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1.
J Enzyme Inhib Med Chem ; 39(1): 2284113, 2024 Dec.
Article in English | MEDLINE | ID: mdl-38078360

ABSTRACT

Anthraquinones have attracted considerable interest in the realm of cancer treatment owing to their potent anticancer properties. This study evaluates the potential of a series of new anthraquinone derivatives as anticancer agents for non-small-cell lung cancer (NSCLC). The compounds were subjected to a range of tests to assess their cytotoxic and apoptotic properties, ability to inhibit colony formation, pro-DNA damage functions, and capacity to inhibit the activity of tyrosine kinase proteins (PTKs). Based on the research findings, it has been discovered that most active derivatives (i84, i87, and i90) possess a substantial capability to impede the viability of NSCLC while having mostly a negligible effect on the human kidney cell line. Moreover, the anthraquinones displayed pro-apoptotic and genotoxic attributes while blocking the phosphorylation of multiple PTKs. Collectively, our findings indicate that these derivatives may demonstrate promising potential as effective anticancer agents for lung cancer treatment.


Subject(s)
Antineoplastic Agents , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/metabolism , Lung Neoplasms/drug therapy , Lung Neoplasms/metabolism , Protein-Tyrosine Kinases , Apoptosis , Cell Line, Tumor , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Anthraquinones/pharmacology , Anthraquinones/therapeutic use , Cell Proliferation
2.
Cell Death Dis ; 13(11): 1005, 2022 11 28.
Article in English | MEDLINE | ID: mdl-36437244

ABSTRACT

Telomerase reactivation is one of the hallmarks of cancer, which plays an important role in cellular immortalization and the development and progression of the tumor. Chemical telomerase inhibitors have been shown to trigger replicative senescence and apoptotic cell death both in vitro and in vivo. Due to its upregulation in various cancers, telomerase is considered a potential target in cancer therapy. In this study, we identified potent, small-molecule telomerase inhibitors using a telomerase repeat amplification protocol assay. The results of the assay are the first evidence of telomerase inhibition by anthraquinone derivatives that do not exhibit G-quadruplex-stabilizing properties. The stability of telomerase in the presence of its inhibitor was evaluated under nearly physiological conditions using a cellular thermal shift assay. Our data showed that the compound induced aggregation of the catalytic subunit (hTERT) of human telomerase, and molecular studies confirmed the binding of the hit compound with the active site of the enzyme. The ability of new derivatives to activate DNA double-strand breaks (DSBs) was determined by high-resolution microscopy and flow cytometry in tumor cell lines differing in telomere elongation mechanism. The compounds triggered DSBs in TERT-positive A549 and H460 lung cancer cell lines, but not in TERT-negative NHBE normal human bronchial epithelial and ALT-positive U2OS osteosarcoma cell lines, which indicates that the induction of DSBs was dependent on telomerase inhibition. The observed DNA damage activated DNA damage response pathways involving ATM/Chk2 and ATR/Chk1 cascades. Additionally, the compounds induced apoptotic cell death through extrinsic and intrinsic pathways in lung cancer cells. Taken together, our study demonstrated that anthraquinone derivatives can be further developed into novel telomerase-related anticancer agents.


Subject(s)
Bone Neoplasms , Lung Neoplasms , Telomerase , Humans , Telomere , DNA Damage , Anthraquinones/pharmacology , Cell Line, Tumor
3.
Acta Chim Slov ; 69(3): 584-595, 2022 Sep 26.
Article in English | MEDLINE | ID: mdl-36196813

ABSTRACT

The synthesis of new N-(9,10-dioxo-9,10-dihydroanthracen-1(2)-yl)-2-(R-thio) acetamides was carried out using reaction of 2-chloro-N-(9,10-dioxo-9,10-dihydroanthracene-1(2)-yl)acetamides with functionalized thiols in the presence of potassium carbonate in N,N-dimethylformamide (DMF) at room temperature. Evaluation of the synthesized compounds on such indicators of radical scavenging activity as lipid peroxidation (LP) and oxidative modification of proteins (OMP) in vitro in rat liver homogenate was carried out. It was determined that the compounds with a substituent in the first position of anthracedione core showed better antioxidant properties than their isomers with a substituent in the second position. The compounds 6 and 7 with the best indicators of radical-scavenging activity were determined. Antioxidant effect in OMP processes was also determined for compound 10. The antiplatelet activity study in vitro revealed compound 10 with the inhibited effect of ADP-induced aggregation.


Subject(s)
Acetamides , Antioxidants , Acetamides/pharmacology , Adenosine Diphosphate , Animals , Antioxidants/pharmacology , Dimethylformamide , Rats , Structure-Activity Relationship , Sulfhydryl Compounds
4.
Molecules ; 27(18)2022 Sep 12.
Article in English | MEDLINE | ID: mdl-36144663

ABSTRACT

The [1,2,3]triazin-4(3H)-one ring is a synthetically important molecular platform for a variety of chemical transformations. Despite this, currently, there has been little research on the reaction of the thermal opening of the [1,2,3]triazin-4(3H)-one nucleus. In this work, we describe the synthetic potential of anthra[1,2-d][1,2,3]triazine-4,7,12(3H)-trione in the reaction of the thermal opening of a cycle following the [4+2]-cycloaddition reaction with a number of pyridine derivatives and quinoline. It is shown that this method is effective for the synthesis of the 6H-naphtho[2,3-H]pyrido(quinolino)[2,1-b]quinazoline-6,9,14-trione system. We also investigate the influence of the position of substituents in the structure of pyridine on the formation characteristics of the target products.


Subject(s)
Quinolines , Triazines , Molecular Structure , Pyridines/chemistry , Quinazolines , Triazines/chemistry
5.
Chem Biodivers ; 19(7): e202100931, 2022 Jul.
Article in English | MEDLINE | ID: mdl-35674435

ABSTRACT

The ketene dithioacetal 3 generated from 2-nitroperchlorobutadiene 1 reacted with various heterocyclic amines and aliphatic, aromatic and heterocyclic thiols to produce functionalized new ketene-N,S,S-acetals and S,S,S-acetals 4a-f, 5a-h as heterocyclic dithiolanes. They were separated/purified by chromatographic methods and their exact structure characterization were made clear by spectroscopic methods. These compounds synthesized could act as effective drugs for versatile activity. Evaluation of the antimicrobial effect of the obtained substances determined derivatives 4e and 5h, which have MIC=15.6 µg/mL for the test culture of Mycobacterium luteum bacteria closing to the control drug Vancomycin. The obtained compounds can be proposed as a promising synthetic objects for future molecular design to enhance the antimicrobial action. Ketene dithioacetals 3, 4a, 4b, 4e, 5g (50 mg/kg) exhibited antiseizure effect comparable with reference drug (valproic acid) on the model of pentylenetetrazole-induced convulsions after single oral administration both at 3 h and 24 h. Furthermore, tested dithioacetals possessed prolonged antidepressant activity in forced swim test (FST) considerable decreasing the duration of immobility time compared to reference drug amitriptyline. This is the first study of the investigation of anticonvulsant and antidepressant activities of ketene dithioacetals.


Subject(s)
Acetals , Antifungal Agents , Acetals/chemistry , Acetals/pharmacology , Anti-Bacterial Agents/pharmacology , Anticonvulsants/pharmacology , Antidepressive Agents/chemistry , Antidepressive Agents/pharmacology , Antifungal Agents/pharmacology , Ethylenes , Ketones
6.
Molecules ; 24(24)2019 Dec 13.
Article in English | MEDLINE | ID: mdl-31847306

ABSTRACT

The development and spread of resistance of human pathogenic bacteria to the action of commonly used antibacterial drugs is one of the key problems in modern medicine. One of the especially dangerous and easily developing antibiotic resistant bacterial species is Staphylococcus aureus. Anthra[1,2-d][1,2,3]triazine-4,7,12(3H)-triones 22-38 have been developed as novel effective antistaphylococcal agents. These compounds have been obtained by sequential conversion of 1-amino-9,10-dioxo-9,10-dihydroanthracene-2-carboxylic acid (1) and 1-amino-4-bromo-9,10-dioxo-9,10-dihydroanthracene-2-carboxylic acid (2) into the corresponding amides 5-21, followed by subsequent endo-cyclization under the influence of sodium nitrite in acetic acid. Evaluation of the antimicrobial activity of the synthesized compounds against selected species of Gram-positive and Gram-negative bacteria as well as pathogenic yeasts of the Candida genus has been carried out by the serial dilution method. It has been established that anthra[1,2-d][1,2,3]triazine-4,7,12(3H)-triones exhibit selective antibacterial activity against Gram-positive bacteria. Eight, six and seven, out of seventeen compounds tested, effectively inhibited the growth of S. aureus ATCC 25923, S. aureus ATCC 29213 and S. epidermidis ATCC12228, respectively, at a concentration equal to 1 µg/mL or lower. The high antistaphylococcal potential of the most active compounds has been also confirmed against clinical isolates of S. aureus, including the MRSA strains. However, bacteria of the Staphylococcus genus have demonstrated apparent resistance to the novel compounds when grown as a biofilm. None of the four selected compounds 3234 and 36 at a concentration of 64 µg/mL (128 or 256 × MIC-against planktonic cells) has caused any decrease in the metabolic activity of the staphylococcal cells forming the biofilm. The kinetic time-kill assay revealed some important differences in the activity of these substances. Compound 33 is bacteriostatic, while the other three demonstrate bactericidal activity.


Subject(s)
Anti-Bacterial Agents/chemical synthesis , Biofilms/growth & development , Triazines/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Biofilms/drug effects , Drug Resistance, Bacterial , Gram-Positive Bacteria/drug effects , Microbial Sensitivity Tests , Molecular Structure , Staphylococcus aureus/drug effects , Staphylococcus aureus/physiology , Staphylococcus epidermidis/drug effects , Staphylococcus epidermidis/physiology , Triazines/chemistry , Triazines/pharmacology
7.
J Agric Food Chem ; 67(11): 3114-3117, 2019 Mar 20.
Article in English | MEDLINE | ID: mdl-30811195

ABSTRACT

Derivatives of 2(5 H)-furanone (γ-crotonolactone) are important intermediate synthetic products with a wide range of biological effects that have become widely used in the pharmaceutical industry, medicine, and veterinary medicine, in particular in the prevention and treatment of fish diseases. However, the environmental issue of obtaining these compounds while reducing the negative impact on the surrounding environment remains relevant. This article describes for the first time a method of γ-crotonolactone synthesis that is based on the concept of green chemistry. Synthesis is carried out under mild conditions using nontoxic reagents by furfural oxidation. For the first time, a mixture of hydrogen peroxide and acetic acid was used for the oxidation of furfural in a ratio of 1:0.05. A mixture of organic acids (succinic, maleic, fumaric, formic, and cinnamic acids), obtained as a byproduct in the synthesis of γ-crotonolactone, can be used as a highly effective, ecofriendly organic fertilizer or in a preparation with a stimulating effect.


Subject(s)
Food Preservatives/chemical synthesis , Furans/chemistry , Green Chemistry Technology/methods , Hydrogen Peroxide/chemistry , 4-Butyrolactone/analogs & derivatives , 4-Butyrolactone/chemistry , Acetic Acid/chemistry , Acids/chemistry , Oxidation-Reduction
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