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Molecules (Basel, Switzerland) Jan 2021Malaria is among the deadliest infectious diseases in the world caused by parasites. Due to the high complexity of the parasite's life cycle, we partly depend on... (Review)
Review
Malaria is among the deadliest infectious diseases in the world caused by parasites. Due to the high complexity of the parasite's life cycle, we partly depend on antimalarial drugs to fight this disease. However, the emergence of resistance, mainly by , has dethroned most of the antimalarials developed to date. Given recent reports of resistance to artemisinin combination therapies, first-line treatment currently recommended by the World Health Organization, in Western Cambodia and across the Greater Mekong sub-region, it seems very likely that artemisinin and its derivatives will follow the same path of other antimalarial drugs. Consequently, novel, safe and efficient antimalarial drugs are urgently needed. One fast and low-cost strategy to accelerate antimalarial development is by recycling classical pharmacophores. Quinacrine, an acridine-based compound and the first clinically tested synthetic antimalarial drug with potent blood schizonticide but serious side effects, has attracted attention due to its broad spectrum of biological activity. In this sense, the present review will focus on efforts made in the last 20 years for the development of more efficient, safer and affordable antimalarial compounds, through recycling the classical quinacrine drug.
Topics: Acridines; Animals; Antimalarials; Humans; Malaria, Falciparum; Plasmodium falciparum
PubMed: 33498868
DOI: 10.3390/molecules26030600 -
International Journal of Molecular... Dec 2022We report herein the design and synthesis of a series of novel acridine-triazole and acridine-thiadiazole derivatives. The newly synthesized compounds and the key...
We report herein the design and synthesis of a series of novel acridine-triazole and acridine-thiadiazole derivatives. The newly synthesized compounds and the key intermediates were all evaluated for their antitumor activities against human foreskin fibroblasts (HFF), human gastric cancer cells-803 (MGC-803), hepatocellular carcinoma bel-7404 (BEL-7404), large cell lung cancer cells (NCI-H460), and bladder cancer cells (T24). Most of the compounds exhibited high levels of antitumor activity against MGC-803 and T24 but low toxicity against human normal liver cells (LO2), and their effect was even better than the commercial anticancer drugs, 5-fluorouracil (5-FU) and cis-platinum. Further, pharmacological mechanisms such as topo I, cell cycle, cell apoptosis, and neovascularization were all evaluated. Only a few compounds exhibited potent topo I inhibitory activity at 100 μM. In addition, the most active compounds with an IC value of 5.52-8.93 μM were chosen, and they could induce cell apoptosis in the G2 stage of MGC-803 or mainly arrest T24 cells in the S stage. To our delight, most of the compounds exhibited lower zebrafish cytotoxicity but could strongly inhibit the formation of zebrafish sub-intestinal veins, indicating a potential for clinical application.
Topics: Animals; Humans; Zebrafish; Triazoles; Thiadiazoles; Acridines; Cell Line, Tumor; Drug Screening Assays, Antitumor; Antineoplastic Agents; Fluorouracil; Apoptosis; Dermatologic Agents; Cell Proliferation; Structure-Activity Relationship; Molecular Structure; Neoplasms
PubMed: 36613504
DOI: 10.3390/ijms24010064 -
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 -
Anti-cancer Agents in Medicinal... 2015In the past decades, tricyclic acridone ring system has become one of the major research interests of the medicinal chemists due to the biological significance of this... (Review)
Review
In the past decades, tricyclic acridone ring system has become one of the major research interests of the medicinal chemists due to the biological significance of this moiety in drug design and drug discovery. Acridone scaffold has substantial bio-potential since it possess crucial activities such as antibacterial, antimalarial, antiviral and anti-neoplastic. The diverse biological activity of acridone and its prospective in reversal of multi-drug resistance has attracted attention of medicinal chemists to explore this scaffold especially to treat multi-drug resistance in cancer. Considering this potential in this review we have summarized the synthesis and the antitumor activities of different acridone derived compounds reported from 2000 to 2014.
Topics: Acridines; Acridones; Animals; Antineoplastic Agents; Drug Design; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Humans; Neoplasms
PubMed: 25584694
DOI: 10.2174/1871520615666150113104457 -
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 -
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 -
Life Sciences Oct 2023Click Chemistry is providing valuable tools to biomedical research, but its direct use in therapies remains nearly unexplored. For cancer treatment, nucleoside analogues...
AIMS
Click Chemistry is providing valuable tools to biomedical research, but its direct use in therapies remains nearly unexplored. For cancer treatment, nucleoside analogues (NA) such as 5-vinyl-2'-deoxyuridine (VdU) can be metabolically incorporated into cancer cell DNA and subsequently "clicked" to form a toxic product. The inverse electron-demand Diels-Alder (IEDDA) reaction between VdU and an acridine-tetrazine conjugate (PINK) has previously been used to label cell nuclei of cultured cells. Here, we report tandem usage of VdU and PINK to induce cytotoxicity.
MAIN METHODS
Cell lines were subsequently treated with VdU and PINK, and cell viability was measured via well confluency and 3D tumor spheroid assays. DNA damage and apoptosis were evaluated using Western Blotting and cell cycle analysis by flow cytometry. Double stranded DNA break (DSB) formation was measured using the comet assay. Apoptosis was assessed by fluorescent detection of externalized phosphatidylserine residues.
KEY FINDINGS
We report that the combination of VdU and PINK synergistically induces cytotoxicity in cultured human cells. The combination of VdU and PINK strongly reduced cell viability in 2D and 3D cultured cancer cells. Mechanistically, the compounds induced DNA damage through DSB formation, which leads to S-phase accumulation and apoptosis.
SIGNIFICANCE
The combination of VdU and PINK represents a novel and promising DNA-templated "click" approach for cancer treatment via selective induction of DNA damage.
Topics: Humans; Click Chemistry; Acridines; DNA Damage; DNA; Apoptosis; Neoplasms
PubMed: 37541577
DOI: 10.1016/j.lfs.2023.122000 -
Current Medicinal Chemistry 2018The possible use of acridines as anticancer agents was first considered in the 1920´s. Since then, a large number of acridine drugs have been tested as antitumour... (Review)
Review
BACKGROUND
The possible use of acridines as anticancer agents was first considered in the 1920´s. Since then, a large number of acridine drugs have been tested as antitumour agents, including compounds containing sulphur on the acridine chromophore. In this review, we will discuss recent studies which have investigated the anticancer activity of this class of acridine derivatives.
METHODS
We present the results both of our own decade-long research and also of existing research literature into the anticancer activity of acridine derivatives containing sulphur. The evidence of specific tumor-cell killing properties displayed by these compounds suggest the potential of using such molecules as anticancer therapeutics.
RESULTS
During the last decade, a number of acridine analogs have been developed by modifying the position and the nature of the substituent on the acridine core. In this paper, we published results on the anticancer activity of acridine derivatives containing sulfur (acridine thioureas, acridine thiazolidine/thiazoidinone, and acridine thiosemicarbazones/ thiosemicarbazides). In cancer chemotherapy, the mechanism of the drugs is complex, although the study of the anticancer activity of acridines has yielded exciting results.
CONCLUSION
In this review we have summarized recent literature on the anticancer activity of acridine derivatives containing sulfur. A considerable amount of published data suggests that these compounds exhibit promising anticancer activity against selected cancer cell lines. The obtained results can be helpful in the development of new pharmaceutical agents.
Topics: Acridines; Animals; Antineoplastic Agents; Cell Line, Tumor; Drug Screening Assays, Antitumor; Humans; Thiazolidines; Thiosemicarbazones; Thiourea
PubMed: 28413957
DOI: 10.2174/0929867324666170414165019