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Journal of the American Chemical Society Aug 2013We report formal [3 + 3] annulations of aromatic azides with aromatic imines and azobenzenes to give acridines and phenazines, respectively. These transformations...
We report formal [3 + 3] annulations of aromatic azides with aromatic imines and azobenzenes to give acridines and phenazines, respectively. These transformations proceed through a cascade process of Rh(III)-catalyzed amination followed by intramolecular electrophilic aromatic substitution and aromatization. Acridines can be directly prepared from aromatic aldehydes by in situ imine formation using catalytic benzylamine.
Topics: Acridines; Amination; Catalysis; Cyclization; Molecular Structure; Organoselenium Compounds; Phenazines; Rhodium
PubMed: 23957711
DOI: 10.1021/ja406131a -
International Journal of Molecular... Jun 2015In this work, the acridine nucleus was used as a lead-compound for structural modification by adding different substituted thiosemicarbazide moieties. Eight new...
In this work, the acridine nucleus was used as a lead-compound for structural modification by adding different substituted thiosemicarbazide moieties. Eight new (Z)-2-(acridin-9-ylmethylene)-N-phenylhydrazinecarbothioamide derivatives (3a-h) were synthesized, their antiproliferative activities were evaluated, and DNA binding properties were performed with calf thymus DNA (ctDNA) by electronic absorption and fluorescence spectroscopies. Both hyperchromic and hypochromic effects, as well as red or blue shifts were demonstrated by addition of ctDNA to the derivatives. The calculated binding constants ranged from 1.74 × 10(4) to 1.0 × 10(6) M(-1) and quenching constants from -0.2 × 10(4) to 2.18 × 10(4) M(-1) indicating high affinity to ctDNA base pairs. The most efficient compound in binding to ctDNA in vitro was (Z)-2-(acridin-9-ylmethylene)-N- (4-chlorophenyl) hydrazinecarbothioamide (3f), while the most active compound in antiproliferative assay was (Z)-2-(acridin-9-ylmethylene)-N-phenylhydrazinecarbothioamide (3a). There was no correlation between DNA-binding and in vitro antiproliferative activity, but the results suggest that DNA binding can be involved in the biological activity mechanism. This study may guide the choice of the size and shape of the intercalating part of the ligand and the strategic selection of substituents that increase DNA-binding or antiproliferative properties.
Topics: Acridines; Antineoplastic Agents; Cell Proliferation; DNA; MCF-7 Cells; Thiosemicarbazones
PubMed: 26068233
DOI: 10.3390/ijms160613023 -
International Journal of Biological... May 2024The B-MYB gene encodes a transcription factor (B-MYB) that regulates cell growth and survival. Abnormal expression of B-MYB is frequently observed in lung cancer and...
The B-MYB gene encodes a transcription factor (B-MYB) that regulates cell growth and survival. Abnormal expression of B-MYB is frequently observed in lung cancer and poses challenges for targeted drug therapy. Oncogenes often contain DNA structures called G-quadruplexes (G4s) in their promoter regions, and B-MYB is no exception. These G4s play roles in genetic regulation and are potential cancer treatment targets. In this study, a probe was designed to specifically identify a G4 within the promoter region of the B-MYB gene. This probe combines an acridine derivative ligand with a DNA segment complementary to the target sequence, enabling it to hybridize with the adjacent sequence of the G4 being investigated. Biophysical studies demonstrated that the acridine derivative ligands CNH and CNH not only effectively stabilized the G4 structure but also exhibited moderate affinity. They were capable of altering the G4 topology and exhibited enhanced fluorescence emission in the presence of this quadruplex. Additionally, these ligands increased the number of G4s observed in cellular studies. Through various biophysical studies, the target sequence was shown to form a G4 structure, even with an extra nucleotide tail added to its flanking region. Cellular studies confirmed the co-localization between the target sequence and the developed probe.
Topics: G-Quadruplexes; Humans; Fluorescent Dyes; Promoter Regions, Genetic; Proto-Oncogene Mas; Ligands; Trans-Activators; Acridines; Cell Cycle Proteins
PubMed: 38522681
DOI: 10.1016/j.ijbiomac.2024.131055 -
Scientific Reports Sep 2020Cytotoxic drugs that are mechanistically distinct from current chemotherapies are attractive components of personalized combination regimens for combatting aggressive...
Cytotoxic drugs that are mechanistically distinct from current chemotherapies are attractive components of personalized combination regimens for combatting aggressive forms of cancer. To gain insight into the cellular mechanism of a potent platinum-acridine anticancer agent (compound 1), a correlation analysis of NCI-60 compound screening results and gene expression profiles was performed. A plasma membrane transporter, the solute carrier (SLC) human multidrug and toxin extrusion protein 1 (hMATE1, SLC47A1), emerged as the dominant predictor of cancer cell chemosensitivity to the hybrid agent (Pearson correlation analysis, p < 10) across a wide range of tissues of origin. The crucial role of hMATE1 was validated in lung adenocarcinoma cells (A549), which expresses high levels of the membrane transporter, using transporter inhibition assays and transient knockdown of the SLC47A1 gene, in conjunction with quantification of intracellular accumulation of compound 1 and cell viability screening. Preliminary data also show that HCT-116 colon cancer cells, in which hMATE1 is epigenetically repressed, can be sensitized to compound 1 by priming the cells with the drugs EPZ-6438 (tazemetostat) and EED226. Collectively, these results suggest that hMATE1 may have applications as a pan-cancer molecular marker to identify and target tumors that are likely to respond to platinum-acridines.
Topics: A549 Cells; Acridines; Antineoplastic Agents; Benzamides; Biphenyl Compounds; Cell Proliferation; Cell Survival; Drug Synergism; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; HCT116 Cells; Humans; Molecular Structure; Morpholines; Organic Cation Transport Proteins; Organoplatinum Compounds; Platinum; Pyridones; Pyrimethamine; Sulfones; Triazoles
PubMed: 32939009
DOI: 10.1038/s41598-020-72099-z -
Drug Metabolism and Disposition: the... Aug 2012The objective of this study was to determine the bioavailability and disposition of elacridar (GF120918;...
The objective of this study was to determine the bioavailability and disposition of elacridar (GF120918; N-(4-(2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl)phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide) in plasma and brain after various routes of administration in the mouse. Elacridar is a potent inhibitor of P-glycoprotein and breast cancer resistance protein and has been used to examine the influence of these efflux transporters on drug distribution to brain. Friend leukemia virus strain B mice were administered 100 mg/kg elacridar either orally or intraperitoneally. The absolute bioavailability of elacridar after oral or intraperitoneal dosing was determined with respect to an intravenous dose of 2.5 mg/kg. At these doses, the absolute bioavailability was 0.22 for oral administration and 0.01 for intraperitoneal administration. The terminal half-life of elacridar was approximately 4 h after intraperitoneal and intravenous administration and nearly 20 h after oral dosing. The brain-to-plasma partition coefficient (Kp,brain) of elacridar increased as plasma exposure increased, suggesting saturation of the efflux transporters at the blood-brain barrier. The Kp,brain after intravenous, intraperitoneal, and oral dosing was 0.82, 0.43, and 4.31, respectively. The low aqueous solubility and high lipophilicity of elacridar result in poor oral absorption, most likely dissolution-rate-limited. These results illustrate the importance of the route of administration and the resultant plasma exposure in achieving effective plasma and brain concentrations of elacridar and can be used as a guide for future studies involving elacridar administration and in developing formulation strategies to overcome the poor absorption.
Topics: Acridines; Animals; Biological Availability; Brain; Mice; Tetrahydroisoquinolines
PubMed: 22611067
DOI: 10.1124/dmd.112.045930 -
Journal of Bacteriology Mar 1973Evidence for genetic recombination between Mycobacterium smegmatis strain Rabinowitchi (Rab) and strain Jucho or PM5 is presented. Backcrosses of recombinants by either...
Evidence for genetic recombination between Mycobacterium smegmatis strain Rabinowitchi (Rab) and strain Jucho or PM5 is presented. Backcrosses of recombinants by either parental strain indicated four different types of mating behavior, suggesting that the mycobacterial compatibilities are controlled by at least two different factors. No sex factor that transfers at a high frequency or that is sensitive to acridine dyes was detected. Analysis of segregation of unselected markers revealed that strain Jucho, or PM5, contributes the majority of alleles in almost all recombinants obtained from different selective media. Efforts to construct linkage maps for the markers employed failed because of ordering ambiguities. Mating medium containing streptomycin prevented genetic recombination when strain Rab was resistant to the antibiotic and Jucho, or PM5, was sensitive, but it did not prevent recombination when Rab was sensitive to streptomycin and Jucho, or PM5, was resistant. Very low frequency of recombinant formation was observed when Jucho, or PM5, had been treated with streptomycin, whereas recombinants were formed at fairly high frequencies when Rab had been treated with the antibiotic, suggesting that the roles of parental strains in zygote formation were not identical. The results suggest a polar transfer of genetic material from Rab to Jucho, or PM5, although an alternative possibility of cell fusion followed by exclusion could not be excluded.
Topics: Acridines; Amino Acids; Conjugation, Genetic; Crosses, Genetic; Culture Media; DNA, Bacterial; Drug Resistance, Microbial; Mutation; Mycobacterium; Recombination, Genetic; Streptomycin
PubMed: 4691386
DOI: 10.1128/jb.113.3.1104-1111.1973 -
Molecules (Basel, Switzerland) Oct 2020Several new amino-substituted aza-acridine derivatives bearing a basic side chain have been designed and synthesized. The antiproliferative activity of the target...
Several new amino-substituted aza-acridine derivatives bearing a basic side chain have been designed and synthesized. The antiproliferative activity of the target compounds has been evaluated against three cancer cell lines-namely HCT-116 (colorectal), the uterine sarcoma MES-SA, and its doxorubicin-resistant variant MES-SA/Dx5. A limited number of the new acridines showed marginal cytotoxicity against the tested cell lines; nevertheless, these analogues possessed a similar substitution pattern. The moderate biological activity of these derivatives was attributed to their instability in aqueous media, which has been studied by mass spectrometry and computational chemistry experiments at the density functional level of theory (DFT).
Topics: Acridines; Aza Compounds; Cell Line, Tumor; Cell Proliferation; Doxorubicin; Drug Resistance, Neoplasm; Female; HCT116 Cells; Humans; Sarcoma; Uterine Neoplasms
PubMed: 33049986
DOI: 10.3390/molecules25194584 -
Bioorganic & Medicinal Chemistry Letters Jul 2008Novel thiourea- and guanidine-modified acridine-4-carboxamides (4, 7) and a corresponding platinum-intercalator conjugate (4') have been synthesized and evaluated as...
Novel thiourea- and guanidine-modified acridine-4-carboxamides (4, 7) and a corresponding platinum-intercalator conjugate (4') have been synthesized and evaluated as cytotoxic agents in human promyelocytic leukemia, HL-60, and a non-small cell lung cancer, NCI-H460. Modification of thiourea sulfur in derivative 4 with a DNA platinating moiety, giving 4', resulted in a pronounced cytotoxic enhancement, and the conjugate proved to be the most active of the newly synthesized compounds in NCI-H460 cells. Conjugate 4' represents a new chemotype with potential applications in the treatment of chemoresistant tumors.
Topics: Acridines; Antineoplastic Agents; Cell Line, Tumor; Chemistry, Pharmaceutical; Drug Design; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Guanidine; HL-60 Cells; Humans; Inhibitory Concentration 50; Models, Chemical; Platinum; Structure-Activity Relationship; Thiourea; Urea
PubMed: 18515101
DOI: 10.1016/j.bmcl.2008.05.043 -
Biomedicine & Pharmacotherapy =... Oct 2020This paper concerns the cytotoxicity of 9-chloro-1-nitroacridine (1a) and 9-chloro-4-methyl-1-nitroacridine (1b) against two biologically different melanoma forms:...
PURPOSE
This paper concerns the cytotoxicity of 9-chloro-1-nitroacridine (1a) and 9-chloro-4-methyl-1-nitroacridine (1b) against two biologically different melanoma forms: melanotic and amelanotic. Melanomas are tumors characterized by high heterogeneity and poor susceptibility to chemotherapies. Among new analogs synthesized by us, compound 1b exhibited the highest anticancer potency. Because of that, in this study, we analyzed the mechanism of action for 1a and its 4-methylated derivative, 1b, against a pair of biological melanoma forms, with regard to proliferation, cell death mechanism and energetic state.
METHODS
Cytotoxicity was evaluated by XTT assay. Cell death was estimated by plasma membrane structure changes (phosphatidylserine externalization), caspase activation, and ROS presence. The energetic state of cells was estimated based on NAD and ATP levels, and the activity of tricarboxylic acid cycle enzymes (pyruvate dehydrogenase complex, aconitase, isocitrate dehydrogenase).
RESULTS
The chloroacridines affect biological forms of melanoma in different ways. Amelanotic (Ab) melanoma (with inhibited melanogenesis and higher malignancy) was particularly sensitive to the action of the chloroacridines. The Ab melanoma cells died through apoptosis and through death without caspase activation. Diminished activity of TAC enzymes was noticed among Ab melanoma cells together with ATP/NAD depletion, especially in the case of 1b.
CONCLUSION
Our data show that the biological forms of the tumors responded to 1a and its 4-methylated analog in different ways. 1a and 1b could be inducers of regulated melanoma cell death, especially the amelanotic form. Although the mechanism of the cell death is not fully understood, 1b may act by interfering with the TAC enzymes and blocking specific pathways leading to tumor growth. This could encourage further investigation of its anticancer activity, especially against the amelanotic form of melanoma.
Topics: Acridines; Adenosine Triphosphate; Antineoplastic Agents; Apoptosis; Biomarkers; Cell Death; Cell Line, Tumor; Citric Acid Cycle; Energy Metabolism; Enzyme Inhibitors; Humans; NAD; Reactive Oxygen Species
PubMed: 34321163
DOI: 10.1016/j.biopha.2020.110515 -
Zeitschrift Fur Naturforschung. C,... 1998The effects of acridine derivatives (proflavine and 2,7-dialkyl derivatives, diacridines and triacridines, 9-aminoacridine carboxamides, and 9-anilinoacridine, amsacrine...
The effects of acridine derivatives (proflavine and 2,7-dialkyl derivatives, diacridines and triacridines, 9-aminoacridine carboxamides, and 9-anilinoacridine, amsacrine and its congeners) on overall RNA synthesis in vitro, on synthesis of initiating oligonucleotides and the binding of the enzyme to DNA were studied. The primary mechanism of action is related to inhibition of the enzyme binding to DNA. The acridines (intercalating or non-intercalating and bis-intercalating ligands) assayed here differ in the properties of their complexes with DNA. Correlation is generally observed between inhibition of RNA synthesis in vitro and cytotoxicity in cell cultures for di- and triacridines and 9-aminoacridine carboxamide derivatives. No relationship was found between the effect on RNA polymerase system and biological effects for amsacrine and its derivatives in contrast to the other series of acridines studied here. The aniline ring seems to decrease the inhibitory potency of a ligand. The discrepancy between the biological effect and RNA synthesis inhibition may be due to a different mechanism of cytotoxicity action of amsacrine which is a potent topoisomerase II poison.
Topics: Acridines; Bacteriophage T7; DNA-Directed DNA Polymerase; Escherichia coli; Intercalating Agents; Molecular Structure; RNA; Structure-Activity Relationship; Transcription, Genetic
PubMed: 9679327
DOI: 10.1515/znc-1998-5-610