Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 5 de 5
Filter
Add more filters










Database
Language
Publication year range
1.
Int J Mol Sci ; 22(11)2021 May 22.
Article in English | MEDLINE | ID: mdl-34067346

ABSTRACT

Prenylated flavonoids are an important class of naturally occurring flavonoids with important biological activity, but their low abundance in nature limits their application in medicines. Here, we showed the hemisynthesis and the determination of various biological activities of seven prenylated flavonoids, named 7-13, with an emphasis on antimicrobial ones. Compounds 9, 11, and 12 showed inhibitory activity against human pathogenic fungi. Compounds 11, 12 (flavanones) and 13 (isoflavone) were the most active against clinical isolated Staphylococcus aureus MRSA, showing that structural requirements as prenylation at position C-6 or C-8 and OH at positions C-5, 7, and 4' are key to the antibacterial activity. The combination of 11 or 12 with commercial antibiotics synergistically enhanced the antibacterial activity of vancomycin, ciprofloxacin, and methicillin in a factor of 10 to 100 times against drug-resistant bacteria. Compound 11 combined with ciprofloxacin was able to decrease the levels of ROS generated by ciprofloxacin. According to docking results of S enantiomer of 11 with ATP-binding cassette transporter showed the most favorable binding energy; however, more studies are needed to support this result.


Subject(s)
Anti-Bacterial Agents/pharmacology , Flavonoids/pharmacology , Prenylation/physiology , ATP-Binding Cassette Transporters/metabolism , Animals , Cell Line , Cell Line, Tumor , Computer Simulation , Flavanones/pharmacology , Fungi/drug effects , Humans , Isoflavones/pharmacology , Mice , Microbial Sensitivity Tests/methods , Reactive Oxygen Species/metabolism , Staphylococcus aureus/drug effects
2.
Front Pharmacol ; 11: 1125, 2020.
Article in English | MEDLINE | ID: mdl-32848744

ABSTRACT

Flavanones (-)-(2S)-5,4'-dihydroxy-7-methoxyflavanone (1) and (-)-(2S)-5,3',4'-trihydroxy-7-methoxyflavanone (2) were isolated from the extracts of Calceolaria thyrsiflora Graham, an endemic perennial small shrub growing in the central zone of Chile. The absolute configuration of these compounds was resolved by optical rotation experiments and in silico calculations. Three analogs (3, 4, and 5) were synthesized to do structure-activity relationships with the biological assays studied. Biological tests revealed that only flavanone 2 exhibited a moderate inhibitory activity against the methicillin-resistant strain S. aureus MRSA 97-77 (MIC value of 50 µg/ml). In addition, flavanone 2 showed a potent, selective, and competitive inhibition of 5-hLOX, which supports the traditional use of this plant as an anti-inflammatory in diseases of the respiratory tract. Also, 2 exhibited cytotoxic and selective effects against B16-F10 (8.07 ± 1.61 µM) but 4.6- and 17-fold lesser activity than etoposide and taxol.

3.
Bioorg Chem ; 82: 385-392, 2019 02.
Article in English | MEDLINE | ID: mdl-30428417

ABSTRACT

We investigated twelve benzyl phenyl ketone derivatives which are synthetic precursors of isoflavonoids that are shown be good 5-hLOX inhibitors, especially those that have the catechol group, but these precursors never have been assayed as 5-hLOX inhibitors being a novelty as inhibitors of the enzyme, due to sharing important structural characteristics. Screening assays, half maximal inhibitory concentration (IC50) and kinetic assays of all the studied molecules (5 µg/ml in media assay) showed that 1-(2,4-dihydroxy-3-methylphenyl)-2-(3-chlorophenyl)-ethanone (K205; IC50 = 3.5 µM; Ki = 4.8 µM) and 1-(2,4-dihydroxy-3-methylphenyl)-2-(2-nitrophenyl)-ethanone (K206; IC50 = 2.3 µM; Ki = 0.7 µM) were potent, selective, competitive and nonredox inhibitors of 5-hLOX. Antioxidant behavior was also assayed by DPPH, FRAP, and assessing ROS production, and those with antibacterial and antiproliferative properties relating to 1-(2,4-dihydroxy-3-methylphenyl)-2-(2-chlorophenyl)-ethanone (K208) established it as the most interesting and relevant compound studied, as it showed nearly 100% inhibition of bacterial growth of Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). Finally, docking studies were done that helped to characterize how the inhibitor structures correlated to decreased 5-hLOX activity.


Subject(s)
Anti-Bacterial Agents/pharmacology , Benzoin/analogs & derivatives , Benzoin/pharmacology , Lipoxygenase Inhibitors/pharmacology , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Arachidonate 5-Lipoxygenase/chemistry , Arachidonate 5-Lipoxygenase/metabolism , Benzoin/chemical synthesis , Catalytic Domain , Cell Line, Tumor , Drug Synergism , Escherichia coli/drug effects , Humans , Lipoxygenase Inhibitors/chemical synthesis , Lipoxygenase Inhibitors/chemistry , Methicillin/pharmacology , Mice , Microbial Sensitivity Tests , Molecular Docking Simulation , Reactive Oxygen Species/metabolism , Staphylococcus aureus/drug effects
4.
Exp Gerontol ; 110: 73-78, 2018 09.
Article in English | MEDLINE | ID: mdl-29782967

ABSTRACT

Immunosenescence has been described as age-associated changes in the immune function which are thought to be responsible for the increased morbidity with age. Human Natural Killer (NK) cells are a specialized heterogeneous subpopulation of lymphocytes involved in immune defense against tumor and microbial diseases. Interestingly, aging-related NK cell dysfunction is associated with features of aging such as tumor incidence, reduced vaccination efficacy, and short survival due to infection. It is known that NK cell effector functions are critically dependent on cytokines and metabolic activity. Our aim was to determine whether there is a difference in purified human NK cell function in response to high concentration of IL-2 between young and elder donors. Here, we report that the stimulation of human NK cells with IL-2 (2000 U/mL) enhance NK cell cytotoxic activity from both young and elderly donors. However, while NK cells from young people responded to IL-2 signaling by increasing mitochondrial mass and mitochondrial membrane potential, no increase in these mitochondrial functional parameters was seen in purified NK cells from elderly subjects. Moreover, as purified NK cells from the young exhibited an almost three-fold increase in PGC-1α expression after IL-2 (2000 U/mL) stimulation, PGC-1α expression was inhibited in purified NK cells from elders. Furthermore, this response upon PGC-1α expression after IL-2 stimulation promoted an increase in ROS production in NK cells from elderly humans, while no increase in ROS production was observed in NK cells of young donors. Our data show that IL-2 stimulates NK cell effector function through a signaling pathway which involves a PGC-1α-dependent mitochondrial function in young NK cells, however it seems that NK cells from older donors exhibit an altered IL-2 signaling which affects mitochondrial function associated with an increased production of ROS which could represent a feature of NK cell senescence.


Subject(s)
Killer Cells, Natural/metabolism , Mitochondria/metabolism , Organelle Biogenesis , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism , Aged , Aged, 80 and over , Cells, Cultured , Enzyme Inhibitors/pharmacology , Female , Humans , Interleukin-2/pharmacology , K562 Cells , Killer Cells, Natural/drug effects , Male , Membrane Potential, Mitochondrial , Middle Aged , Mitochondria/drug effects , Mitochondrial Proton-Translocating ATPases/antagonists & inhibitors , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics , Signal Transduction , Up-Regulation
5.
Molecules ; 23(2)2018 Feb 16.
Article in English | MEDLINE | ID: mdl-29462956

ABSTRACT

The synthesis of five novel homodimers is reported based on the anilinoisoquinolinequinone scaffold. In these twin-drug derivatives, two units of the anilinoquinone pharmacophores are linked through a methylene spacer. The formation of dimers was achieved by reaction of isoquinolinequinones with 4, 4'-diaminodiphenylmethane via a sequence of two oxidative amination reactions. A preliminary in vitro screening of the homodimers reveals moderate to high cytotoxic activities against MDA-MB-21 breast adenocarcinoma and B16-F10 murine metastatic melanoma cell lines. The asymmetrical homodimer 15 stands out due to its cytotoxic potencies at submicromolar concentrations and high selectivity index (mean IC50 = 0.37 µM; SI = 6.97) compared to those of etoposide (mean IC50 = 3.67; SI = 0.32) and taxol (mean IC50 = 0.35; SI = 0.91) employed as reference anticancer drugs.


Subject(s)
Aniline Compounds/chemical synthesis , Antineoplastic Agents/chemical synthesis , Benzoquinones/chemical synthesis , Isoquinolines/chemical synthesis , Aniline Compounds/pharmacology , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Benzoquinones/pharmacology , Breast Neoplasms/drug therapy , Cell Line, Tumor , Drug Screening Assays, Antitumor , Female , Humans , Isoquinolines/pharmacology , Melanoma, Experimental/drug therapy , Mice
SELECTION OF CITATIONS
SEARCH DETAIL
...