9,10-Dioxoanthracenyldithiocarbamates effectively inhibit the proliferation of non-small cell lung cancer by targeting multiple protein tyrosine kinases.

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.

Teloxantron inhibits the processivity of telomerase with preferential DNA damage on telomeres.

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.

N-(9,10-Dioxo-9,10-dihydroanthracen-1(2)-yl)-2-(R-thio) Acetamides: Synthesis, Antioxidant and Antiplatelet Activity.

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.

A Ring Opening-Annulation Reaction of Anthra[1,2-d][1,2,3]triazine-4,7,12(3H)-trione in the Presence of Pyridines as an Efficient Approach to the Construction of Naphtho[2,3-H]pyrido(quinolino)[2,1-b]quinazoline System.

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.

New Ketene Dithioacetals Generated from 2-Nitroperchlorobutadiene and Investigation of Their Antibacterial, Antifungal, Anticonvulsant and Antidepressant Activities.

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.

Anthra[1,2-d][1,2,3]triazine-4,7,12(3H)-triones as a New Class of Antistaphylococcal Agents: Synthesis and Biological Evaluation.

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.

Design, Synthesis, Biological Evaluation, and Antioxidant and Cytotoxic Activity of Heteroatom-Substituted 1,4-Naphtho- and Benzoquinones.

In the present paper, we report the synthesis, characterization, and biological evaluation as antifungal, antibacterial, antioxidant, and cytotoxic/anticancer agents of N-, S-, O-substituted-1,4-naphtho- and 2,5-bis(amino-substituted)-1,4-benzoquinone derivatives. In the synthesized compounds, antimicrobial activity at low concentrations against Escherichia coli B-906, Staphylococcus aureus 209-P, and Mycobacterium luteum B-917 bacteria and Candida tenuis VKM Y-70 and Aspergillus niger F-1119 fungi in comparison with controls was identified. 2-(N-Diphenylmethylpiperazin-1-yl)-3-chloro-1,4-naphthoquinone 9a was the most potent, with a minimum inhibitory concentration value of 3.9 µg/mL against test culture M. luteum. The synthesized compounds were screened for their antioxidant capacity using the cupric-reducing antioxidant capacity (CUPRAC) method. 2,2'-[1-(2-Aminoethyl)piperazin-1-yl]-3,3'-dichloro-bis(1,4-naphthoquinone) 10 showed the highest antioxidant capacity, with a 0.455 CUPRAC-trolox equivalent antioxidant capacity (TEAC) coefficient. Other parameters of antioxidant activity (scavenging effects on OH(·), O2(·ï¼), and H2O2) of these compounds were also determined. The cytotoxic activity of the compounds was investigated by employing the sulforhodamine B cell viability assay against A549 (lung), MCF-7 (breast), DU145 (prostate), and HT-29 (colon) cancer cell lines. Compound 10 exhibited the most powerful cytotoxic activity at a concentration of 20 µM against all cell lines. In addition to the strongest antioxidant activity of compound 10, it also had lowest IC50 values (<3 µM), warranting further in vivo studies due to its anticancer activity.

Synthesis and antimicrobial activity of N-substituted-ß-amino acid derivatives containing 2-hydroxyphenyl, benzo[b]phenoxazine and quinoxaline moieties.

3-[(2-Hydroxyphenyl)amino]butanoic and 3-[(2-hydroxy-5-methyl(chloro)phenyl)amino]butanoic acids were converted to a series of derivatives containing hydrazide, pyrrole and chloroquinoxaline moieties. The corresponding benzo[b]phenoxazine derivatives were synthesized by the reaction of the obtained compounds with 2,3-dichloro-1,4-naphthoquinone. Five of the synthesized compounds exhibited good antimicrobial activity against Staphylococcus aureus and Mycobacterium luteum, whereas three compounds showed significant antifungal activity against Candida tenuis and Aspergillus niger.

Tracking down biotransformation to the genetic level: identification of a highly flexible glycosyltransferase from Saccharothrix espanaensis.

Saccharothrix espanaensis is a member of the order Actinomycetales. The genome of the strain has been sequenced recently, revealing 106 glycosyltransferase genes. In this paper, we report the detection of a glycosyltransferase from Saccharothrix espanaensis which is able to rhamnosylate different phenolic compounds targeting different positions of the molecules. The gene encoding the flexible glycosyltransferase is not located close to a natural product biosynthetic gene cluster. Therefore, the native function of this enzyme might be not the biosynthesis of a secondary metabolite but the glycosylation of internal and external natural products as part of a defense mechanism.

Synthesis and microbiological evaluation of new 2- and 2,3-diphenoxysubstituted naphthalene-1,4-diones with 5-oxopyrrolidine moieties.

New 3-substituted 1-(3-hydroxyphenyl)-5-oxopyrrolidine derivatives containing hydrazone, azole, diazole, oxadiazole fragments, as well as 2-phenoxy- and 2,3-diphenoxy-1,4-naphthoquinone derivatives were synthesized. The structure of all compounds has been confirmed by NMR, IR, mass spectra, and elemental analysis data. Methyl 1-{3-[(3-chloro-1,4-dioxo-1,4-dihydro-2-naphthalenyl)oxy]phenyl}-5-oxo-3-pyrrolidinecarboxylate demonstrated potential antibacterial and antifungal activities as determined by diffusion and serial dilution methods, while N'-[(4-bromophenyl)methylidene]-1-{3-[(3-chloro-1,4-dioxo-1,4-dihydro-2-naphthalenyl)oxy]phenyl}-5-oxo-3-pyrrolidinecarbohydrazide and 2-{3-[4-(1,2,3-oxadiazol-5-yl)-2-oxo-1-pyrrolidinyl]phenoxy}-3-{3-[4-(1,3,4-oxadiazol-2-yl)-2-oxo- 1-pyrrolidinyl]phenoxy}naphthoquinone showed antifungal activity against Candida tenuis and Aspergillus niger at low concentrations, as determined by the serial dilution method. The substitution of the methoxy fragment by N-containing substituents in monophenoxy substituted naphthoquinones was found to decrease their activity against Mycobacterium luteum. Besides, introduction of the second phenoxy substituted fragment increased the antifungal activity against Candida tenuis and Aspergillus niger at lower concentrations.

Synthesis and biological evaluation of novel nitrogen- and sulfur-containing hetero-1,4-naphthoquinones as potent antifungal and antibacterial agents.

1,4-Naphthoquinones are unique reagents in organic synthesis and have been employed in several well known and recently developed areas of application. Furthermore, these 1,4-naphthoquinones have demonstrated high reactivity in nucleophilic vinylic substitutions, in the preparation of sulfurated, (hetero)cyclic and several other transformations. This study describes the synthesis and biological evaluation of derivatives of monosulfurated naphthalene-1,4-dione (3), 3-chloro-2-ethoxy-naphthalene-1,4-dione (4), disulfurated naphthalene-1,4-dione (5), and symmetrical bis-1,4-naphthoquinones (7, 9) were obtained from the reaction of 2,3-dichloro-naphthaquinone (1) with S-, O-substituted mono-, di-, and tetrathiols, respectively. The structures of the novel products were characterized by spectroscopic methods.