-
Journal of Oleo Science Mar 2023Novel acridinium esters containing several methyl groups, at least one of which is in the 1 or 8-position, have been synthesized and their structures established. The...
Novel acridinium esters containing several methyl groups, at least one of which is in the 1 or 8-position, have been synthesized and their structures established. The influence of the methyl substituents on the chemiluminescent properties of the synthesized acridinium esters has been investigated.
Topics: Luminescent Measurements; Esters; Acridines
PubMed: 36908180
DOI: 10.5650/jos.ess22327 -
Molecules (Basel, Switzerland) May 2021In order to improve pharmaceutical properties of drugs, complexes are synthesized as combinations with other chemical substances. The complexes of fenamic acid and its...
In order to improve pharmaceutical properties of drugs, complexes are synthesized as combinations with other chemical substances. The complexes of fenamic acid and its derivatives, such as mefenamic-, tolfenamic- and flufenamic acid, with acridine were obtained and the X-ray structures were discussed. Formation of the crystals is determined by the presence of the intermolecular O-HN hydrogen bond that occur between fenamic acids and acridine. Intermolecular interactions stabilizing the crystals such as ππ stacking, C-HX (X = O, Cl) intermolecular hydrogen bonds as well as C-Hπ and other dispersive interactions were analyzed by theoretical methods: the quantum theory of atoms in molecules (QTAIM) and noncovalent interaction (NCI) approaches.
Topics: Acridines; Crystallography, X-Ray; Heterocyclic Compounds; Hydrogen Bonding; Models, Molecular; Molecular Structure; Quantum Theory; ortho-Aminobenzoates
PubMed: 34065674
DOI: 10.3390/molecules26102956 -
Journal of Oleo Science 2021Methyl groups were introduced on the acridine moiety in chemiluminescent acridinium esters that have electron-withdrawing groups (trifluoromethyl, cyano, nitro,...
Methyl groups were introduced on the acridine moiety in chemiluminescent acridinium esters that have electron-withdrawing groups (trifluoromethyl, cyano, nitro, ethoxycarbonyl) at the 4-position on the phenyl ester. The introduction of methyl groups at the 2-, 2,7-, and 2,3,6,7-positions on the acridine moiety shifted the optimal pH that gave relatively strong chemiluminescence intensity from neutral conditions to alkaline conditions. 4-(Ethoxycarbonyl)phenyl 2,3,6,7,10-pentamethyl-10λ-acridine-9-carboxylate, trifluoromethanesulfonate salt showed long-lasting chemiluminescence under alkaline conditions. Acridinium esters to determine hydrogen peroxide concentration at pH 7-10 were newly developed.
Topics: Acridines; Electrons; Esters; Hydrogen Peroxide; Hydrogen-Ion Concentration; Luminescence
PubMed: 34732638
DOI: 10.5650/jos.ess21186 -
Chemical Research in Toxicology Nov 2015The cellular recognition and processing of monofunctional-intercalative DNA adducts formed by [PtCl(en)(L)](NO3)2 (P1-A1; en = ethane-1,2-diamine; L =...
The cellular recognition and processing of monofunctional-intercalative DNA adducts formed by [PtCl(en)(L)](NO3)2 (P1-A1; en = ethane-1,2-diamine; L = N-[2-(acridin-9-ylamino)ethyl]-N-methylpropionamidine, acridinium cation), a cytotoxic hybrid agent with potent anticancer activity, was studied. Excision of these adducts and subsequent DNA repair synthesis were monitored in plasmids modified with platinum using incubations with mammalian cell-free extract. On the basis of the levels of [α-(32)P]-dCTP incorporation, P1-A1-DNA adducts were rapidly repaired with a rate approximately 8 times faster (t1/2 ≈ 18 min at 30 °C) than the adducts (cross-links) formed by the drug cisplatin. Cellular responses to P1-A1 and cisplatin were also studied in NCI-H460 lung cancer cells using immunocytochemistry in conjunction with confocal fluorescence microscopy. At the same dose, P1-A1, but not cisplatin, elicited a distinct requirement for DNA double-strand break repair and stalled replication fork repair, which caused nuclear fluorescent staining related to high levels of MUS81, a specialized repair endonuclease, and phosphorylated histone protein γ-H2AX. The results confirm previous observations in yeast-based chemical genomics assays. γ-H2AX fluorescence is observed as a large number of discrete foci signaling DNA double-strand breaks, pan-nuclear preapoptotic staining, and unique circularly shaped staining around the nucleoli and nuclear rim. DNA cleavage assays indicate that P1-A1 does not act as a typical topoisomerase poison, suggesting the high level of DNA double-strand breaks in cells is more likely a result of topoisomerase-independent replication fork collapse. Overall, the cellular response to platinum-acridines shares striking similarities with that reported for DNA adduct-forming derivatives of the drug doxorubicin. The results of this study are discussed in light of the cellular mechanism of action of platinum-acridines and their ability to overcome resistance to cisplatin.
Topics: Acridines; Cell Line, Tumor; DNA; DNA Adducts; DNA Damage; DNA Repair; DNA Topoisomerases, Type I; Humans; Organoplatinum Compounds
PubMed: 26457537
DOI: 10.1021/acs.chemrestox.5b00327 -
Chembiochem : a European Journal of... Jan 2015Fluorogenic enzyme probes go from a dark to a bright state following hydrolysis and can provide a sensitive, real-time readout of enzyme activity. They are useful for...
Fluorogenic enzyme probes go from a dark to a bright state following hydrolysis and can provide a sensitive, real-time readout of enzyme activity. They are useful for examining enzymatic activity in bacteria, including the human pathogen Mycobacterium tuberculosis. Herein, we describe two fluorogenic esterase probes derived from the far-red fluorophore 7-hydroxy-9H-(1,3-dichloro-9,9-dimethylacridin-2-one) (DDAO). These probes offer enhanced optical properties compared to existing esterase probes because the hydrolysis product, DDAO, excites above 600 nm while retaining a good quantum yield (ϕ=0.40). We validated both probes with a panel of commercially available enzymes alongside known resorufin- and fluorescein-derived esterase substrates. Furthermore, we used these probes to reveal esterase activity in protein gel-resolved mycobacterial lysates. These probes represent new tools for esterase detection and characterization and should find use in a variety of applications.
Topics: Acridines; Bacterial Proteins; Biological Transport; Esterases; Fluorescent Dyes; Fungal Proteins; Fungi; Gram-Negative Bacteria; Gram-Positive Bacteria; Hydrolysis; Limit of Detection; Lipase; Molecular Structure; Spectrometry, Fluorescence; Stereoisomerism; Structure-Activity Relationship; Substrate Specificity
PubMed: 25469918
DOI: 10.1002/cbic.201402548 -
ACS Infectious Diseases Feb 2022During infection, bacteria use an arsenal of resistance mechanisms to negate antibiotic therapies. In addition, pathogenic bacteria form surface-attached biofilms...
During infection, bacteria use an arsenal of resistance mechanisms to negate antibiotic therapies. In addition, pathogenic bacteria form surface-attached biofilms bearing enriched populations of metabolically dormant persister cells. Bacteria develop resistance in response to antibiotic insults; however, nonreplicating biofilms are innately tolerant to all classes of antibiotics. As such, molecules that can eradicate antibiotic-resistant and antibiotic-tolerant bacteria are of importance. Here, we report modular synthetic routes to fluorine-containing halogenated phenazine (HP) and halogenated acridine (HA) agents with potent antibacterial and biofilm-killing activities. Nine fluorinated phenazines were rapidly accessed through a synthetic strategy involving (1) oxidation of fluorinated anilines to azobenzene intermediates, (2) SAr with 2-methoxyaniline, and (3) cyclization to phenazines upon treatment with trifluoroacetic acid. Five structurally related acridine heterocycles were synthesized using SAr and Buchwald-Hartwig approaches. From this focused collection, phenazines , , , and acridine demonstrated potent antibacterial activities against Gram-positive pathogens (MIC = 0.04-0.78 μM). Additionally, and eradicated , and biofilms with excellent potency (, MBEC = 4.69-6.25 μM; , MBEC = 4.69-50 μM). Using real-time quantitative polymerase chain reaction (RT-qPCR), , , , and rapidly induce the transcription of iron uptake biomarkers and in methicillin-resistant (MRSA) biofilms, and we conclude that these agents operate through iron starvation. Overall, fluorinated phenazine and acridine agents could lead to ground-breaking advances in the treatment of challenging bacterial infections.
Topics: Acridines; Anti-Bacterial Agents; Biofilms; Fluorine; Iron; Methicillin-Resistant Staphylococcus aureus; Phenazines
PubMed: 35089005
DOI: 10.1021/acsinfecdis.1c00402 -
Chemistry (Weinheim An Der Bergstrasse,... Oct 2021To study the DNA damage caused by a potent platinum-acridine anticancer agent (PA) in cancer cells, an assay based on biorthogonal post-labeling using a click...
DNA Adduct Detection after Post-Labeling Technique with PCR Amplification (DNA-ADAPT-qPCR) Identifies the Pre-ribosomal RNA Gene as a Direct Target of Platinum-Acridine Anticancer Agents.
To study the DNA damage caused by a potent platinum-acridine anticancer agent (PA) in cancer cells, an assay based on biorthogonal post-labeling using a click chemistry-enabled, azide-modified derivative (APA) was developed. The method involves biotinylation, affinity capture, and bead-based enrichment of APA-modified genomic DNA. The key steps of the assay were validated and optimized in model duplexes, including full-length plasmids, restriction fragments, and a DNA ladder. Native DNA treated with APA and subsequently subjected to post-labeling with a biotin affinity tag was enzymatically digested and fragments were analyzed by in-line LC-MS and MS/MS. The monofunctional-intercalative adducts formed by APA in 5'-pyrimidine/guanine sequences in double-stranded DNA were quantitatively biotinylated by strain-promoted 1,3-dipolar cycloaddition chemistry. When applied to DNA extracted from A549 lung cancer cells, the assay in combination with qPCR amplification demonstrates that platinum-acridines form adducts in the gene sequences encoding pre-ribosomal RNA, a potential pharmacological target of these agents.
Topics: Acridines; Antineoplastic Agents; DNA; DNA Adducts; Genes, rRNA; Platinum; Polymerase Chain Reaction; Tandem Mass Spectrometry
PubMed: 34375484
DOI: 10.1002/chem.202102263 -
The Biochemical Journal Aug 19661. The effect of proflavine on the metabolism of RNA, DNA and protein of HeLa cells was studied. 2. The synthesis of RNA, DNA and protein was progressively inhibited by...
1. The effect of proflavine on the metabolism of RNA, DNA and protein of HeLa cells was studied. 2. The synthesis of RNA, DNA and protein was progressively inhibited by concentrations of proflavine up to 43mum. 3. There was no simple relationship between the degrees of inhibition of synthesis of RNA, DNA and protein by increasing concentrations of proflavine: the synthesis of RNA was most readily inhibited, and the synthesis of protein was relatively insensitive. 4. A concentration of 22mum-proflavine inhibited synthesis of RNA and DNA and caused a progressive loss of RNA from both nucleus and cytoplasm without any accompanying loss of DNA or dry weight from the cells. 5. The rapidly labelled RNA in the nucleus was preferentially degraded and was not transferred in a stable form to the cytoplasm.
Topics: Acridines; Animals; Carbon Isotopes; Culture Techniques; DNA; HeLa Cells; Protein Biosynthesis; RNA; Sulfates
PubMed: 5968544
DOI: 10.1042/bj1000467 -
Scientific Reports Apr 2019Cytosolic phospholipase A2α (cPLA2α) has been shown to be elevated in breast cancer and is a potential biomarker in the differentiation of molecular sub-types. Using a...
Cytosolic phospholipase A2α (cPLA2α) has been shown to be elevated in breast cancer and is a potential biomarker in the differentiation of molecular sub-types. Using a cPLA2α activatable fluorophore, DDAO arachidonate, we explore its ability to function as a contrast agent in fluorescence-guided surgery. In cell lines ranging in cPLA2α expression and representing varying breast cancer sub-types, we show DDAO arachidonate activates with a high correlation to cPLA2α expression level. Using a control probe, DDAO palmitate, in addition to cPLA2α inhibition and genetic knockdown, we show that this activation is a result of cPLA2α activity. In mouse models, using an ex vivo tumor painting technique, we show that DDAO arachidonate activates to a high degree in basal-like versus luminal-like breast tumors and healthy mammary tissue. Finally, we show that using an in vivo model, orthotopic basal-like tumors give significantly high probe activation compared to healthy mammary fat pads and surrounding tissue. Together we conclude that cPLA2α activatable fluorophores such as DDAO arachidonate may serve as a useful contrast agent for the visualization of tumor margins in the fluorescence-guided surgery of basal-like breast cancer.
Topics: Acridines; Administration, Topical; Animals; Arachidonic Acid; Breast Neoplasms; Contrast Media; Female; Fluorescent Dyes; Group IV Phospholipases A2; Humans; Injections, Intraperitoneal; MCF-7 Cells; Mammary Glands, Animal; Mastectomy; Mice; Optical Imaging; Video-Assisted Surgery; Xenograft Model Antitumor Assays
PubMed: 30992473
DOI: 10.1038/s41598-019-41626-y -
The Journal of Toxicological Sciences 2017Previously, we showed that phototoxicity assessments in Sprague-Dawley (SD) rats can detect phototoxic potential to the same degree as those in guinea pigs. In this...
Previously, we showed that phototoxicity assessments in Sprague-Dawley (SD) rats can detect phototoxic potential to the same degree as those in guinea pigs. In this study, we examined whether phototoxicity assessments can be incorporated into general toxicology studies, using SD rats. Three phototoxic compounds were tested. Acridine and 8-methoxypsoralen (8-MOP) were transdermally administered, and 8-MOP and lomefloxacin were orally administered. The animals were allocated to three groups for each compound: single-dose, repeated-dose, and repeated-dose plus toxicokinetics (TK). The single-dose group was irradiated with UV-A and UV-B after a single administration of the drug. The repeated-dose and TK groups were irradiated after 8 days of repeated administration of the drug. Blood samples were also collected from the TK group on days 1 and 7 after administration. The phototoxic compounds resulted in skin reactions in all the groups, with no difference in the degree of skin reaction among the three groups. In the TK measurements, all of the phototoxic compounds were detected in the plasma samples, and the irradiation timing was close to the T. These results indicate that phototoxic potential could be evaluated in the TK group, and phototoxicity assessments could be incorporated into general toxicology studies. This reduces the number of studies and animals required, thus shortening the research and development period, and supporting the 3Rs principle of animal experiments. The study also provides information regarding appropriate irradiation timings, differences between the sexes, and dose-response, in turn enabling the phototoxic risk of the compounds to be clearly evaluated.
Topics: Acridines; Administration, Cutaneous; Administration, Oral; Animals; Dermatitis, Phototoxic; Fluoroquinolones; Male; Methoxsalen; Photosensitizing Agents; Rats, Sprague-Dawley; Skin; Toxicity Tests
PubMed: 28321041
DOI: 10.2131/jts.42.145