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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 -
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 -
Mutation Research Sep 1991Acridine and its derivatives are planar polycyclic aromatic molecules which bind tightly but reversibly to DNA by intercalation, but do not usually covalently interact... (Review)
Review
Acridine and its derivatives are planar polycyclic aromatic molecules which bind tightly but reversibly to DNA by intercalation, but do not usually covalently interact with it. Acridines have a broad spectrum of biological activities, and a number of derivatives are widely used as antibacterial, antiprotozoal and anticancer drugs. Simple acridines show activity as frameshift mutagens, especially in bacteriophage and bacterial assays, by virtue of their intercalative DNA-binding ability. Acridines bearing additional fused aromatic rings (benzacridines) show little activity as frameshift mutagens, but interact covalently with DNA following metabolic activation (forming predominantly base-pair substitution mutations). Compounds where the acridine acts as a carrier to target alkylating agents to DNA (e.g. the ICR compounds) cause predominantly frameshift as well as base-pair substitution mutations in both bacterial and mammalian cells. Nitroacridines may act as simple acridines or (following nitro group reduction) as alkylating agents, depending upon the position of the nitro group. Acridine-based topoisomerase II inhibitors, although frameshift mutagens in bacteria and bacteriophage systems, are primarily chromosomal mutagens in mammalian cells. These mutagenic activities are important, since the compounds have considerable potential as clinical antitumour drugs. Although evidence suggests that simple acridines are not animal or human carcinogens, a number of the derived compounds are highly active in this capacity.
Topics: Acridines; Alkylating Agents; Aminoacridines; Animals; Chromosome Aberrations; DNA Damage; Frameshift Mutation; Intercalating Agents; Mutagenesis
PubMed: 1881402
DOI: 10.1016/0165-1110(91)90006-h -
Pharmacological Reports : PR 2011Acridine derivatives constitute a class of compounds that are being intensively studied as potential anticancer drugs. Acridines are well-known for their high cytotoxic... (Review)
Review
Acridine derivatives constitute a class of compounds that are being intensively studied as potential anticancer drugs. Acridines are well-known for their high cytotoxic activity; however, their clinical application is limited or even excluded because of side effects. Numerous synthetic methods are focused on the preparation of target acridine skeletons or modifications of naturally occurring compounds, such as acridone alkaloids, that exhibit promising anticancer activities. They have been examined in vitro and in vivo to test their importance for cancer treatment and to establish the mechanism of action at both the molecular and cellular level, which is necessary for the optimization of their properties so that they are suitable in chemotherapy. In this article, we review natural and synthetic acridine/acridone analogs, their application as anticancer drugs and methods for their preparation.
Topics: Acridines; Acridones; Animals; Antineoplastic Agents; Biological Products; Drug Screening Assays, Antitumor; Humans; Neoplasms
PubMed: 21602588
DOI: 10.1016/s1734-1140(11)70499-6 -
Current Medicinal Chemistry Sep 2002In the field of antitumor DNA-binding agents, the class of acridine derivatives play an important role either as number of compounds or as importance of their anticancer... (Review)
Review
In the field of antitumor DNA-binding agents, the class of acridine derivatives play an important role either as number of compounds or as importance of their anticancer properties. We have synthesized a number of acridine derivatives as potential antitumor drugs, in which the chromophore is fully or partially constituted by acridine or by 9-acridone ring systems: from the pyrimido[5,6,1-de]acridines, to the pyrimido[4,5,6-kl]acridines, the bis(amine-functionalized) 9-acridone-4-carboxamides, the bis(amine-functionalized) acridine-4-carboxamides, and the pyrazolo[3,4,5-kl]acridine-5-carboxamides. In the present revue we will describe the rational design, the synthesis, and the salient biological characteristics of these classes of acridine derivatives.
Topics: Acridines; Animals; Antineoplastic Agents; DNA; Drug Design; Humans; Pyrimidines; Structure-Activity Relationship
PubMed: 12171552
DOI: 10.2174/0929867023369268 -
Postepy Higieny I Medycyny... May 2011Acridines belong to a group of polycyclic heteroaromatic compounds and exhibit a broad spectrum of biological activity including antiprotozoal, antibacterial, antiviral...
Acridines belong to a group of polycyclic heteroaromatic compounds and exhibit a broad spectrum of biological activity including antiprotozoal, antibacterial, antiviral and antitumor activity. Acridine derivatives with antitumor activity have different mechanisms of action at the molecular level. The data obtained so far indicate that one of the main steps is the formation of physico-chemical complexes with DNA. Among acridine derivatives with anticancer activity we can distinguish five main classes of compounds: nitroacridines, 9-anilinoacridines, pyrazoloacridines, imidazoacridines, and triazoloacridines. Compounds from different classes differ both in mechanism of action and spectrum of antitumor activity.
Topics: Acridines; Antineoplastic Agents; Humans; Neoplasms
PubMed: 21677347
DOI: 10.5604/17322693.941521 -
Molecules (Basel, Switzerland) Jan 2023A series of novel 3,9-disubstituted acridines were synthesized and their biological potential was investigated. The synthetic plan consists of eight reaction steps,...
A series of novel 3,9-disubstituted acridines were synthesized and their biological potential was investigated. The synthetic plan consists of eight reaction steps, which produce the final products, derivatives -, in a moderate yield. The principles of cheminformatics and computational chemistry were applied in order to study the relationship between the physicochemical properties of the 3,9-disubstituted acridines and their biological activity at a cellular and molecular level. The selected 3,9-disubstituted acridine derivatives were studied in the presence of DNA using spectroscopic (UV-Vis, circular dichroism, and thermal denaturation) and electrophoretic (nuclease activity, relaxation and unwinding assays for topoisomerase I and decatenation assay for topoisomerase IIα) methods. Binding constants (2.81-9.03 × 10 M) were calculated for the derivatives from the results of the absorption titration spectra. The derivatives were found to have caused the inhibition of both topoisomerase I and topoisomerase IIα. Molecular docking simulations suggested a different way in which the acridines - can interact with topoisomerase I versus topoisomerase IIα. A strong correlation between the lipophilicity of the derivatives and their ability to stabilize the intercalation complex was identified for all of the studied agents. Acridines - were also subjected to in vitro screening conducted by the Developmental Therapeutic Program of the National Cancer Institute (NCI) against a panel of 60 cancer cell lines. The strongest biological activity was displayed by aniline acridine (MCF7-GI 18.6 nM) and ,-dimethylaniline acridine (SR-GI 38.0 nM). The relationship between the cytostatic activity of the most active substances (derivatives , , and -) and their values of , Log, Δ°, and δ was also investigated. Due to the fact that a significant correlation was only found in the case of charge density, δ, it is possible to assume that the cytostatic effect might be dependent upon the structural specificity of the acridine derivatives.
Topics: DNA Topoisomerases, Type I; Molecular Docking Simulation; Acridines; Cytostatic Agents; DNA Topoisomerases, Type II; Circular Dichroism; Antineoplastic Agents; Structure-Activity Relationship; Topoisomerase II Inhibitors
PubMed: 36770975
DOI: 10.3390/molecules28031308 -
International Journal of Biological... Nov 2016Two new spiro-acridines were synthesized by introducing cyano-N-acylhydrazone between the acridine and phenyl rings followed by spontaneous cyclization. The final...
Two new spiro-acridines were synthesized by introducing cyano-N-acylhydrazone between the acridine and phenyl rings followed by spontaneous cyclization. The final compounds (E)-1'-(benzylideneamino)-5'-oxo-1',5'-dihydro-10H-spiro[acridine-9,2'-pyrrole]-4'-carbonitrile (AMTAC-01) and (E)-1'-((4-methoxybenzylidene)amino)-5'-oxo-1',5'-dihydro-10H-spiro[acridine-9,2'-pyrrole]-4'-carbonitrile (AMTAC-02) were evaluated for their interactions with calf thymus DNA, antiproliferative and human topoisomerase I and IIα inhibitory activities. Both compounds presented ability to bind DNA. The binding constant determined by UV-vis spectroscopy was found to be 10M. Antiproliferative assay demonstrated that AMTAC-01 and AMTAC-02 were most active against prostate and melanoma tumor cell lines, respectively. The compound did not present Topo I inhibitory activity. However, both derivatives displayed topoisomerase IIα inhibitory activity comparable to amsacrine, and AMTAC-02 was more potent than AMTAC-01 with methoxy substituent group on phenyl ring. This study demonstrates that the new derivatives are promising molecules with topoisomerase IIα inhibitory and antiproliferative activities.
Topics: Acridines; Animals; Carbon-13 Magnetic Resonance Spectroscopy; Cattle; Cell Line, Tumor; Cell Proliferation; DNA; DNA Topoisomerases; Humans; Proton Magnetic Resonance Spectroscopy; Spectrometry, Fluorescence; Spectrophotometry, Ultraviolet; Spiro Compounds; Topoisomerase Inhibitors
PubMed: 27435006
DOI: 10.1016/j.ijbiomac.2016.07.057 -
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 -
Molecules (Basel, Switzerland) Nov 2018A new synthesis of substituted acridines is achieved by palladium-catalyzed addition of terminal acetylenes between the aryl rings of bis(2-bromophenyl)amine. By...
A new synthesis of substituted acridines is achieved by palladium-catalyzed addition of terminal acetylenes between the aryl rings of bis(2-bromophenyl)amine. By including a diamine base and elevating the temperature, the reaction pathway favors the formation of acridine over a double Sonogashira reaction to form bis(tolan)amine. This method is demonstrated with several aryl-alkynes and alkyl-alkynes.
Topics: Acridines; Alkynes; Amines; Molecular Structure; Temperature
PubMed: 30400283
DOI: 10.3390/molecules23112867