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The Journal of Clinical Investigation Jul 2023Many patients with diabetic eye disease respond inadequately to anti-VEGF therapies, implicating additional vasoactive mediators in its pathogenesis. We demonstrate that...
Many patients with diabetic eye disease respond inadequately to anti-VEGF therapies, implicating additional vasoactive mediators in its pathogenesis. We demonstrate that levels of angiogenic proteins regulated by HIF-1 and -2 remain elevated in the eyes of people with diabetes despite treatment with anti-VEGF therapy. Conversely, by inhibiting HIFs, we normalized the expression of multiple vasoactive mediators in mouse models of diabetic eye disease. Accumulation of HIFs and HIF-regulated vasoactive mediators in hyperglycemic animals was observed in the absence of tissue hypoxia, suggesting that targeting HIFs may be an effective early treatment for diabetic retinopathy. However, while the HIF inhibitor acriflavine prevented retinal vascular hyperpermeability in diabetic mice for several months following a single intraocular injection, accumulation of acriflavine in the retina resulted in retinal toxicity over time, raising concerns for its use in patients. Conversely, 32-134D, a recently developed HIF inhibitor structurally unrelated to acriflavine, was not toxic to the retina, yet effectively inhibited HIF accumulation and normalized HIF-regulated gene expression in mice and in human retinal organoids. Intraocular administration of 32-134D prevented retinal neovascularization and vascular hyperpermeability in mice. These results provide the foundation for clinical studies assessing 32-134D for the treatment of patients with diabetic eye disease.
Topics: Humans; Mice; Animals; Acriflavine; Diabetes Mellitus, Experimental; Retina; Retinal Neovascularization; Diabetic Retinopathy; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit
PubMed: 37227777
DOI: 10.1172/JCI163290 -
Mini Reviews in Medicinal Chemistry 2022Acridine derivatives have been thoroughly investigated and discovered to have multitarget qualities, inhibiting topoisomerase enzymes that regulate topological changes... (Review)
Review
UNLABELLED
Acridine derivatives have been thoroughly investigated and discovered to have multitarget qualities, inhibiting topoisomerase enzymes that regulate topological changes in DNA and interfering with DNA's vital biological function. This article discusses current progress in the realm of novel 9-substituted acridine heterocyclic compounds, including the structure and structure- activity connection of the most promising molecules. The IC values of the new compounds against several human cancer cell lines will also be presented in the publication. The review also looks into the inhibition of topoisomerase by polycyclic aromatic compounds.
BACKGROUND
Acridine rings can be found in molecules used in many different areas, including industry and medicine. Nowadays, acridines with anti-bacterial activity are of research interest due to decreasing bacterial resistance. Some acridine derivatives showed antimalarial or antiviral activity. Acridine derivatives were also investigated for anti-tumor activity due to the interaction with topoisomerase II and DNA base pairs. Considering these possible uses of acridine derivatives, this work overviewed all significant structure performances for the specific action of these compounds.
OBJECTIVE
The objective of this study is to review the activity of acridines as anti-proliferative agents.
METHODS
This review is designed as acridines acting as topoisomerase I and II inhibitors/ poison, Acridines on the G-quadraplux interaction, Acridines with metal complexes, Acridines with quinacrine scaffold, Acridines with sulphur moiety.
CONCLUSION
Although introduced in the 19 century, acridine derivatives are still of scientific interest. In this review, acridine derivatives with various biological activities (antiparasitic, antiviral, anti-bacterial, and antiproliferative) and their structure-activity relationship analyses are presented. Although several mechanisms of their action are known, the only important are discussed here. It can be concluded that the dominant mechanisms are DNA intercalation and interaction with enzymes.
Topics: Acridines; Antimalarials; Antineoplastic Agents; Antiviral Agents; Coordination Complexes; DNA; DNA Topoisomerases, Type I; DNA Topoisomerases, Type II; Humans; Poisons; Quinacrine; Structure-Activity Relationship; Sulfur
PubMed: 35546777
DOI: 10.2174/1389557522666220511125744 -
International Journal of Molecular... Jan 2023Alzheimer's disease (AD) is a neurodegenerative disorder which is characterized by β-amyloid (Aβ) aggregation, τ-hyperphosphorylation, and loss of cholinergic... (Review)
Review
Alzheimer's disease (AD) is a neurodegenerative disorder which is characterized by β-amyloid (Aβ) aggregation, τ-hyperphosphorylation, and loss of cholinergic neurons. The other important hallmarks of AD are oxidative stress, metal dyshomeostasis, inflammation, and cell cycle dysregulation. Multiple therapeutic targets may be proposed for the development of anti-AD drugs, and the "one drug-multiple targets" strategy is of current interest. Tacrine (THA) was the first clinically approved cholinesterase (ChE) inhibitor, which was withdrawn due to high hepatotoxicity. However, its high potency in ChE inhibition, low molecular weight, and simple structure make THA a promising scaffold for developing multi-target agents. In this review, we summarized THA-based hybrids published from 2006 to 2022, thus providing an overview of strategies that have been used in drug design and approaches that have resulted in significant cognitive improvements and reduced hepatotoxicity.
Topics: Humans; Tacrine; Alzheimer Disease; Cholinesterase Inhibitors; Amyloid beta-Peptides; Chemical and Drug Induced Liver Injury; Acetylcholinesterase
PubMed: 36675233
DOI: 10.3390/ijms24021717 -
The Alkaloids. Chemistry and Biology 2023The families of pyridoacridine, pyridoacridone, and pyrroloacridine alkaloids are fascinating classes of natural products that have attracted the attention of chemists... (Review)
Review
The families of pyridoacridine, pyridoacridone, and pyrroloacridine alkaloids are fascinating classes of natural products that have attracted the attention of chemists for over 80 years. Since the first purification of a brightly colored molecule isolated from the sea anemone Calliactis parasitica in 1940, over 110 examples of these alkaloids have been reported from marine organisms. While the paucity of numbers of protons relative to carbons and nitrogens in these molecules presents challenges in structure solution, the chemist is rewarded by their bright pigmented colors and typically diverse biological activities. In the past, several authors have proposed biosynthetic relationships within the pyridoacridine family of alkaloids, formulating a family tree derived from the reaction of dopaminequinone and kynuramine to tie together over 75 alkaloids. Inclusion of two additional quinones, and one homologous diamine, building blocks, for which there is biomimetic synthesis support, is suggestive of a more expansive connected biogenesis that encompasses not only pyridoacridines, but also pyridoacridone, and pyrroloacridine alkaloids. This review covers the isolation, structure elucidation, and proposed biosynthesis and biogenesis of pyridoacridine, pyridoacridone and pyrroloacridine marine alkaloids published to the end of 2022. Biomimetic or bio-inspired syntheses of the compound classes are described and new biological activities reported since 2004 are updated.
Topics: Acridines; Alkaloids; Biological Products; Biomimetics
PubMed: 37716797
DOI: 10.1016/bs.alkal.2023.06.001 -
Current Medicinal Chemistry 2020Alzheimer's disease (AD) is a complex, neurodegenerative pathology showing, among others, high cholinergic and neurotransmitter deficits, oxidative stress, inflammation,... (Review)
Review
Alzheimer's disease (AD) is a complex, neurodegenerative pathology showing, among others, high cholinergic and neurotransmitter deficits, oxidative stress, inflammation, Aβ-aggregation resulting in senile plaques formation, and hyperphosphorylation of tau-protein leading to neurofibrillary tangles. Due to its multifactorial and complex nature, multitarget directed small-molecules able to simultaneously inhibit or bind diverse biological targets involved in the progress and development of AD are considered now the best therapeutic strategy to design new compounds for AD therapy. Among them, tacrine is a very well known standard-gold ligand, and natural products have been a traditional source of new agents for diverse therapeutic treatments. In this review, we will update recent developments of multitarget tacrinenatural products hybrids for AD therapy.
Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Biological Products; Cholinesterase Inhibitors; Humans; Tacrine; tau Proteins
PubMed: 29611473
DOI: 10.2174/0929867325666180403151725 -
Seminars in Cancer Biology Jan 2021Quinacrine, also known as mepacrine, has originally been used as an antimalarial drug for close to a century, but was recently rediscovered as an anticancer agent. The... (Review)
Review
Quinacrine, also known as mepacrine, has originally been used as an antimalarial drug for close to a century, but was recently rediscovered as an anticancer agent. The mechanisms of anticancer effects of quinacrine are not well understood. The anticancer potential of quinacrine was discovered in a screen for small molecule activators of p53, and was specifically shown to inhibit NFκB suppression of p53. However, quinacrine can cause cell death in cells that lack p53 or have p53 mutations, which is a common occurrence in many malignant tumors including high grade serous ovarian cancer. Recent reports suggest quinacrine may inhibit cancer cell growth through multiple mechanisms including regulating autophagy, FACT (facilitates chromatin transcription) chromatin trapping, and the DNA repair process. Additional reports also suggest quinacrine is effective against chemoresistant gynecologic cancer. In this review, we discuss anticancer effects of quinacrine and potential mechanisms of action with a specific focus on gynecologic and breast cancer where treatment-refractory tumors are associated with increased mortality rates. Repurposing quinacrine as an anticancer agent appears to be a promising strategy based on its ability to target multiple pathways, its selectivity against cancer cells, and the synergistic cytotoxicity when combined with other anticancer agents with limited side effects and good tolerability profile.
Topics: Animals; Antimalarials; Antineoplastic Agents; Drug Discovery; Drug Repositioning; Drug Resistance, Neoplasm; Humans; Neoplasms; Quinacrine
PubMed: 31562955
DOI: 10.1016/j.semcancer.2019.09.021 -
Biomedicine & Pharmacotherapy =... Feb 2022Acetylcholinesterase (AChE) inhibitor is the first choice for the treatment of Alzheimer's disease (AD), but it has some defects, such as dose limitation and... (Review)
Review
Acetylcholinesterase (AChE) inhibitor is the first choice for the treatment of Alzheimer's disease (AD), but it has some defects, such as dose limitation and unsatisfactory long-term treatment effect. Recent studies have shown that butyrylcholinesterase (BuChE) inhibitors or double acetyl and butyryl cholinesterase inhibitors have better curative effects on AD, and the side effects are lower than those of specific AChE inhibitors. Dual target cholinesterase inhibitors have become a new hotspot in the research of anti-AD drugs. Herein, the synthesis and bioactivities of BuChE inhibitors were reviewed.
Topics: Acridines; Alzheimer Disease; Butyrylcholinesterase; Cholinesterase Inhibitors; Humans; Methoxsalen; Structure-Activity Relationship
PubMed: 34953393
DOI: 10.1016/j.biopha.2021.112556 -
Journal of Applied Toxicology : JAT Jan 2020Proflavine derivatives are extremely interesting chemotherapeutic agents, which have shown promising pharmaceutical potential due to their wide range of biological... (Review)
Review
Proflavine derivatives are extremely interesting chemotherapeutic agents, which have shown promising pharmaceutical potential due to their wide range of biological activities. This review summarizes the current state of research into the anticancer, antimicrobial, antimalarial and antileishmanial properties of these attractive compounds. Our attention has focused on new classes of proflavine conjugates, which display significant levels of anticancer activity. Highly promising cytotoxic properties have been identified in proflavine conjugates with imidazolidinones, ureas and thioureas. In particular, proflavine-dialkyldithioureas displayed substantial cytotoxic effect against the human leukemia HL-60 cells with IC values from 7.2 to 34.0 μm. As well, palladium complexes with proflavine ligand have important biologic activity. The LC values of these complexes were significantly lower than that of cisplatin against the SK-BR-3 cell line.
Topics: Acriflavine; Animals; Anti-Infective Agents; Antineoplastic Agents; Dose-Response Relationship, Drug; Humans; Inhibitory Concentration 50; Molecular Structure; Proflavine; Structure-Activity Relationship
PubMed: 31222780
DOI: 10.1002/jat.3818 -
Cytometry. Part a : the Journal of the... Jun 2020Briefly depicted are the publications in CYTOMETRY that received the highest frequency of citations. Among them are seminal papers describing application of...
Briefly depicted are the publications in CYTOMETRY that received the highest frequency of citations. Among them are seminal papers describing application of metachromatic fluorochrome acridine orange to differentially stain DNA versus RNA or to analyze susceptibility of DNA in situ to denaturation; both features being markers of different sections of the cell cycle including identification of noncycling quiescent cells. The papers reviewing detection of cyclins D1, E, A or B1, each in relation to cell cycle phase, were also among the highly cited ones. The highest citation rates received publications describing development of the TUNEL methodology to detect apoptotic DNA fragmentation, and more recently expression of ϒH2AX to reveal DNA damage. © 2020 International Society for Advancement of Cytometry.
Topics: Acridine Orange; Cell Cycle; DNA; Flow Cytometry; Fluorescent Dyes
PubMed: 32511890
DOI: 10.1002/cyto.a.24043 -
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