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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 -
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 -
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 -
Biochemistry. Biokhimiia Dec 2009Application of chemiluminescence (CL) for study of free-radical reactions in human and animal cells and tissues is considered in this review. Historically, the study of... (Review)
Review
Application of chemiluminescence (CL) for study of free-radical reactions in human and animal cells and tissues is considered in this review. Historically, the study of intrinsic (ultraweak) luminescence gave place to the measurement of CL in the presence of chemical activators (CL probes) and physical activators (sensitizers) of luminescence, which made the method much more sensitive and specific. The methods of CL and EPR are direct methods of radical investigation, though the advantage of the CL method consists in the fact that CL intensity is directly proportional to a steady-state concentration of the radicals responsible for luminescence (first of all, lipid and oxygen radicals) irrespective the activity of these radicals. The mechanisms of CL reactions in the absence of activators and in the presence of luminol and lucigenin are considered. Examples of various applications of the CL method in medical, biological, and clinical investigations are given including those for estimation of the phagocytic activity of cells, antioxidant activity, determination of toxicity, and other purposes.
Topics: Acridines; Animals; Antioxidants; Disease; Free Radicals; Humans; Iron; Lipid Peroxidation; Luminescence; Luminescent Agents; Luminescent Measurements; Luminol; Molecular Structure; Oxidative Stress; Peroxidases; Reactive Oxygen Species
PubMed: 20210708
DOI: 10.1134/s0006297909130082 -
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 -
Acta Poloniae Pharmaceutica 2012Acridine is a heterocyclic nucleus. It plays an important role in various medicines. A number of therapeutic agents are based on acridine nucleus such as quinacrine... (Review)
Review
Acridine is a heterocyclic nucleus. It plays an important role in various medicines. A number of therapeutic agents are based on acridine nucleus such as quinacrine (antimalarial), acriflavine and proflavine (antiseptics), ethacridine (abortifacient), amsacrine and nitracine (anticancer), and tacrine. Acridine is obtained from high boiling fraction of coal tar. It is also obtained in nature from plant and marine sources. Acridine undergoes a number of reactions such as nucleophilic addition, electrophilic substitution, oxidation, reduction, reductive alkylation and photoalkylation. The present review article summarizes the synthesis, reaction, literature review and pharmaceutical importance of acridine.
Topics: Abortifacient Agents; Acridines; Animals; Anti-Infective Agents, Local; Antimalarials; Antineoplastic Agents; Humans
PubMed: 22574501
DOI: No ID Found -
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 -
European Journal of Medicinal Chemistry Jan 2022O-Methylguanine-DNA-methyltransferase (MGMT) is a key DNA repair enzyme involved in chemoresistance to DNA-alkylating anti-cancer drugs such as Temozolomide (TMZ)...
O-Methylguanine-DNA-methyltransferase (MGMT) is a key DNA repair enzyme involved in chemoresistance to DNA-alkylating anti-cancer drugs such as Temozolomide (TMZ) through direct repair of drug-induced O-methylguanine residues in DNA. MGMT substrate analogues, such as O-benzylguanine (BG), efficiently inactivate MGMT in vitro and in cells; however, these drugs failed to reach the clinic due to adverse side effects. Here, we designed hybrid drugs combining a BG residue covalently linked to a DNA-interacting moiety (6-chloro-2-methoxy-9-aminoacridine). Specifically, two series of hybrids, encompassing three compounds each, were obtained by varying the position of the attachment point of BG (N of guanine vs. the benzyl group) and the length and nature of the linker. UV/vis absorption and fluorescence data indicate that all six hybrids adopt an intramolecularly stacked conformation in aqueous solutions in a wide range of temperatures. All hybrids interact with double-stranded DNA, as clearly evidenced by spectrophotometric titrations, without intercalation of the acridine ring and do not induce thermal stabilization of the duplex. All hybrids, as well as the reference DNA intercalator (6-chloro-2-methoxy-9-aminoacridine 8), irreversibly inhibit MGMT in vitro with variable efficiency, comparable to that of BG. In a multidrug-resistant glioblastoma cell line T98G, benzyl-linked hybrids 7a-c and the N-linked hybrid 19b are moderately cytotoxic (GI ≥ 15 μM after 96 h), while N-linked hybrids 19a and 19c are strongly cytotoxic (GI = 1-2 μM), similarly to acridine 8 (GI = 0.6 μM). Among all compounds, hybrids 19a and 19c, similarly to BG, display synergic cytotoxic effect upon co-treatment with subtoxic doses of TMZ, with combination index (CI) values as low as 0.2-0.3. In agreement with in vitro results, compound 19a inactivates cellular MGMT but, unlike BG, does not induce significant levels of DNA damage, either alone or in combination with TMZ, as indicated by the results of γH2AX immunostaining experiments. Instead, and unlike BG, compound 19a alone induces significant apoptosis of T98G cells, which is not further increased in a combination with TMZ. These results indicate that molecular mechanisms underlying the cytotoxicity of 19a and its combination with TMZ are distinct from that of BG. The strongly synergic properties of this combination represent an interesting therapeutic opportunity in treating TMZ-resistant cancers.
Topics: Acridines; Animals; Antineoplastic Agents; Binding Sites; Cattle; Cell Proliferation; DNA; DNA Modification Methylases; DNA Repair Enzymes; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Guanine; Humans; Molecular Structure; Structure-Activity Relationship; Tumor Suppressor Proteins
PubMed: 34731767
DOI: 10.1016/j.ejmech.2021.113909 -
Molecules (Basel, Switzerland) Dec 2019The antitumor effects of thiophene and acridine compounds have been described; however, the clinical usefulness of these compounds is limited due to the risk of high...
The antitumor effects of thiophene and acridine compounds have been described; however, the clinical usefulness of these compounds is limited due to the risk of high toxicity and drug resistance. The strategy of molecular hybridization presents the opportunity to develop new drugs which may display better target affinity and less serious side effects. Herein, 2-((6-Chloro-2-methoxy-acridin-9-yl)amino)-5,6,7,8-tetrahydro-4H-cyclohepta[b]-thiophene-3-carbonitrile (ACS03), a hybrid thiophene-acridine compound with antileishmanial activity, was tested for toxicity and antitumor activity. The toxicity was evaluated in vitro (on HaCat and peripheral blood mononuclear cells) and in vivo (zebrafish embryos and acute toxicity in mice). Antitumor activity was also assessed in vitro in HCT-116 (human colon carcinoma cell line), K562 (chronic myeloid leukemic cell line), HL-60 (human promyelocytic leukemia cell line), HeLa (human cervical cancer cell line), and MCF-7 (breast cancer cell line) and in vivo (Ehrlich ascites carcinoma model). ACS03 exhibited selectivity toward HCT-116 cells (Half maximal inhibitory concentration, IC50 = 23.11 ± 1.03 µM). In zebrafish embryos, ACS03 induced an increase in lactate dehydrogenase, glutathione S-transferase, and acetylcholinesterase activities. The LD50 (lethal dose 50%) value in mice was estimated to be higher than 5000 mg/kg (intraperitoneally). In vivo, ACS03 (12.5 mg/kg) induced a significant reduction in tumor volume and cell viability. In vivo antitumor activity was associated with the nitric oxide cytotoxic effect. In conclusion, significant antitumor activity and weak toxicity were recorded for this hybrid compound, characterizing it as a potential anticancer compound.
Topics: Acridines; Animals; Antineoplastic Agents; Ascitic Fluid; Biomarkers; Carcinoma, Ehrlich Tumor; Cell Death; Cell Line, Tumor; Embryo, Nonmammalian; Female; Fluorouracil; Humans; Mice; Nitrites; Thiophenes; Toxicity Tests, Acute; Zebrafish
PubMed: 31878135
DOI: 10.3390/molecules25010064 -
Angewandte Chemie (International Ed. in... May 2020The development of efficient and selective C-N bond-forming reactions from abundant feedstock chemicals remains a central theme in organic chemistry owing to the key...
The development of efficient and selective C-N bond-forming reactions from abundant feedstock chemicals remains a central theme in organic chemistry owing to the key roles of amines in synthesis, drug discovery, and materials science. Herein, we present a dual catalytic system for the N-alkylation of diverse aromatic carbocyclic and heterocyclic amines directly with carboxylic acids, by-passing their preactivation as redox-active esters. The reaction, which is enabled by visible-light-driven, acridine-catalyzed decarboxylation, provides access to N-alkylated secondary and tertiary anilines and N-heterocycles. Additional examples, including double alkylation, the installation of metabolically robust deuterated methyl groups, and tandem ring formation, further demonstrate the potential of the direct decarboxylative alkylation (DDA) reaction.
Topics: Acridines; Alkylation; Amines; Aniline Compounds; Catalysis; Heterocyclic Compounds; Oxidation-Reduction
PubMed: 32050048
DOI: 10.1002/anie.201916710