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Current Topics in Medicinal Chemistry 2021Cancer, a complex disease which involves abnormalities of multiple cellular pathways, is one of the most serious threatens to human health across the world. Chemotherapy... (Review)
Review
Cancer, a complex disease which involves abnormalities of multiple cellular pathways, is one of the most serious threatens to human health across the world. Chemotherapy with a single agent or a combined regimen is a standardized strategy for the treatment of almost all human cancers, and the cure rate of cancer increases with the continuous discovery of anticancer agents and the optimization of chemotherapy options. However, drug resistance, especially multidrug resistance, remains an obstacle in the effective treatment of cancer. Hence, it is urgent to develop novel agents with potential activity against cancers, especially drug-resistant forms. Acridine, which bears three fused rings, could intercalate into DNA and interfere with metabolic processes. Recently, acridines have been found with anticancer activity in a variety of malignancies through suppressing cell proliferation, stimulating apoptosis, and inducing cell cycle arrest, retarding migration, invasion and metastasis. Thus, acridines are useful scaffolds for the discovery of novel drug candidates with potent anticancer activity. This review focused on the current scenario of acridine hybrids with potential activity against cancers reported from Jan, 2015 to Feb, 2021. The mechanisms of action, the criteria of compound design as well as structure-activity relationships were also summarized to pave the way for a further rational design of novel anticancer agents.
Topics: Acridines; Antineoplastic Agents; Apoptosis; Cell Proliferation; Drug Screening Assays, Antitumor; Humans; Molecular Structure
PubMed: 34348622
DOI: 10.2174/1568026621666210804115203 -
Molecules (Basel, Switzerland) Dec 2022This review summarized the current breakthroughs in the chemistry of acridines as anti-cancer agents, including new structural and biologically active acridine... (Review)
Review
This review summarized the current breakthroughs in the chemistry of acridines as anti-cancer agents, including new structural and biologically active acridine attributes. Acridine derivatives are a class of compounds that are being extensively researched as potential anti-cancer drugs. Acridines are well-known for their high cytotoxic activity; however, their clinical application is restricted or even excluded as a result of side effects. The photocytotoxicity of propyl acridine acts against leukaemia cell lines, with C1748 being a promising anti-tumour drug against UDP-UGT's. CK0403 is reported in breast cancer treatment and is more potent than CK0402 against estrogen receptor-negative HER2. Acridine platinum (Pt) complexes have shown specificity on the evaluated DNA sequences; 9-anilinoacridine core, which intercalates DNA, and a methyl triazene DNA-methylating moiety were also studied. Acridine thiourea gold and acridinone derivatives act against cell lines such as MDA-MB-231, SK-BR-3, and MCF-7. Benzimidazole acridine compounds demonstrated cytotoxic activity against Dual Topo and PARP-1. Quinacrine, thiazacridine, and azacridine are reported as anti-cancer agents, which have been reported in the previous decade and were addressed in this review article.
Topics: Humans; Female; Antineoplastic Agents; Cell Line; Intercalating Agents; DNA; Breast Neoplasms; Acridines; Cell Line, Tumor
PubMed: 36615391
DOI: 10.3390/molecules28010193 -
Journal of Applied Toxicology : JAT Apr 2022The potential of acridines (amsacrine) as a topoisomerase II inhibitor or poison was first discovered in 1984, and since then, a considerable number of acridine... (Review)
Review
The potential of acridines (amsacrine) as a topoisomerase II inhibitor or poison was first discovered in 1984, and since then, a considerable number of acridine derivatives have been tested as topoisomerase inhibitors/poisons, containing different substituents on the acridine chromophore. This review will discuss a series of studies published over the course of the last decade, which have investigated various novel acridine derivatives against topoisomerase II activity.
Topics: Acridines; Amsacrine; Antineoplastic Agents; DNA Topoisomerases, Type II; Poisons
PubMed: 34514603
DOI: 10.1002/jat.4238 -
Journal of Applied Toxicology : JAT Jan 2021Heterocycles have long been the focus of intensive study in attempts to develop novel therapeutic compounds, and acridine, a polynuclear nitrogen molecule containing a... (Review)
Review
Heterocycles have long been the focus of intensive study in attempts to develop novel therapeutic compounds, and acridine, a polynuclear nitrogen molecule containing a heterocycle, has attracted a considerable amount of scientific attention. Acridine derivatives have been studied in detail and have been found to possess multitarget properties, which inhibit topoisomerase enzymes that regulate topological changes in DNA and interfere with the essential biological function of DNA. This article describes some recent advancements in the field of new 9-substituted acridine heterocyclic agents and describes both the structure and the structure-activity relationship of the most promising molecules. The article will also present the IC values of the novel derivatives against various human cancer cell lines. The mini review also investigates the topoisomerase inhibition and antibacterial and antimalarial activity of these polycyclic aromatic derivatives.
Topics: Acridines; Anti-Bacterial Agents; Antimalarials; Antineoplastic Agents; Humans; Structure-Activity Relationship; Topoisomerase II Inhibitors; Tumor Cells, Cultured
PubMed: 32969520
DOI: 10.1002/jat.4072 -
Molecular Neurodegeneration Dec 2022Microglia regulate the response to injury and disease in the brain and spinal cord. In white matter diseases microglia may cause demyelination. However, how microglia...
BACKGROUND
Microglia regulate the response to injury and disease in the brain and spinal cord. In white matter diseases microglia may cause demyelination. However, how microglia respond and regulate demyelination is not fully understood.
METHODS
To understand how microglia respond during demyelination, we fed mice cuprizone-a potent demyelinating agent-and assessed the dynamics of genetically fate-mapped microglia. We then used single-cell RNA sequencing to identify and track the microglial subpopulations that arise during demyelination. To understand how microglia contribute to the clearance of dead oligodendrocytes, we ablated microglia starting at the peak of cuprizone-induced cell death and used the viability dye acridine orange to monitor apoptotic and lytic cell morphologies after microglial ablation. Lastly, we treated serum-free primary microglial cultures to model distinct aspects of cuprizone-induced demyelination and assessed the response.
RESULTS
The cuprizone diet generated a robust microglial response by week 4 of the diet. Single-cell RNA sequencing at this time point revealed the presence of several cuprizone-associated microglia (CAM) clusters. These clusters expressed a transcriptomic signature indicative of cytokine regulation and reactive oxygen species production with altered lysosomal and metabolic changes consistent with ongoing phagocytosis. Using acridine orange to monitor apoptotic and lytic cell death after microglial ablation, we found that microglia preferentially phagocytose lytic carcasses. In culture, microglia exposed to lytic carcasses partially recapitulated the CAM state, suggesting that phagocytosis contributes to this distinct microglial state during cuprizone demyelination.
CONCLUSIONS
Microglia serve multiple roles during demyelination, yet their transcriptomic state resembles other neurodegenerative conditions. The phagocytosis of cellular debris is likely a universal cause for a common neurodegenerative microglial state.
Topics: Animals; Mice; Cuprizone; Microglia; Demyelinating Diseases; Transcriptome; Acridine Orange; Mice, Inbred C57BL; Disease Models, Animal
PubMed: 36514132
DOI: 10.1186/s13024-022-00584-2 -
Molecules (Basel, Switzerland) Mar 2020Frequent fungal infections in immunocompromised patients and mortality due to invasive mycosis are important clinical problems. Opportunistic pathogenic species remain... (Review)
Review
Frequent fungal infections in immunocompromised patients and mortality due to invasive mycosis are important clinical problems. Opportunistic pathogenic species remain one of the leading causes of systemic mycosis worldwide. The repertoire of antifungal chemotherapeutic agents is very limited. Although new antifungal drugs such as lanosterol 14α-demethylase and β-glucan synthase inhibitors have been introduced into clinical practice, the development of multidrug resistance has become increasingly significant. The urgency to expand the range of therapeutic options for the treatment of fungal infections has led researchers in recent decades to seek alternative antifungal targets to the conventional ones currently used. Among them, many compounds containing an acridine scaffold have been synthesized and tested. In this review, the applicability of acridines and their functional analogues acridones as antifungal agents is described. Acridine derivatives usage in photoantifungal chemotherapy, interactions with fungal transporters resulting in modulation of efflux/influx pumps and the effect of acridine derivatives on fungal topoisomerases are discussed. This article explores new perspectives on the mechanisms of antifungal acridine-peptide conjugates and acridine-based hybrid molecules to effectively combat fungal infections.
Topics: Acridines; Animals; Antifungal Agents; Biofilms; Drug Resistance, Fungal; Humans; Microbial Sensitivity Tests; Photosensitizing Agents
PubMed: 32218216
DOI: 10.3390/molecules25071480 -
Annual Review of Medicine Jan 2017The best known of the naturally occurring antimalarial compounds are quinine, extracted from cinchona bark, and artemisinin (qinghao), extracted from Artemisia annua in... (Review)
Review
The best known of the naturally occurring antimalarial compounds are quinine, extracted from cinchona bark, and artemisinin (qinghao), extracted from Artemisia annua in China. These and other derivatives are now chemically synthesized and remain the mainstay of therapy to treat malaria. The beneficial effects of several of the antimalarial drugs (AMDs) on clinical features of autoimmune disorders were discovered by chance during World War II. In this review, we discuss the chemistry of AMDs and their mechanisms of action, emphasizing how they may impact multiple pathways of innate immunity. These pathways include Toll-like receptors and the recently described cGAS-STING pathway. Finally, we discuss the current and future impact of AMDs on systemic lupus erythematosus, rheumatoid arthritis, and devastating monogenic disorders (interferonopathies) characterized by expression of type I interferon in the brain.
Topics: Acridines; Animals; Antimalarials; Artemisinins; Arthritis, Rheumatoid; Autoimmune Diseases; Autophagy; Endosomes; Humans; Immunity, Innate; Immunomodulation; Lupus Erythematosus, Systemic; Membrane Proteins; Nucleotidyltransferases; Quinolines; Signal Transduction; Toll-Like Receptors
PubMed: 27813878
DOI: 10.1146/annurev-med-043015-123453 -
Chemistry & Biodiversity Jan 2016Pyridoacridines are a class of strictly marine-derived alkaloids that constitute one of the largest chemical families of marine alkaloids. During the last few years,... (Review)
Review
Pyridoacridines are a class of strictly marine-derived alkaloids that constitute one of the largest chemical families of marine alkaloids. During the last few years, both natural pyridoacridines and their analogues have constituted excellent targets for synthetic works. They have been the subject of intense study due to their significant biological activities; cytotoxic, antibacterial, antifungal, antiviral, insecticidal, anti-HIV, and anti-parasitic activities. In the present review, 95 pyridoacridine alkaloids isolated from marine organisms are discussed in term of their occurrence, biosynthesis, biological activities, and structural assignment.
Topics: Acridines; Alkaloids; Animals; Anti-HIV Agents; Anti-Infective Agents; Antineoplastic Agents; Antiparasitic Agents; Cell Proliferation; Humans; Insecticides; Molecular Structure; Phenanthrolines
PubMed: 26765351
DOI: 10.1002/cbdv.201400434 -
European Journal of Medicinal Chemistry Mar 2019Tacrine was the first drug approved for the treatment of Alzheimer's disease (AD) in 1993, which was withdrawn in 2013 due to its hepatotoxicity. However, new,... (Review)
Review
Tacrine was the first drug approved for the treatment of Alzheimer's disease (AD) in 1993, which was withdrawn in 2013 due to its hepatotoxicity. However, new, non-hepatotoxic tacrine derivatives have been constantly searched for. In this context, since 1997, we have prepared a number of diversely functionalized tacrines by changing the benzene ring present in tacrine to five- or six-membered aromatic ring cores that could present anticholinesterasic activity and additional pharmacological properties. The new compounds were designed as juxtaposed structures between tacrine and the well-known Ca antagonists 1,4-dihydropyridines, with the goal of obtaining multi-target directed ligands for AD. In this account, we present our results on the PyridoTacrine (PyrTac) family of tacrine analogues, resulting from the substitution of the benzene ring by a pyridine. We highlight their pharmacological profile and review similar analogues in the literature. A first set of PyrTac showed inhibitory activity of cholinesterases (ChE) and a blocking profile of voltage-gated Ca channels (VGCC). A second family with improved ChE inhibition lost VGCC blocking activity. However, the lead compound of this family (5f) presented an activating profile of the phosphatase 2A (PP2A) and showed interesting outcomes in experimental in vivo models of AD and stroke. We have identified the PyrTac ethyl 5-amino-2-methyl-6,7,8,9-tetrahydrobenzo[b] [1,8]naphthyridine-3-carboxylate (5f), which presents additional pharmacological properties beyond the mere cholinergic improvement. These new properties warrant attention to 5f and its further development as a new potential therapeutic agent for AD therapy.
Topics: Alzheimer Disease; Animals; Drug Discovery; Humans; Tacrine
PubMed: 30739821
DOI: 10.1016/j.ejmech.2019.02.005 -
Anti-cancer Agents in Medicinal... 2022In recent years, there has been a crucial need for the design and development of novel anticancer drugs that can lessen the serious health problems and unwanted side... (Review)
Review
BACKGROUND
In recent years, there has been a crucial need for the design and development of novel anticancer drugs that can lessen the serious health problems and unwanted side effects associated with currently used anticancer drugs. The triazole nucleus is well-recognized to possess numerous pharmacological activities, including anticancer, as revealed by various investigations on anticancer drugs and the latest research findings.
OBJECTIVE
The aim of this review article is to summarise the anticancer potential of 1, 2, 3-triazole, 1, 2, 4-triazole and heterocycle-fused triazole derivatives against several human cancer cell lines, compiling research articles published between 2010 and 2021.
METHODS
Data were collected from PubMed, Google scholar and Research Gate using keywords "anticancer activity of 1, 2, 3-triazole derivatives", "anticancer activity of 1, 2, 4-triazole derivatives" and "anticancer activity of heterocycle- fused triazole derivatives" and reviewed comprehensively.
RESULTS
This review examines the anticancer potential of 1,2,3-triazole coupledoleanolic acid/dithiocarbamate/ pyrido[ 2,3-d] pyrimidine derivatives, 1,2,3-triazole linked pyrimidine/1,4-naphthoquinone hybrids, and 1,2,4-triazole substituted methanone derivatives, acridine-based 1,2,4-triazole derivatives, 1,2,4-thiadiazol coupled with 1,2,4- triazole and 5-ene-thiazolo[3,2-b][1,2,4]triazole-6(5H)-one derivatives against several human cancer cell lines.
CONCLUSION
This review highlights the key findings in the area of cancer therapy. Triazole derivatives possess anticancer activity against various human cancer cell lines, and hence the triazole core may act as a lead molecule for the synthesis of novel anticancer drugs.
Topics: Acridines; Antineoplastic Agents; Cell Proliferation; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Neoplasms; Prospective Studies; Pyrimidines; Structure-Activity Relationship; Triazoles
PubMed: 35418291
DOI: 10.2174/1871520622666220412133112