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Luminescence : the Journal of... Jun 2021Multicolor chemiluminescent acridinium derivatives were synthesized by attaching various common fluorophores to the N -acridinium position through a piperazine linker....
Multicolor chemiluminescent acridinium derivatives were synthesized by attaching various common fluorophores to the N -acridinium position through a piperazine linker. Triggering of each acridinium derivative using alkaline hydrogen peroxide resulted in a chemiluminescence spectrum dominated by a strong emission (>95%) from the attached fluorophore. The highly quenched emission from the triggered acridinium, acting as a donor, points to a highly efficient intramolecular energy transfer in acridinium-based chemiluminophore-fluorophore tandems. A variable, and in many cases minimal, spectral overlap between the donor emission and the acceptor absorption may indicate that in such tandems the energy transfer follows the Dexter electron exchange mechanism. Moreover, fluorophores affixed through the acridinium 9-position produce a typical acridinium emission profile, demonstrating the need for close distances and favorable intramolecular orientation of the donor and acceptor moieties for the energy transfer to occur. A family of red-shifted chemiluminescent labels, all sharing a uniform triggering method, will find immediate application in multicolor ligand-receptor assays. Along with the multiplexing capabilities, the red-shifted chemiluminescent detection offers a higher tolerance to green-colored biological interferences and will therefore benefit many screening and diagnostic clinical tests.
Topics: Acridines; Hydrogen Peroxide; Luminescence; Luminescent Measurements
PubMed: 33617125
DOI: 10.1002/bio.4038 -
Molecules (Basel, Switzerland) Aug 2022Oral squamous cell carcinoma (OSCC) is a global public health problem with high incidence and mortality. The chemotherapeutic agents used in the clinic, alone or in...
Oral squamous cell carcinoma (OSCC) is a global public health problem with high incidence and mortality. The chemotherapeutic agents used in the clinic, alone or in combination, usually lead to important side effects. Thus, the discovery and development of new antineoplastic drugs are essential to improve disease prognosis and reduce toxicity. In the present study, acridine-core naphthoquinone compounds were synthesized and evaluated for their antitumor activity in OSCC cells. The mechanism of action, pharmacokinetics, and toxicity parameters of the most promising compound was further analyzed using in silico, in vitro, and in vivo methods. Among the derivatives, compound was highly cytotoxic (29.99 µM) and selective (SI 2.9) at levels comparable and generally superior to chemotherapeutic controls. Besides, compound proved to be non-hemolytic, stable, and well tolerated in animals at all doses tested. Mechanistically, compound promoted cell death by apoptosis in the OSCC cell, and molecular docking studies suggested this compound possibly targets enzymes important for tumor progression, such as RSK2, PKM2, and topoisomerase IIα. Importantly, compound presented a pharmacological profile within desirable parameters for drug development, showing promise for future preclinical trials.
Topics: Acridines; Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Head and Neck Neoplasms; Molecular Docking Simulation; Mouth Neoplasms; Naphthoquinones; Squamous Cell Carcinoma of Head and Neck
PubMed: 36014389
DOI: 10.3390/molecules27165148 -
Journal of Cellular Biochemistry Sep 2022Rhein is an anthraquinone found in Rheum palmatum, used in Chinese medicine. Due to potential anticancer properties, the study assessed its effect on the lysosomal...
Rhein is an anthraquinone found in Rheum palmatum, used in Chinese medicine. Due to potential anticancer properties, the study assessed its effect on the lysosomal compartment, which indirectly influences cell death. The experiment was performed on HeLa cells by treating them with rhein at concentrations of 100-300 µM. LC3-II protein and caspase 3/7 activity, level of apoptosis, the concentration of reactive oxide species (ROS), and mitochondrial potential (Δψm) were evaluated by the cytometric method. To evaluate the permeability of the lysosomal membrane (LMP), staining with acridine orange and the assessment of activity of cathepsin D and L in the lysosomal and extralysosomal fractions were used. Cell viability was assessed by -(3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) (MTT) and neutral red (NR) assays. Changes in cells were also demonstrated at the level of electron, optical, confocal, and fluorescence microscopy. Inhibition of autophagy was done using chloroquine. Rhein-induced degradation processes were confirmed by an increase in the number of primary lysosomes, autophagosomes, and autolysosomes. At high concentrations, rhein caused the generation of ROS, which induced LMP expressed by quenching of acridine orange fluorescence. These results correlated with a reduction of lysosomes, as visualized in graphical modeling, with the decreased uptake of NR by lysosomes, and increased activity of cathepsin D and L in the extralysosomal fraction. The studies also showed an increase in the activity of caspase 3/7 and a decrease in the expression of Bcl-2 protein, indicative of rhein-stimulated apoptosis. At the same time, we demonstrated that preincubation of cells with chloroquine inhibited rhein-induced autophagy and contributed to increased cytotoxicity to HeLa cells. Rhein also induced DNA damage and led to cycle arrest in the S phase. Our results indicate that rhein, by inducing changes in the lysosomal compartment, indirectly affects apoptosis of HeLa cells and in combination with autophagy inhibitors may be an effective form of anticancer therapy.
Topics: Acridine Orange; Anthraquinones; Apoptosis; Autophagy; Caspase 3; Cathepsin D; Chloroquine; HeLa Cells; Humans; Lysosomes; Neutral Red; Oxides; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species
PubMed: 35901236
DOI: 10.1002/jcb.30311 -
Lupus Science & Medicine Oct 2020Cutaneous lupus erythematosus (CLE) is a disfiguring and potentially disabling disease that causes significant morbidity in patients. Antimalarials are an important... (Review)
Review
Cutaneous lupus erythematosus (CLE) is a disfiguring and potentially disabling disease that causes significant morbidity in patients. Antimalarials are an important class of medication used to treat this disease and have been the first-line systemic therapy since the 1950s. Quinacrine, in particular, is used as an adjuvant therapy to other antimalarials for improved control of CLE. Quinacrine is currently unavailable in the USA, which has taken away an important component of the treatment regimen of patients with CLE. This paper reviews the evidence of available local and systemic therapies in order to assist providers in choosing alternative treatments for patients who previously benefited from quinacrine therapy.
Topics: Antimalarials; Humans; Lupus Erythematosus, Cutaneous; Pharmaceutical Preparations; Quinacrine
PubMed: 33082164
DOI: 10.1136/lupus-2020-000430 -
European Journal of Pharmaceutics and... Jan 2022Glioblastomas have been historically difficult to treat with poor long-term survival. With novel strategies focused on targeting hypoxia-inducible factor (HIF)...
Glioblastomas have been historically difficult to treat with poor long-term survival. With novel strategies focused on targeting hypoxia-inducible factor (HIF) regulatory pathways, recent evidence has shown that Acriflavine (ACF) can effectively target glioma invasiveness and recurrence. However, local delivery of ACF and its combinatory effects with Temozolomide (TMZ) and radiation therapy (XRT) have not yet been optimized. In this study we test a novel polymeric matrix that can gradually release ACF at the tumor bed site in combination with systemic TMZ and XRT. In vitro cytotoxicity assays of ACF in combination with TMZ and XRT were performed on rodent and human cell lines with CCK-8 and flow cytometry. In vitro drug release was measured and intracranial safety was assessed in tumor-free animals. Finally, efficacy was assessed in an intracranial gliosarcoma model and combination therapy with TMZ and XRT evaluated. Combination therapy of ACF, TMZ, and XRT was able to reduce cell viability and induce apoptosis in glioma cells. In vitro and in vivo release of ACF was measured in benchtop and animal models. Efficacy was established in an in vivo gliosarcoma model in which intracranial ACF (p < 0.01) significantly improved median survival and the combination therapy of ACF, TMZ and XRT (p < 0.01) significantly improved median survival and led to long-term survival (LTS). We provide evidence that ACF, combined with TMZ and XRT, led to LTS in an intracranial model of rat gliosarcoma. These findings, in combination with the use of a novel polymeric matrix that allows more gradual drug delivery, constitute a first step in the translation of this novel strategy to human use.
Topics: Absorbable Implants; Acriflavine; Animals; Apoptosis; Brain Neoplasms; Cell Line, Tumor; Cell Survival; Combined Modality Therapy; Drug Implants; Glioma; Polymers; Radiotherapy Dosage; Rats; Rats, Inbred F344; Survival Rate; Temozolomide; Xenograft Model Antitumor Assays
PubMed: 34968646
DOI: 10.1016/j.ejpb.2021.12.011 -
Regulatory Toxicology and Pharmacology... Aug 2021Quinacrine sterilization (QS) is a nonsurgical female method used by more than 175,000 women in over 50 countries. With FDA approval, QS is expected to be used by...
Quinacrine sterilization (QS) is a nonsurgical female method used by more than 175,000 women in over 50 countries. With FDA approval, QS is expected to be used by hundreds of millions of women. The negative international health consequences of the results of a 2-year rat study in 2010 by Cancel et al. in Regulatory Toxicology and Pharmacology (RTP) (56:156-165) are incalculable. S1C(R2) was ignored in this study, including the fundamental concept of maximum tolerated dose (MTD), which resulted in the use of massive doses (up to 35 times the MTD) which killed many of the rats and destroyed the uterus of survivors. The design of this rat study was built on the false assertion that this study mimics what happens in women. Cancel et al. (2010), concludes it "seems most likely" that genotoxicity was a major factor in the carcinogenicity observed, prompting the FDA to halt further research of QS. In RTP, McConnell et al. (2010), and Haseman et al. (2015), using the authors' data, definitively determined the carcinogenicity to be secondary to necrosis and chronic inflammation. Decisions made in the design, conduct, analysis, interpretation and reporting in this study lack scientific foundation. This paper explores these decisions.
Topics: Animals; Data Accuracy; Drug Approval; Female; Humans; Maximum Tolerated Dose; Quinacrine; Rats; Research Design; Sterilization, Reproductive; Toxicity Tests, Chronic; United States; United States Food and Drug Administration
PubMed: 34062206
DOI: 10.1016/j.yrtph.2021.104968 -
Nucleic Acids Research Oct 2022The short oligodeoxynucleotide (ODN) probes are suitable for good discrimination of point mutations. However, the probes suffer from low melting temperatures. In this...
The short oligodeoxynucleotide (ODN) probes are suitable for good discrimination of point mutations. However, the probes suffer from low melting temperatures. In this work, the strategy of using acridine-4-carboxamide intercalators to improve thermal stabilisation is investigated. The study of large series of acridines revealed that optimal stabilisation is achieved upon decoration of acridine by secondary carboxamide carrying sterically not demanding basic function bound through a two-carbon linker. Two highly active intercalators were attached to short probes (13 or 18 bases; designed as a part of HFE gene) by click chemistry into positions 7 and/or 13 and proved to increase the melting temperate (Tm) of the duplex by almost 8°C for the best combination. The acridines interact with both single- and double-stranded DNAs with substantially preferred interaction for the latter. The study of interaction suggested higher affinity of the acridines toward the GC- than AT-rich sequences. Good discrimination of two point mutations was shown in practical application with HFE gene (wild type, H63D C > G and S65C A > C mutations). Acridine itself can also serve as a fluorophore and also allows discrimination of the fully matched sequences from those with point mutations in probes labelled only with acridine.
Topics: Acridines; Carbon; DNA; Intercalating Agents; Oligodeoxyribonucleotides
PubMed: 36156152
DOI: 10.1093/nar/gkac777 -
Clinical and Experimental Dermatology Dec 2022
Topics: Humans; Dermatologists; Quinacrine; Dermatology; Surveys and Questionnaires
PubMed: 35941764
DOI: 10.1111/ced.15367 -
Molecules (Basel, Switzerland) Sep 2023The synthesis of the first conjugates of acridine with cobalt bis(dicarbollide) are reported. A novel 9-azido derivative of acridine was prepared through the reaction of...
The synthesis of the first conjugates of acridine with cobalt bis(dicarbollide) are reported. A novel 9-azido derivative of acridine was prepared through the reaction of 9-methoxyacridine with NCHCHNH, and its solid-state molecular structure was determined via single-crystal X-ray diffraction. The azidoacridine was used in a copper (I)-catalyzed azide-alkyne cycloaddition reaction with cobalt bis(dicarbollide)-based terminal alkynes to give the target 1,2,3-triazoles. DNA interaction studies via absorbance spectroscopy showed the weak binding of the obtained conjugates with DNA. The antiproliferative activity (IC) of the boronated conjugates against a series of human cell lines was evaluated through an MTT assay. The results suggested that acridine derivatives of cobalt bis(dicarbollide) might serve as a novel scaffold for the future development of new agents for boron neutron capture therapy (BNCT).
Topics: Humans; Boron; Molecular Structure; Acridines; Cobalt; DNA
PubMed: 37764412
DOI: 10.3390/molecules28186636 -
Journal of Enzyme Inhibition and... Dec 2020The significant role of topoisomerases in the control of DNA chain topology has been confirmed in numerous research conducted worldwide. The prevalence of these enzymes,... (Review)
Review
The significant role of topoisomerases in the control of DNA chain topology has been confirmed in numerous research conducted worldwide. The prevalence of these enzymes, as well as the key importance of topoisomerase in the proper functioning of cells, have made them the target of many scientific studies conducted all over the world. This article is a comprehensive review of knowledge about topoisomerases and their inhibitors collected over the years. Studies on the structure-activity relationship and molecular docking are one of the key elements driving drug development. In addition to information on molecular targets, this article contains details on the structure-activity relationship of described classes of compounds. Moreover, the work also includes details about the structure of the compounds that drive the mode of action of topoisomerase inhibitors. Finally, selected topoisomerases inhibitors at the stage of clinical trials and their potential application in the chemotherapy of various cancers are described.
Topics: Acridines; Animals; Antineoplastic Agents; DNA Topoisomerases; Dexrazoxane; Drug Screening Assays, Antitumor; Humans; Molecular Docking Simulation; Quinolones; Structure-Activity Relationship; Thiobarbiturates; Topoisomerase Inhibitors
PubMed: 32975138
DOI: 10.1080/14756366.2020.1821676