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Some of the wound dressings on the market cause skin tearing and bleeding when removed, slowing the healing process. So, it is difficult to treat infected wounds of sensitive skin patients. Herein, antibacterial and biocompatibility self-healing hydrogel loaded with 9-Aminoacridine and kanamycin sulfate were prepared by grafting poly(β-carboxyethyl acrylate-co-acrylamide) onto sodium alginate. The biological assay demonstrated the hydrogels' good biocompatibility, which showed no harmful effects on normal human melanocyte cells. In addition, the hydrogels had a powerful antibacterial impact on the various bacterial strains utilized in the investigation. From the study of the rheological properties of the prepared hydrogel, it was found that it is a non-Newtonian fluid. These results suggest the possible utilization of the as-prepared hydrogels in the fabrication of wound healing. [ABSTRACT FROM AUTHOR]

Structure-guided design of novel pharmacologically active molecules relies at least in part on functionally relevant accuracy of macromolecular structures for template based drug design. Currently, about 95% of all macromolecular X-ray structures available in the PDB (Protein Data Bank) were obtained from diffraction experiments at low, cryogenic temperatures. However, it is known that functionally relevant conformations of both macromolecules and pharmacological ligands can differ at higher, physiological temperatures. We describe in this article development and properties of new human acetylcholinesterase (AChE) crystals of space group P31 and a new unit cell, amenable for room-temperature X-ray diffraction studies. We co-crystallized hAChE in P31 unit cell with the reversible inhibitor 9-aminoacridine that binds at the base of the active center gorge in addition to inhibitors that span the full length of the gorge, donepezil (Aricept, E2020) and AChE specific inhibitor BW284c51. Their new low temperature P31 space group structures appear similar to those previously obtained in the different P3121 unit cell. Successful solution of the new room temperature 3.2 Å resolution structure of BW284c51*hAChE complex from large P31 crystals enables us to proceed with studying room temperature structures of lower affinity complexes, such as oxime reactivators bound to hAChE, where temperature-related conformational diversity could be expected in both oxime and hAChE, which could lead to better informed structure-based design under conditions approaching physiological temperature.

ABSTRACT The increasing occurrence of extensively drug-resistant and pan-drug-resistant K. pneumoniae has posed a serious threat to global public health. Therefore, new antimicrobial strategies are urgently needed to combat these resistant K. pneumoniae-related infections. Drug repurposing and combination are two effective strategies to solve this problem. By a high-throughput screening assay of FDA-approved drugs, we found that the potential small molecule 9-aminoacridine (9-AA) could be used as an antimicrobial alone or synergistically with rifampin (RIF) against extensively/pan-drug-resistant K. pneumoniae. In addition, 9-AA could overcome the shortcomings of RIF by reducing the occurrence of resistance. Mechanistic studies revealed that 9-AA interacted with bacterial DNA and disrupted the proton motive force in K. pneumoniae. Through liposomeization and combination with RIF, the cytotoxicity of 9-AA was significantly reduced without affecting its antimicrobial activity. In addition, we demonstrated the in vivo antimicrobial activity of 9-AA combined with RIF without detectable toxicity. In summary, 9-AA has the potential to be an antimicrobial agent or a RIF adjuvant for the treatment of multidrug-resistant K. pneumoniae infections. IMPORTANCE Klebsiella pneumoniae is a leading cause of clinically acquired infections. The increasing occurrence of drug-resistant K. pneumoniae has posed a serious threat to global public health. We found that the potential small molecule 9-AA could be used as an antimicrobial alone or synergistically with RIF against drug-resistant K. pneumoniae in vitro and with low resistance occurrence. The combination of 9-AA or 9-AA liposomes with RIF possesses effective antimicrobial activity in vivo without detected toxicity. 9-AA exerted its antimicrobial activity by interacting with specific bacterial DNA and disrupting the proton motive force in K. pneumoniae. In summary, we found that 9-AA has the potential to be developed as a new antibacterial agent and adjuvant for RIF. Therefore, our study can reduce the risk of antimicrobial resistance and provide an option for the exploitation of new clinical drugs and a theoretical basis for the research on a new antimicrobial agent.

9-Aminoacridine structures hold much potential for accessing small molecule therapeutics. This core is present in a range of pharmaceuticals for the treatment of ailments such as malaria, inflammation, viral and bacterial infections, and cancer. For the latter, there remains a need to develop and/or improve chemotherapeutics to counteract issues of uptake, drug resistance, and selectivity for cancer cells over healthy cells. In the design of molecules to address these issues, identifying structural units that present as promising leads for drug developments is key. In this study, four 9-aminoacridine derivatives under consideration as precursors for a drug design project are assessed for their cytotoxicity with representative cell lines PC3 and A549, and for their leadlikeness with SwissADME. Together, the cytotoxicity and in silico investigations coalesce around the same derivative as the most promising lead.

We developed a one-pot, two-stage synthetic route to access 9-aminoacridines involving a Buchwald-Hartwig coupling reaction followed by acid-mediated cycloaromatization. This one-pot reaction affords pharmaceutically valuable 9-aminoacridines from readily available 2-bromobenzonitriles and arylamines. The reaction was easily scaled-up to gram quantities. This methodology was extended to the preparation of various useful 9-aminoacridines, and further exemplified by the synthesis of 9-amino-6-chloro-2-methoxy acridine, an important scaffold of marketed drugs such as mepacrine and quinpramine. [ABSTRACT FROM AUTHOR]

The electrochemical behavior of two chemically related acridine compounds: tacrine (TAC) and 9-aminoacridine (9-AA) was investigated on a hanging mercury drop electrode (HDME). The electrochemical study was carried out by using Osteryoung square wave voltammetry (OSWV) and cyclic voltammetry (CV) techniques in the Britton-Robinson (B-R) buffer solution at pH = 2.0-12.0, KCl (0.1/0.2/0.3 M) and methanol (0.0-50%) mixture as supporting electrolyte. TAC showed maximum current at pH 7.5 while 9-AA at pH 10, KCl (0.3M), and 10% methanol. The study of electrochemical reduction of 9-AA and TAC on the HDME by using CV resulted in a quasi-reversibility, mainly diffusion-controlled reaction. The reaction involved 1e-/1H+ reduction at nitrogen atom in the case of the 9-AA while the second process involved the 2e-/2H+ reduction of the intra-cyclic azomethine group. The reduction peak potential of structurally related acridine compounds is influenced by the pH values and percentage of the organic solvent of the supporting electrolytes. Also, the study may provide insight into the electron transfer pathways of biological reactions of the acridines and their electrochemical behavior on the electrode. [ABSTRACT FROM AUTHOR]

Dimers of 9‐aminoacridine linked via the 9‐amino group with polymethylene chains, termed diacridines, are known to bisintercalate into DNA when the linker comprises 6 or more methylene units. There are no literature reports of crystal or NMR solution structures for bisintercalated diacridine‐DNA complexes, and the issue of the structure of the C6 ([CH2]n linker where n = 6) diacridine complex remains unresolved. Previously, based on simple geometric considerations, it was proposed that C6 diacridine could only span a single base pair, which requires that its bifunctional reaction violates the widely‐observed "neighbor exclusion principle" where bound intercalators are separated by at least 2 base pairs. Here we have explored the structure of diacridine‐DNA complexes using unrestrained molecular dynamics in explicit solvent using the parmbsc0 forcefield in AMBER14. We studied the C4 to C8 dimers, intercalated via both the minor and major DNA grooves, to a variety of nucleotide sequences. We find that C6, C7, and C8 diacridine are able to form 2 base pair bisintercalated complexes from either groove, whereas the C4 and C5 homologues cannot. We conclude that C6 diacridine does have the capacity to bisintercalate without violating neighbor exclusion, and that the previous proposed binding model needs revision. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • The two new fluorescent, 9-aminoacridine derivatives (AC-PA and AC-ACYL) have been synthesized and structurally characterized by various spectroscopic techniques. • Steady-state and time-resolved fluorescence properties of saturated fatty acid containing 9-aminoacridine derivative (AC-PA) were used to understand the micellization process of two bile salts (NaDC and NaC). • Further, the saturated fatty acid containing 9-aminoacridine derivative (AC-PA) has been used as a fluorophore to understand the micellization process of cationic, anionic and neutral surfactants such as CTAB, SDS and TritonX-100. • The study state and time-resolved fluorescence of the short hydrophobic tail containing 9-aminoacridine derivative were not sensitive toward the micellization process of bile salts as well as surfactants. Abstract The present work describes the synthesis and photophysical studies of two 9-aminoacridine derivatives (N -(acridine-9-yl)palmitamide (AC-PA) and N -(acridine-9-yl)acetamide (AC-ACYL)). For AC-PA and AC-ACYL, the -NH 2 group of 9-aminoacridine is acylated by a long hydrophobic tail (palmitic acid, a saturated fatty acid), and a short hydrophobic tail (acetic acid), respectively. The steady-state and time-resolved fluorescence of AC-PA are sensitive towards the micellization of sodium deoxycholate and sodium cholate bile salts. Fluorescence of AC-PA is also senstive to microenviornment of different type of suffactants and is used to monitor the anionic, cationic and neutral surfactants. The critical micellar concentration determined from the fluorescene studies of AC-PA in the bile salts and surfactants are consistent with the values reported in the literatur. In contrast, steady-state and time-resolved fluorescence of AC-ACYL are insenstive to towards the micellization process of bile-salts and surfactants. The comparative study presented here shows the importance of a hydrophobic long tail, attached to a fluorophore, to make its fluorescence properties sensitive towards microenvironment and, in the process, make such molecules suitable for investigation of structure and dynamics of various organized systems. [ABSTRACT FROM AUTHOR]

Quinacrine (QC), a synthetic antimalarial drug, was consistently used worldwide to combat malaria during the last century. Interestingly, later studies revealed that it also displays various additional properties, specifically antitumor activity. QC's antitumor activity occurs via a variety of pathways, including DNA intercalation, angiogenesis inhibition, signal transduction regulation, cell cycle arrest and autophagy induction. In combination with traditional therapies such as chemotherapy and radiotherapy, QC has also displayed synergistic effects against tumors, which may open promising therapeutic avenues. However, the breadth and complexity of its antitumor mechanisms have not yet been fully elucidated. In this review, we have systematically categorized QC's reported antitumor mechanisms from recent studies, to enable a deeper understanding of its antitumor activity. [ABSTRACT FROM AUTHOR]

Nowadays, the combined knowledge and experience in biomedical research and material sciences results in the innovation of smart materials that could efficiently overcome the problems of microbial contaminations. Herein, a new drug delivery platform prepared by grafting sodium alginate with β -carboxyethyl acrylate and acrylamide was described and characterized. 9-Aminoacridine (9-AA), and kanamycin sulfate (KS) were separately loaded into the hydrogel in situ during graft polymerization. The grafting efficiency for the resulting hydrogels was 70.01–78.08 %. The chemical structure of the hydrogels, thermogravimetric analysis, and morphological features were investigated. The swelling study revealed that the hydrogel without drugs achieved a superior swelling rate compared to drug-loaded hydrogels. The hydrogel tuned the drug-release rate in a pH-dependent manner. Furthermore, the antibacterial study suggested that the hydrogels encapsulating 9-AA (88.6 %) or KS (89.3 %) exhibited comparable antibacterial activity against Gram-positive and Gram-negative bacterial strains. Finally, the cytocompatibility study conducted on normal lung cell line (Vero cells) demonstrated neglectable to tolerable toxicity for the drug-loaded hydrogel. More interestingly, the cell viability for the blank hydrogel was 92.5 %, implying its suitability for biomedical applications. [ABSTRACT FROM AUTHOR]

In an attempt to develop effective and safe anticancer agents, we designed, synthesized and examined 23 novel quinacrine (QC) derivatives by combining the 9-aminoacridine scaffold and the [1,3]thiazinan-4-ones group. Most of these hybrids showed strong anticancer activities, among which 3-(3-(6-chloro-2-methoxyacridin-9-ylamino)propyl)-2-(thiophen-2-yl)-1,3-thiazinan-4-one ( 25 ; VR151 ) effectively killed many different cancer cell types, including eight breast cancer cell lines with different genetic background, two prostate cancer and two lung cancer cell lines. In contrast, compound 25 is less effective against non-cancer cells, suggesting it may be less toxic to humans. Our data showed that cancer cells are arrested in S phase for a prolonged period due to the down-regulation of DNA replication, leading to eventual cell death. We have also shown that the S phase arrest may be resulted by the down-regulation of cyclin A coupled with the continued up-regulation of cyclin E, which coincide with the down-regulation of mTor-S6K and mTor-4EBP1 pathways. [ABSTRACT FROM AUTHOR]

Both quinacrine, which contains a 9-aminoacridine scaffold, and thiazolidin-4-one are promising anticancer leads. In an attempt to develop effective and potentially safe anticancer agents, we synthesized 23 novel hybrid compounds by linking the main structural unit of the 9-aminoacridine ring with the thiazolidin-4-one ring system, followed by examination of their anticancer effects against three human breast tumor cell lines and matching non-cancer cells. Most of the hybrid compounds showed good activities, and many of them possessed the preferential killing property against cancer over non-cancer cells. In particular, 3-[3-(6-chloro-2-methoxy-acridin-9-ylamino)-propyl]-2-(2,6-difluoro-phenyl)-thiazolidin-4-one ( 11 ; VR118) effectively killed/inhibited proliferation of cancer cells at IC 50 values in the range of 1.2–2.4 μM. Furthermore, unlike quinacrine or cisplatin, compound 11 showed strong selectivity for cancer cell killing, as it could kill cancer cells 7.6-fold (MDA-MB231 vs MCF10A) to 14.7-fold (MCF7 vs MCF10A) more effectively than matching non-cancer cells. Data from flow cytometry, TUNEL and Western blot assays showed that compound 11 kills cancer cells by apoptosis through the down-regulation of Bcl-2 (but not Bcl-X L ) survival protein and up-regulation of Bad and Bax pro-apoptotic proteins. Thus, compound 11 is a highly promising lead for an effective and potentially anticancer therapy. [ABSTRACT FROM AUTHOR]

The interactions of dye molecules with gold nanoparticles are of great interest owing to the potential applications in the areas of bioimaging, sensing and photodynamic therapy applications. In many cases the distances between fluorophores and the metal particles can change during the experiment and the spectral features of the units are not taken into account. In this work, the fluorescence behaviour of two dyes with different spectral properties (Rhodamine B and 9-aminoacridine) are investigated in the presence of gold nanoparticles having diameters of 2 or 26 nm and hence different plasmonic properties. In order to fix the distance between the dye and the gold nanoparticles, the dyes are entrapped in 20 nm silica nanoparticles, and the metal colloids are adsorbed on the silica surface. The distance between the fluorescent units and the metal particles is tuned by growing additional silica layers on the pristine nanoparticles. Steady-state and time-resolved fluorescence measurements show that in the presence of gold nanoparticles, having 2 nm diameter, a drastic quenching of the dye emission is observed, for all the prepared samples, despite the average dye-metal distances. When gold nanoparticles with 26 nm diameters are used, their interactions with the dyes are strongly dependent on the averaged distances between the metal colloids and the dyes and on the overlap of their spectral properties. Indeed, an enhanced emission is observed for 9-aminoacridine while the fluorescence of longer wavelength emitting Rhodamine B is quenched. The steady state and time-resolved data are analysed to evaluate the plasmonic impact of the radiative and non-radiative rate constants of the dyes. [ABSTRACT FROM AUTHOR]

The influence of phenols upon the fluorescence quenching of 9-aminoacridine (9-AA) was examined in acetonitrile solution by employing steady state and time-resolved fluorescence measurements. On increasing the concentration of quencher molecules the absorption spectra of 9-AA change with significant bathochromic shift. The fluorescence intensity of 9-AA change in presence of quencher molecules were measured at various temperatures as a function of the quencher concentrations. The observed bimolecular quenching rate constant (kq) depends on the nature and electronic effect of substituent present in the quencher molecules. The bimolecular quenching rate constant (kq) decreases on increasing the oxidation potential of quencher molecules. To examine the quenching behavior, kq values were correlated with the free energy change (ΔG). To get forthcoming in the quenching process, fluorescence quenching experiments were carried out in different solvents of varying polarities. The observed result suggest the involvement of charge-transfer quenching mechanism. Lifetime measurements support static quenching. Further, the radical scavenging potential is calculated from density functional theory (DFT) calculations to address the quenching behavior of the quencher molecules. DFT result reveals that electronic features are important in tuning the quenching ability of the quencher molecules and found to agree with the obtained experiment result. [ABSTRACT FROM AUTHOR]

We report on a matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF) method to analyze naphthenic acids (NAs), from petrochemical samples, using 9-aminoacridine (9-AA) and a proton sponge 1,8-bis(dimethylamino) naphthalene (DMAN), as matrices. Singly charged deprotonated molecules of NAs, [M−H] − , dominated the negative ion MALDI mass spectra. The negative ions were pre-formed in solution through an acid/base Brönsted-Lowry reaction promoted by the highly basic matrices (9-AA and DMAN). The DMAN afforded cleaner spectra with absence of clusters, aggregates or matrix interferences at low m / z ; in addition, it provides molecular weight distributions similar to those observed with negative ion electrospray ionization (ESI). In contrast, MALDI spectra obtained with 9-AA exhibits matrix interferences at low mass, and bias towards aliphatic NAs. Finally, we observe the presence of monomeric species in the low mass region and non-covalent aggregates at higher masses in the negative mode MALDI spectra with both matrices, much like with negative mode ESI. We demonstrate that MALDI-TOF/MS is a viable tool for NAs analyses with added advantages such as high throughput and exceptional tolerance to the presence of impurities and salts in the samples, when compared with ESI. [ABSTRACT FROM AUTHOR]

The title complex salt, [Pt(C16H17N3)(NH3)2](NO3)2, is of interest with respect to anticancer activity. The secondary amine of 9-aminoacridine coordinates with the platinum(II) atom, leading to imine–platinum complex cation formation. The crystal structure displays extensive N—H...O and N—H...N hydrogen bonding and weak C—H...Cl and C—H...O hydrogen bonding.

A simple and fast method of lipid analysis of isolated intact mitochondria by means of MALDI-TOF mass spectrometry is described. Mitochondria isolated from bovine heart and yeast have been employed to set up and validate the new method of lipid analysis. The mitochondrial suspension is directly applied over the target and, after drying, covered by a thin layer of the 9-aminoacridine matrix solution. The lipid profiles acquired with this procedure contain all peaks previously obtained by analyzing the lipid extracts of isolated mitochondria by TLC and/or mass spectrometry. The novel procedure allows the quick, simple, precise, and accurate analysis of membrane lipids, utilizing only a tiny amount of isolated organelle; it has also been tested with intact membranes of the bacterium Paracoccus denitrificans for its evolutionary link to present-day mitochondria. The method is of general validity for the lipid analysis of other cell fractions and isolated organelles.

Alzheimer’s disease (AD) is a neurodegenerative disorder mostly influencing the elderly, and causes death due to dementia. The main pathogenic feature connected with the progression of this multifactorial disease is the weakening of the cholinergic system in the brain. Cholinesterase (ChE) inhibitors are recognized as one of the choices in the treatment of AD. The inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) were approved as a therapeutic strategy to reduce the symptoms of AD and prevent its progression. The capacity of BChE is not completely known yet; rather, it is accepted to assume a part in a few disorders such as AD. Thus, BChE inhibitors may have a greater role for the treatment of AD in the future. In the present study, 2-(9-acridinylamino)-2-oxoethyl piperazine/piperidine/morpholinecarbodithioate derivatives were synthesized in order to investigate anticholinesterase activity. Eight derivatives demonstrated a specific and promising action against BChE. Furthermore, compound 4n showed inhibitory activity against both enzymes. It was found that the active compounds were well tolerated in the cytotoxicity test. Possible interactions between the lead compound, 4n, and the BChE enzyme were determined through a docking study. The findings obtained within this paper will contribute to the development of new and effective synthetic anti-Alzheimer compounds, and will ideally encourage future screening against AD.

The present study found that, similarly to 5-fluorouracil, low concentrations (1-10 μM) of 9-aminoacridine (9-AAA) inhibited the growth of the two rat prostate cancer AT-2 and Mat-LyLu cell lines and the human melanoma A375 cell line. However, at the same concentrations, 9-AAA had no effect on the growth and apoptosis of normal human skin fibroblasts (HSFs). The differences between the cellular responses of the AT-2 and Mat-LyLu cell lines, which differ in malignancy, were found to be relatively small compared with the differences between normal HSFs and the cancer cell lines. Visible effects on the cell growth and survival of tumor cell lines were observed after 24-48 h of treatment with 9-AAA, and increased over time. The inhibition of cancer cell growth was found to be due to the gradually increasing number of cells dying by apoptosis, which was observed using two methods, direct counting and FlowSight analysis. Simultaneously, cell motile activity decreased to the same degree in cancer and normal cells within the first 8 h of incubation in the presence of 9-AAA. The results presented in the current study suggest that short-lasting tests for potential anticancer substances can be insufficient; which may result in cell type-dependent differences in the responses of cells to tested compounds that act with a delay being overlooked. The observed differences in responses between normal human fibroblasts and cancer cells to 9-AAA show the requirement for additional studies to be performed simultaneously on differently reacting cancer and normal cells, to determine the molecular mechanisms responsible for these differences. [ABSTRACT FROM AUTHOR]

This study investigated the effect of CpG methylation on the DNA binding of cisplatin analogues with an attached aminoacridine intercalator. DNA-targeted 9-aminoacridine carboxamide Pt complexes are known to bind at 5′-CpG sequences. Their binding to methylated and non-methylated 5′-CpG sequences was determined and compared with cisplatin. The damage profiles of each platinum compound were quantified via a polymerase stop assay with fluorescently labelled primers and capillary electrophoresis. Methylation at 5′-CpG was shown to significantly increase the binding intensity for the 9-aminoacridine carboxamide compounds, whereas no significant increase was found for cisplatin. 5′-CpG methylation had the largest effect on the 9-ethanolamine-acridine carboxamide Pt complex, followed by the 9-aminoacridine carboxamide Pt complex and the 7-fluoro complex. The methylation state of a cell’s genome is important in maintaining normal gene expression, and is often aberrantly altered in cancer cells. An analogue of cisplatin which differentially targets methylated DNA may be able to improve its therapeutic activity, or alter its range of targets and evade the chemoresistance which hampers cisplatin efficacy in clinical use. [ABSTRACT FROM AUTHOR]

Our synthetic approach demonstrates that pyridine-2,6-dicarboxylic acid N -oxide can form a stable Fe III complex with the rare 1:3 metal-to-ligand ratio. This study provides more information about packing features of one crystalline compound, (H9a-acr) 3 [Fe(pydco) 3 ]·6H 2 O ( 1 ) (where H 2 pydco = pyridine-2,6-dicarboxylic acid N -oxide and 9a-acr = 9-aminoacridine) via proton transfer methodology. The structure of 1 was characterized by IR spectroscopy, X-ray diffraction methods and the elemental analysis was performed to check the purity of the compound. On the basis of crystallographic data, compound 1 contains a monomeric anion with distorted octahedral geometry. The metal center is coordinated to six oxygen atoms by three bidentate pyridine-2,6-dicarboxylic acid N -oxide ligands to form a ceiling fan-shaped entity in which only the N -oxide oxygen and one carboxylate oxygen generate a six-membered chelate ring as seen for other N -oxides. Furthermore, the [Fe(pydco) 3 ] 3− and (9a-acr) + units in 1 form 2D anionic and cationic layers. The intermolecular interactions in this novel system consist of electrostatic attraction between ion pairs, different kinds of H-bonding and π-stacking all of which join the 2D layers to create 3D supramolecular architectures. Since pyridine-2,6-dicarboxylic acid N -oxide and pyridine-2,6-dicarboxylic acid have similar frameworks, we also highlighted some areas of current interest in the coordination behavior of the latter ligand in mononuclear monomeric compounds in the reported structures up to now and investigated the influence of the N -oxide moiety on the coordination mode(s) in the crystal lattice as well. [ABSTRACT FROM AUTHOR]

Application of matrix-assisted laser-desorption/ionization mass spectrometry (MALDI MS) to analyze small molecules have some limitations, due to the inhomogeneous analyte/matrix co-crystallization and interference of matrix-related peaks in low m/z region. In this work, carbon dots (CDs) were for the first time applied as a binary matrix with 9-Aminoacridine (9AA) in MALDI MS for small molecules analysis. By 9AA/CDs assisted desorption/ionization (D/I) process, a wide range of small molecules, including nucleosides, amino acids, oligosaccharides, peptides, and anticancer drugs with a higher sensitivity were demonstrated in the positive ion mode. A detection limit down to 5 fmol was achieved for cytidine. 9AA/CDs matrix also exhibited excellent reproducibility compared with 9AA matrix. Moreover, by exploring the ionization mechanism of the matrix, the influence factors might be attributed to the four parts: (1) the strong UV absorption of 9AA/CDs due to their π-conjugated network; (2) the carboxyl groups modified on the CDs surface act as protonation sites for proton transfer in positive ion mode; (3) the thin layer crystal of 9AA/CDs could reach a high surface temperature more easily and lower transfer energy for LDI MS; (4) CDs could serve as a matrix additive to suppress 9AA ionization. Furthermore, this matrix was allowed for the analysis of glucose as well as nucleosides in human urine, and the level of cytidine was quantified with a linear range of 0.05-5 mM (R > 0.99). Therefore, the 9AA/CDs matrix was proven to be an effective MALDI matrix for the analysis of small molecules with improved sensitivity and reproducibility. This work provides an alternative solution for small molecules detection that can be further used in complex samples analysis. [ABSTRACT FROM AUTHOR]

The DNA-damage response (DDR) protects the genome from various types of endogenous and exogenous DNA damage, and can itself be a target of certain chemicals that give rise to chromosomal aberrations. Here, we developed a screening method to detect inhibition of Mediator of DNA damage Checkpoint 1 (MDC1) foci formation (the Enhanced Green Fluorescent Protein (EGFP)-MDC1 foci formation-inhibition assay) using EGFP-MDC1-expressing human cells. The assay identified propyl gallate (PG) and 9-aminoacridine (9-AA) as inhibitors of camptothecin (CPT)-induced MDC1 foci formation. We demonstrated that the inhibition of CPT-induced MDC1 foci formation by PG was caused by the direct suppression of histone H2AX phosphorylation at Ser139 (γH2AX), which is required for MDC1 foci formation, by quantifying cH2AX in cells and in vitro. 9-AA also directly suppressed H2AX Ser139-phosphorylation in vitro but the concentration was much higher than that required to suppress CPT-induced MDC1 foci formation in cells. Consistent with these findings, PG and 9-AA both suppressed CPT-induced G2/M cell-cycle arrest and increased the number of abnormal nuclei. Our results suggest that early DDR-inhibitory effects of PG and 9-AA contribute to their chromosome-damaging potential, and that the EGFP-MDC1 foci formation-inhibition assay is useful for detection of and screening for H2AX Ser139-phosphorylation-inhibitory effects of chemicals. [ABSTRACT FROM AUTHOR]

Quinacrine (QC) causes apoptosis in breast cancer cells by induction of DNA damage, arrest of cells in S-phase, and by topoisomerase inhibition. Here, we show that QC-mediated apoptosis is not only due to increased DNA damage but also by compromising cell cycle checkpoints and base excision repair (BER) capacity in breast cancer cells. QC decreased CHK1, CDKs (CDC2, MDM2, CDC6), cyclins (B1, E1) and CDC25-A in a dose dependent manner. The expression of basal ATR remains unaltered but pATR (Ser-428) increased after QC treatment. A CHK1 inhibitor , SB218078, was also tested alone and in combination with QC. Like QC, SB218078 caused apoptosis by DNA damage and S-phase arrest. The combination of QC and SB218078 increased apoptosis by blocking the cell cycle in G2/M, which caused a mitotic catastrophe, and induced DNA damage at a higher level in comparison to individual compound treatments. Both drugs individually or in combination decreased the levels of replication protein A (RPA). Measurement of the expression of BER (SP- and LP-BER) proteins and direct in vivo BER activity revealed that the QC/SB218078 combination caused apoptosis in cancer cells by disrupting the induction of BER, which represents a novel means of potentially treating breast cancer. [ABSTRACT FROM AUTHOR]

Four new supramolecular coordination complexes and salts based on proton-transferred pyridine-2,6-dicarboxylic acid N-oxide formulated as (Htata)(Hpydco)·HO ( 1), (Htata)(pydco)·2HO ( 2), (H9a-acr)[Zn(pydco)(HO)]·4HO ( 3), and (H9a-acr)[Co(pydco)(HO)]·4HO ( 4) (where Hpydco = pyridine-2,6-dicarboxylic acid N-oxide, tata = 2,4,6-triamino-1,3,5-triazine (melamine) and 9a-acr = 9-aminoacridine) have been synthesized by proton transfer from Hpydco as ligand and to tata and 9a-acr. The structures of 1- 4 were characterized by elemental analysis, infrared spectroscopy, and single crystal X-ray diffraction methods. Compounds 1 and 2 are salts of proton-transferred Hpydco and melamine with two separate formulas. There is a difference between the anionic fragment in 1 and 2, the anionic part of 1 retains one acid proton (Hpydco) which is involved in a strong, intramolecular hydrogen bonding with the oxygen attached to nitrogen, while the acid units in 2 are fully deprotonated (pydco). The linear chains of melaminium cations with an anionic motif and water molecules lead to 2-D zipper layers in 1 and 2-D zigzag layers in 2. These layers are held together via an extensive network of hydrogen bonds, π-π stacking, N-H⋯π, and lp⋯π interactions to extend the structures into the 3-D supramolecular framework. Single-crystal studies revealed that 3 and 4 are isostructural with distorted octahedral geometry about the metal consisting of two pydco ligands acting in bidentate fashion and two trans-disposed water molecules. They also adopt alternating cationic and anionic layers with 9-aminoacridinium cations and transition metal complex anions which are linked to each other by a variety of noncovalent interactions such as ion pairing, hydrogen bonding and π-π stacking. [ABSTRACT FROM AUTHOR]

We herein developed a novel colorimetric polydiacetylene (PDA) sensor for very convenient detection of clinical DNA samples based on the interaction between an intercalator and dsDNA. We modified the terminal carboxyl group of a diacetylene monomer (10,12-pentacosadiynoic acid; PCDA) with the intercalator 9-aminoacridine (9AA) and prepared 9AA-modified PDA liposomes containing PCDA-9AA/PCDA/phospholipid (1,2-dimyristoyl-rac-glycero-3-phosphocholine) at a molar ratio of 1.5:6.5:2.0. The PDA sensor underwent an obvious color transition from blue to red in the presence of dsDNA molecules that were PCR-amplified from genomic DNA due to the insertion of the 9AA head group of PDA into the dsDNA. DNA concentrations as low as 20 nM and relatively small molecules (around 100 base pairs) could be detected by the sensor within 1 h without DNA electrophoresis. This novel colorimetric method is simple, does not require any instrument, and is therefore appropriate for POCT or portable molecular diagnostic kit. [ABSTRACT FROM AUTHOR]

Background: Lipids play different important roles in central nervous system so that dysregulation of lipid pathways has been implicated in a growing number of neurodegenerative disorders including multiple sclerosis (MS). MS is the most prevalent autoimmune disorder of the central nervous system, with neurological symptoms caused by inflammation and demyelination. In this study, a lipidomic analysis was performed for the rapid profile of CD4(+) T lymphocytes from MS patient and control samples in an untargeted approach.Methods: A matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry based approach was used for the analysis of lipid extracts using 9-aminoacridine as matrix. Lipids were analyzed in negative mode and selected species fragmented using MALDI tandem mass spectrometry for their structural assignments.Results: The analysis reveals some modifications in the phospholipid pattern of MS CD4(+) T lymphocytes with respect to healthy controls with a significant increase of cardiolipin species in MS samples.Conclusions: These results demonstrate the feasibility of a MALDI-TOF approach for the analysis of CD4(+) lipid extracts and suggest how alterations in the lipid metabolism characterized lymphocytes of MS patients. [ABSTRACT FROM AUTHOR]

Background: Lipids play different important roles in central nervous system so that dysregulation of lipid pathways has been implicated in a growing number of neurodegenerative disorders including multiple sclerosis (MS). MS is the most prevalent autoimmune disorder of the central nervous system, with neurological symptoms caused by inflammation and demyelination. In this study, a lipidomic analysis was performed for the rapid profile of CD4+ T lymphocytes from MS patient and control samples in an untargeted approach. Methods: A matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry based approach was used for the analysis of lipid extracts using 9-aminoacridine as matrix. Lipids were analyzed in negative mode and selected species fragmented using MALDI tandem mass spectrometry for their structural assignments. Results: The analysis reveals some modifications in the phospholipid pattern of MS CD4+ T lymphocytes with respect to healthy controls with a significant increase of cardiolipin species in MS samples. Conclusions: These results demonstrate the feasibility of a MALDI-TOF approach for the analysis of CD4+ lipid extracts and suggest how alterations in the lipid metabolism characterized lymphocytes of MS patients. [ABSTRACT FROM AUTHOR]

9-Aminoacridinium dodecyl sulfate, a salt consisting of a cationic dye and an anionic surfactant, was synthesized and structurally characterized. In the crystal packing, dodecyl sulfate anions interact via weak C–H⋯O hydrogen bonds and van der Waals interactions to form monolayers. These monolayers have a corrugated surface in which shallow and deep grooves are distinguishable. 9-Aminoacridinium cations form π-stacking columns, which are located in these grooves, and interact with dodecyl sulfate monolayers via N–H⋯O and C–H⋯O hydrogen bonds. The monolayers of dodecyl sulfate ions observed in the crystal structure of the title compound represent a new type of self-assembled monolayers of this surfactant in the crystals. [ABSTRACT FROM AUTHOR]

In this study, the DNA sequence specificity of four DNA-targeted 9-aminoacridine carboxamide Pt complexes was compared with cisplatin, using two specially constructed plasmid templates. One plasmid contained 5′-CG and 5′-GA insert sequences while the other plasmid contained a G-rich transferrin receptor gene promoter insert sequence. The damage profiles of each compound on the different DNA templates were quantified via a polymerase stop assay with fluorescently labelled primers and capillary electrophoresis. With the plasmid that contained 5′-CG and 5′-GA dinucleotides, the four 9-aminoacridine carboxamide Pt complexes produced distinctly different damage profiles as compared with cisplatin. These 9-aminoacridine complexes had greatly increased levels of DNA damage at CG and GA dinucleotides as compared with cisplatin. It was shown that the presence of a CG or GA dinucleotide was sufficient to reveal the altered DNA sequence selectivity of the 9-aminoacridine carboxamide Pt analogues. The DNA sequence specificity of the Pt complexes was also found to be similarly altered utilising the transferrin receptor DNA sequence. [ABSTRACT FROM AUTHOR]

The solid-state structures of the complexes of calix[4]arenediphosphonic acid with piroxicam and 9-aminoacridine are described, in both cases, the classical interdigitated dimer formed by calix[4]arenediphosphonic acid is no longer present. For the 9-aminoacridine complex, a π-π stacked dimer of 9-aminoacridine is surrounded by calix[4]arenediphosphonic acid molecules with dimethyl sulfoxide included in the calix arene cavity. In the case of the piroxicam complex the piroxicam molecule forms a true inclusion complex and the pyridinium ring projects out to hydrogen bond to an opposing calix[4]arenediphosphonic acid, thus spanning the bilayer. Graphical Abstract: The structures of the complexes of calix[4]arenediphosphonic acid with piroxicam and 9-aminoacridine show a breakdown in the classical interdigated calix-arene dimer with formation of trus inclusion complexes and exo-complexation.[Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Highlights: [•] Discovery of a G-quadruplex forming sequence in the promoter sequence of Nrf2. [•] Characterisation of the G-quadruplex by UV, CD and NMR. [•] Conformational switching of G-quadruplex induced by 9-aminoacridine. [Copyright &y& Elsevier]

The current study aims to determine the genotoxic and antigenotoxic potential of four newly synthesized dihydropyridine derivatives using Escherichia coli WP2 and Ames/Salmonella bacterial reversion assay systems. The bacterial mutant tester strains, E. coli WP2uvrA with a point mutation and Salmonella typhimurium TA1537 with a frameshift mutation, were used to determine genotoxic potentials of the test compounds. To determine antigenotoxic potentials of the test compounds, the same strains were also used together with positive mutagens N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) for E. coli WP2uvrA and 9-aminoacridine (9-AA) for S. typhimurium TA1537. According to the results, neither of the test compounds showed significant genotoxic activity on both tester strains at the tested concentrations. However, except compound 4, all the test compounds showed significant antigenotoxic activity on MNNG- or/and 9-AA-induced mutations. The inhibition rates of mutagenesis ranged from 27.0% (compound 2: 2.5 mM/plate) to 65.0% (compound 2: 0.5 mM/plate) for MNNG and from 30.6% (compound 2: 2 mM/plate) to 58.5% (compound 1: 1 mM/plate) for 9-AA genotoxicity. According to these results, it is concluded that all the test compounds do not have a mutagenic potential on the bacterial strains at the tested concentrations, and some of them have antigenotoxic potentials against MNNG- and 9-AA-induced mutagenesis. [ABSTRACT FROM PUBLISHER]

5-Aminouracil (5-AU) is a readily available yet underutilized starting material for the synthesis of labelled nucleobase analogues. We have prepared the derivative of 5-AU with the amine-reactive chromophore 9-chloroacridine for the purpose of investigating its potential as a base-discriminating fluorophore. 9-Chloroacridine readily undergoes substitution by reaction with 5-AU to yield a fluorescent nucleobase that after standard manipulations produced a monomer suitable for incorporation into peptide nucleic acid (PNA) by fluorenylmethyloxycarbonyl (Fmoc)-based oligomerization chemistry. Although the monomer was stable in organic solvents, once incorporated into an oligomer the 5-substitution was found to be thermally labile and hydrolyzed to a small degree in neutral aqueous solution during study of its hybridization to cDNA. We have determined that 5-(acridin-9-ylamino)uracil and related derivatives produce the highly fluorescent acridone and 5-AU by hydrolysis in water. [ABSTRACT FROM AUTHOR]

Highlights: [•] New binary matrix for less ionizable lipid analysis with no interfering peaks. [•] Combined MALDI and X-ray photoelectron spectroscopy (XPS) analyses. [•] Fast lipid fingerprint on Gram positive and Gram negative bacteria by MALDI MS. [•] Mapping of phospholipids by XPS imaging. [•] Very fast membrane lipid extraction procedure. [ABSTRACT FROM AUTHOR]

Highlights: [•] Three supramolecular compounds of Zn(II), Ni(II) and U(IV) have been prepared. [•] The Zn (II) and Ni(II) centers are distorted octahedral but the U(IV) center is hexagonal bipyramidal. [•] All of the compounds are studied both in the solid state and solution. [•] The cyclic-linear water clusters are presented in compounds 1 and 3. [•] The interaction of C–O⋯π and π–π was observed in the three-dimensional supramolecular networks. [Copyright &y& Elsevier]

Inflammation plays an important role in the development of rheumatoid arthritis (RA). NR4A1 is an anti-inflammatory orphan nuclear receptor involved in protection from inflammatory stimuli in RA. In this study we have explored the anti-inflammatory potential of the FDA-approved drug 9-aminoacridine (9AA) and the natural compound caffeic acid (CA) conjugated to nanomicelles for the treatment of RA. We have synthesized methoxy polyethylene glycol polycaprolactone block copolymer (mPEG- b -PCL) by ring opening polymerization of ε-caprolactone. Then, we conjugated the hydrophilic caffeic acid (CA) with mPEG- b -PCL micelles via Steglich esterification and incorporated the 9AA drug. These nanomicelles were formulated by the solvent evaporation method with a size distribution around 190 nm and showed maximum drug loading capacity along with sustained drug release behavior. Furthermore, we tested the therapeutic potential of the formulated 9AA-encapsulated CA-conjugated nanomicelles (9AA-NMs) against an experimental RA model. We observed promising results which showed alleviation of arthritic symptoms by reducing inflammation, joint damage, bone erosion, and swelling. Further, collagen destruction was significantly reduced in articular cartilage, as shown by safranin-O and toluidine blue staining. The protective mechanism might be due to the simultaneous inhibition of NF-κB by 9AA and CA, whereas the activation of NR4A1 by 9AA leads to the suppression of HIF-1α. This combined therapeutic effect of 9AA and CA has enhanced the therapeutic efficacy of 9AA-NM and markedly reduced the severity of inflammatory arthritis. Unlike existing drugs for pain management and with limited efficacy, 9AA-NM exerted a disease-relevant activation/blockade that alleviated inflammation and exhibited marked therapeutic efficacy against RA.

Abstract: 9-Aminoacridine (9-AA) is an important attractive pharmaceutical drug employed as chemotheraptic agent for wound dressings. However, 9-AA possesses limited solubility and rapid metabolic decomposition renders this potential drug to limit its applications. Here we propose cyclodextrins (CDs) as a drug carrier to improve the bioavailability, solubility of 9-AA. The interaction between 9-AA and CDs (α-CD and β-CD) has been studied using UV–Vis absorption, steady state time resolved fluorescence, 1H NMR and FT-IR spectroscopy techniques. The spectroscopic measurements show that 9-AA does not form stable complex with α-CD and also confirmed by DFT calculations. On the other hand, 9-AA forms inclusion complex with β-CD in a 1:1 stoichiometry ratio. Our DFT results suggest that 9-AA stabilizes inside the CD environment through hydrogen bonding that has unambiguously confirmed by AIM analysis. Thus our studies provide a useful insights in the development of Aminoacridine based drugs & its delivery through a suitable carrier like CDs. [Copyright &y& Elsevier]

Abstract: Novel 9-aminoacridine derivatives were synthesized by linking the heteroaromatic core to different cinnamic acids through an aminobutyl chain. The test compounds demonstrated mid-nanomolar in vitro activity against erythrocytic stages of the chloroquine-resistant W2 strain of the human malaria parasite Plasmodium falciparum. Two of the most active derivatives also showed in vitro activity against liver-stage Plasmodium berghei, with activity greater than that of the reference liver-stage antimalarial primaquine. The compounds were not toxic to human hepatoma cells at concentrations up to 5μM. Hence, 9-(N-cinnamoylbutyl)aminoacridines are a new class of leads for prevention and treatment of malaria. [Copyright &y& Elsevier]

Abstract: Acridine and its derivatives, well known as DNA intercalates lead to cell cycle arrest and apoptosis. 9-Aminoacridine derivatives were synthesized, characterized and evaluated against lung cancer (A-549) cell line and cervical cancer (HeLa) cell line by MTT assay. Compound 9 exhibited potent anticancer activity with CTC50 (13.75 & 18.75μg/ml) for cervical cancer cell (HeLa) line and lung cancer cell (A-549) line respectively. In vitro short term cytotoxicity evaluation of compound 9 was carried out by Dalton’s Lymphoma Ascites (DLA) with percentage growth inhibition CTC50 (337.5μg/ml). Compound 7 also exhibited good anticancer activity with CTC50 (31.25 & 36.25μg/ml) for cervical cancer cell (HeLa) line and lung cancer cell (A-549) line respectively. Further in vivo study of newly synthesized 9-aminoacridine derivative can give a ray of light in the field of anticancer drugs. [Copyright &y& Elsevier]

Abstract: The fluorescence quenching of 9-Aminoacridine (9-AA) by various dyes were probed in aqueous medium using steady state and time resolved fluorescence spectroscopic techniques. From these techniques, we had rationalized the interaction of 9-AA with various dyes via ground state complex formation. The binding constant (K) and number of binding sites (n) were calculated from the relevant fluorescence quenching data. The fluorescence emission of 9-Aminoacridine was quenched by the dyes through static quenching followed by the mechanism of energy transfer. The static quenching mechanism was confirmed by lifetime measurements. The thermodynamic parameters such as free energy change (ΔG), enthalpy change (ΔH) and entropy change (ΔS), were calculated by thermodynamic equations. The results showed that Van der Waals interaction or hydrogen bond formation played a major role in the binding of 9-AA with these dyes. [Copyright &y& Elsevier]

The fluorescence quenching of 9-aminoacridine by certain biologically important catechols and rutin was investigated using absorption, steady state and time resolved fluorescence measurements. The in vitro-antioxidant activities of the above compounds were studied using deoxyribose degradation assay and nitric oxide scavenging assay. The experimental results showed that the fluorescence of 9-aminoacridine was quenched by quencher molecules via forming ground state complex. The bimolecular quenching rate constant k, binding constant (K) and number of binding sites (n) were calculated at different temperatures from relevant fluorescence data. Static quenching mechanism was supported by lifetime measurement. The free energy change (ΔG) for electron transfer process was calculated by Rehm-Weller equation. The binding distance of 4-nitrocatechol with 9-aminoacridine was obtained according to Forster's non-radiative energy transfer theory. Nature of binding forces and their interactions was probed based on thermodynamic parameters. [ABSTRACT FROM AUTHOR]

Abstract: Two new kinds of electrochemical sensors were prepared using glassy carbon electrodes modified with poly(9-aminoacridine) (PAA) and PAA-functionalized multi-walled carbon nanotubes (PAA-MWCNTs) for the determination of tryptophan (Trp) in the presence of tyrosine (Tyr). The electrocatalytic response of the modified electrodes towards electrooxidation of Trp and Tyr was investigated and compared by cyclic voltammetry (CV) and differential pulse voltammetry (DPV). The surface of the modified electrodes was characterized using CV, scanning electron microscopy, scanning-tunneling microscopy and scanning-tunneling spectroscopy. The anodic peak current of the electrooxidation of Trp on PAA-MWCNTs electrode was 5.5-fold increased comparing to PAA modified electrode. The anodic peak potential of Trp is shifted about 0.12V to more negative value indicated that PAA-MWCNTs electrode has better electrocatalytic activity for electrooxidation of Trp. Furthermore, the anodic peak current which was attributed to the electrooxidation of Trp did almost not change with the addition of Tyr in buffer solution at pH 3.5. Besides this, at pH 7.4, the anodic peak current obtained at 0.6V increased as the concentration of Tyr was increased. The results demonstrate that PAA-MWCNTs electrode can be used for the simultaneous determination of Trp and Tyr by adjusting the pH of the solution. [Copyright &y& Elsevier]

Abstract: The fluorescence quenching of 9-Aminoacridine by certain estrogens and flavonoids in water was studied using absorption, steady state and time-resolved measurements. The bimolecular quenching rate constants for the chosen estrogens and flavonoids were found to be in the range of 3.2–9.2×1011 and 0.36–14.46×1011 M−1s−1, respectively. From lifetime measurement we observed that the quenching was mainly due to static mechanism through ground state complex formation. The binding constant (K) and the number of binding sites (n) were calculated based on the fluorescence quenching data. The free energy change (ΔG et) for electron transfer process was calculated by Rehm–Weller equation. [Copyright &y& Elsevier]