studied acridines were divided into three structurally different groups depending on the molecule planarity and type of the side chain-planar acridines, spiroacridines and tetrahydroacridines. Thioflavine T fluorescence assay and transmission electron microscopy were used for monitoring the inhibiting activity of acridines. We have found that both the structure of the acridine side chains and molecule planarity influence their antiamyloidogenic activity. The planar acridines inhibited lysozyme aggregation effectively. Spiroacridines and tetrahydroacridines had no significant effect on the prevention of lysozyme fibrillization, probably resulting from the presence of the heterocyclic 5-membered ring and non-planarity of molecule. Moreover, in the presence of some tetrahydroacridines the enhanced extent of aggregation was detected. We identified the most active acridine derivates from studied compound library characterized by low micromolar IC50 values, which indicate their possible application for therapeutic purpose.

Negative ion photoelectron spectroscopy of acridine molecular anion and its monohydrate

Negative ion photoelectron spectroscopy was employed to investigate the electronic structure of the acridine molecular anion and its monohydrated anion in the gas phase. Their adiabatic electron affinities were measured to be 0.896+/-0.010 and 1.18+/-0.05 eV, and the low-lying electronic excited states in both neutral acridine and in its monohydrate were revealed. The photoelectron spectra clearly exhibit the presence of low-lying singlet and triplet states having a (pi,pi*) configuration in an uncomplexed acridine molecule. Comparison of the photoelectron spectrum of acridine with that of anthracene shows that photodetachment processes into the excited states of (n,pi*) configuration have little intensity, implying a relatively large intramolecular structural relaxation in the (n,pi*) states.

Crystal structure and conformation of 9-cyano-9-propyl cyano-10-methyl acridine

Crystals of the title compound are orthorhombic, Space group P212121, with the unit cell dimensions, a =6.839 (1), b=9.919 (3), c =21.311 (1) A, V= 1445.6 (6) A3, and Z=4. The structure was solved with CAD-4 data using MULTAN programs and refined to a final R value of 0.048. The acridine molecule takes up a “bent-propellar” conformation with the propylcyano and the cyano groups on opposite sides of the acridine molecule. No intra- or intermolecular hydrogen bonding is present in the crystal packing, except for some C–H⋅⋅⋅N type of interactions. The crystal structure is stabilized by the stacking of the acridine molecules running parallel to the crystallographic a-axis. The separation of approximately 3.5 A between the aromatic units and the alternating arrangement of the molecules within these stacks indicates that attractive electrostatic π–π interactions play a significant role in the crystal packing.

A Rapid and Simplified Method for Determining Ozone and Other Image Degradation Oxidants in Air

It is now well known that pictures stored in circulating air are subject to degrading oxidants, especially ozone, that attack the dyes or pigments present in the image. This new perception is the result of many field observations and the testing by many manufacturers to explain why accelerated tests on images were under predicting life expectancy.It is also well known that expansion of industrialization, on a global scale, the increased burning of fossil fuels and the proliferation of vehicles of transportation in many new countries that have advanced economically, are creating atmospheric pollution that results in marked increases in ozone and other related oxidants on a world wide scale.So much for our understanding of the causes; this has sparked a great interest in methods that can quickly monitor atmospheric conditions and determine changes that influence image degradation and may allow better quantification between cause and effect.Some of the current accepted methods for quantifying ozone or other oxidants, rely on expensive lab instruments, or costly and slow Drager tubes for field use. Since it is not feasible to sample air and transport in to labs for measurement, without incurring changes during transport, we have developed an alternate chemiluminescent method.Chemiluminescent methods are fast, sensitive and today easy to carry out in the field with small portable instruments (luminometers).New molecules are available that have increased both sensitivity and convenience to various mediums. We have worked with a new material, commercially available from biotech supplier, Capricorn Products Inc., called AcriGlow 301™. The molecule is a water soluble derivative of 9-acridinecarboxylic acid, with good stability in water and is converted to the chemiluminescent by-product, 9-acridinepercarboxylic acid in the presence of trace quantities of peroxyde. To make optimum use of this chemistry we have developed a method that facilitates its use in the field and provides for the capture of oxidants in air.The method begins with the sampling of air from a source of interest, by drawing into a gas syringe containing a buffer and a proprietary fluorinated surfactant, resistant to oxidation. The gas sample is shaken in the syringe to dissolve the oxidizing gases, such as ozone, peroxyde or oxides of nitrogen, and injected into the reading tube of a portable luminometer. The activating AcriGlow molecule is injected before or immediately after the buffer/dissolved gas sample and readings are taken minutes later. Since the photon flux, from the chemiluminescent reaction builds gradually readings can be taken at various time intervals, until a maximum signal is observed. This will occur in less then 15 minutes, but with low concentrations of oxidant in less the 5 minutes. Since chemiluminescent signal is temperature dependent, it is best to do readings at 20°C. or above.The output readings are in arbitrary photon counts per unit of time and are converted to concentration by doing a calibration with known concentrations of gases. Using small commercial ozone generating sources, such as quartz/UV tubes, calibration may be carried out using sampling syringes and using the principle of systematic dilution to generate concentration series. Similarly peroxide concentrations can be generated to do calibration series.Using this information, sample images were placed in atmospheres of different gas concentrations and stored for various periods of time, temperature and humidity to observe image degradation. Image degradation was observed both visually and then measured with a small densitometer.Data will be shown that the simplified chemiluminescent method and the use of the new acridine molecule allows detection of oxidant species such as ozone and peroxide down to the parts per billion range and can be used to correlate with observed image degradation as concentration of gases increase. The method is fast, simple to use and inexpensive. This has the virtue that many measurements can be made, in atmospheres of varying concentration, in the field to better understand how images react and find ways to improve image stability.This method was developed to encourage more field measurements and get better correlation with real life environments to determine conditions for improved image stability.

Bacterial target sites for biocide action

Although biocides have been used for a century, the number of products containing biocides has recently increased dramatically with public awareness of hygiene issues. The antimicrobial efficacy of biocides is now well documented; however, there is still a lack of understanding of their antimicrobial mechanisms of action. There is a wide range of biocides showing different levels of antimicrobial activity. It is generally accepted that, in contrast to chemotherapeutic agents, biocides have multiple target sites within the microbial cell and the overall damage to these target sites results in the bactericidal effect. Information about the antimicrobial efficacy of a biocide (i.e. the eta-value) might give some useful indications about the overall mode of action of a biocide. Bacteriostatic effects, usually achieved by a lower concentration of a biocide, might correspond to a reversible activity on the cytoplasmic membrane and/or the impairment of enzymatic activity. The bacteriostatic mechanism(s) of action of a biocide is less documented and a primary (unique?) target site within the cell might be involved. Understanding the mechanism(s) of action of a biocide has become an important issue with the emergence of bacterial resistance to biocides and the suggestion that biocide and antibiotic resistance in bacteria might be linked. There is still a lack of understanding of the mode of action of biocides, especially when used at low concentrations (i.e. minimal inhibitory concentration (MIC) or sublethal). Although this information might not be required for highly reactive biocides (e.g. alkylating and oxidizing agents) and biocides used at high concentrations, the use of biocides as preservatives or in products at sublethal concentrations, in which a bacteriostatic rather than a bactericidal activity is achieved, is driving the need to better understand microbial target sites. Understanding the mechanisms of action of biocides serves several purposes: (i) it will help to design antimicrobial formulations with an improved antimicrobial efficacy and (ii) it will ensure the prevention of the emergence of microbial resistance.

Antitumor acridines with diaminoalkylo pharmacophoric group

Abstract The substitution of acridine molecule in positions 1 and/or 4 with diaminoalkylo residue may result in obtaining derivatives displaying antitumor activity. The diaminoalkylo residue can be attached to acridine either directly or indirectly as a carboxamido moiety. In the former case, the presence of appropriate substituent in position para to diaminoalkylo residue is crucial for antitumor activity. Also, heterocyclic aromatic rings condensed with the acridine core can be considered as such substituents. Additional substituents introduced into the acridine core, especially those that may be transformed into quinoid systems, significantly increase antitumor activity of modified analogs. It is, however, of utmost importance that the presence of diaminoalkylo residue is the indispensable prerequisite for biological activity of acridines. Among several groups of synthesized diaminoalkyloacridines, the most potent antineoplastic properties toward a wide spectrum of transplantable tumors are exhibited by acridine-4-carboxamides, imidazo-, triazolo-, and pyrazoloacridinones. Two derivatives belonging to the above groups, acridine-4-carboxamide DACA and imidazoacridinone C-1311, are currently in clinical trials. Other derivatives exhibiting potent antitumor activity, that could be considered as close analogs of diaminolkyloacridines, are pyrazoloacridines, one of which is currently under clinical evaluation.

Structural characterization of the acridine–(H 2O) n ( n=1–3) clusters by fluorescence-detected infrared spectroscopy

The vibrational spectra of supersonically cooled acridine–(H 2O) n ( n=1–3) clusters in the electronic ground state have been measured by fluorescence-detected infrared spectroscopy. The observed O–H stretching fundamentals of the solvent have been analyzed with the aid of density functional theory calculations, to assign the structures of the clusters. In the n=1 cluster, the water molecule acts as a proton donor which is hydrogen-bonded to the N atom of acridine. The second (third) water in the higher clusters is further hydrogen-bonded to the first (second) one to form a linear `water chain', which surrounds an edge of the acridine molecule approximately in the plane of the aromatic ring.

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).

Specific inhibition of in vitro transcription elongation by triplex-forming oligonucleotide-intercalator conjugates targeted to HIV proviral DNA.

A 16-base pair oligo(purine)-oligo(pyrimidine) sequence present in the coding region of two HIV 1 proviral genes (pol and nef) was chosen as a target for triplex-forming oligonucleotides in in vitro transcription assays. Inhibition of transcription elongation was observed with triplex-forming oligonucleotide-acridine conjugates (Acr-15-TCG:5'-Acr-T4CT4G6-3' and Acr-9-TC:5'-Acr-T4CT4-3' where C is 5-methylcytosine) under conditions where the unsubstituted oligomers did not exhibit any inhibitory effect. Both SP6 bacteriophage RNA polymerase and eukaryotic RNA polymerase II were physically blocked by such a triplex barrier. The polymerase arrest is caused by the triple-helical complex involving the hydrogen-bonded oligonucleotide stabilized by the intercalated moiety and not solely by the acridine molecule specifically intercalated at the duplex-triplex junction. The stability of the triple-helical complex formed by the 15-mer containing thymines, cytosine, and guanines (15-TCG) and involving the formation of six contiguous C.GxG base triplets was strongly enhanced in the presence of a benzopyridoindole derivative (BePI), which intercalates in triplex structures. This improvement of the binding affinity led to an increased inhibition of transcription elongation. The present results demonstrate the necessity to use triplex-forming oligonucleotides with high binding affinity and a long residence time on their double-stranded target to efficiently inhibit transcription elongation. These data provide a rational basis for the optimization and the development of triplex-forming oligonucleotides as transcriptional blockers, even when they are targeted to the transcribed portion of a gene, downstream of the transcription initiation site.

2'-Methoxy-5'-methoxycarbonylspiro[acridine-9(10H),4'(5'H)-thiazole

The structure of the title ester, methyl 2'-methoxy-spiro[acridine-9(10H),4'(5'H)-thiazole]-5'-carboxylate, C 18 H 16 N 2 O 3 S, is described. The compound is of spiro type. The acridine molecule is not planar, but adopts an arch-like conformation. The thiazole ring is in an envelope form. One of the C-C bonds exhibits an unusual value of 1.610 (3) A. A C=O...H-N-type intermolecular hydrogen bond takes part in the packing of the molecules.

Fluorescence and phosphorescence emission and nonradiative relaxation of acridine in a crystalline matrix of 2,3-dimethylnaphthalene

The results of experimental studies of fluorescence and phosphorescence of acridine, selectively excited within its absorption band, in a crystalline host lattice of 2,3-dimethylnaphthalene, are reported. The energies of the first excited singlet and triplet states of acridine in this crystalline matrix were determined. The spectra of both emissions display a broadening caused by the orientational disorder of the host lattice. The intensity and the decay time of the fluorescence and phosphorescence show moderate temperature dependence (in the 4.2–300 K temperature range). It is concluded that over the whole temperature range the most important mode of the nonradiative relaxation of the excited acridine molecule is that of the (nearly) temperature-independent intersystem crossing from the S 1(π, π ∗) singlet to the T 3(π, π ∗) and/or T 2( n, π ∗) triplet states.