The compounds from eight different thiazolidine and thiazole series were assessed as potential antileishmanial scaffolds. They were tested for antileishmanial activity against promastigotes of Leishmania major using in vitro primary screen and dose response assays. The compounds from six thiazolidine and thiazole series were identified as the hits with antileishmanial activity against L. major. However, the analyses of structure-activity relations (SARs) showed that the interpretable SARs were obtained only for phenyl-indole hybrids (compounds C1, C2, C3 and C5) as the most effective compounds against L. major promastigotes (IC50 < 10 µM) with low toxicity to human fibroblasts. For the scaffold of these compounds, the most significant SAR patterns were: free N3 position of thiazolidinone core, absence of big fragments at the C5 position of thiazolidinone core and presence of halogen atoms or nitro group in the phenyl ring of phenyl-indole fragment. As previous studies showed that these compounds also have activity against the two Trypanosoma species, Trypanosoma brucei and Trypanosoma gambiense, their scaffold could be associated with a broader antiparasitic activity.
- MeSH
- fibroblasty účinky léků MeSH
- knihovny malých molekul chemie farmakologie toxicita MeSH
- Leishmania major účinky léků MeSH
- lidé MeSH
- molekulární struktura MeSH
- parazitické testy citlivosti MeSH
- thiazolidiny chemie farmakologie toxicita MeSH
- trypanocidální látky chemie farmakologie toxicita MeSH
- Trypanosoma brucei brucei účinky léků MeSH
- Trypanosoma brucei gambiense účinky léků MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
(4-Oxo-2-thioxothiazolidin-3-yl)acetic acids exhibit a wide range of pharmacological activities. Among them, the only derivative used in clinical practice is the aldose reductase inhibitor epalrestat. Structurally related compounds, [(5Z)-(5-arylalkylidene-4-oxo-2-thioxo-1,3-thiazolidin-3-yl)]acetic acid derivatives were prepared previously as potential antifungal agents. This study was aimed at the determination of aldose reductase inhibitory action of the compounds in comparison with epalrestat and evaluation of structure-activity relationships (SAR). The aldose reductase (ALR2) enzyme was isolated from the rat eye lenses, while aldehyde reductase (ALR1) was obtained from the kidneys. The compounds studied were found to be potent inhibitors of ALR2 with submicromolar IC50 values. (Z)-2-(5-(1-(5-butylpyrazin-2-yl)ethylidene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid (3) was identified as the most efficacious inhibitor (over five times more potent than epalrestat) with mixed-type inhibition. All the compounds also exhibited low antiproliferative (cytotoxic) activity to the HepG2 cell line. Molecular docking simulations of 3 into the binding site of the aldose reductase enzyme identified His110, Trp111, Tyr48, and Leu300 as the crucial interaction counterparts responsible for the high-affinity binding. The selectivity factor for 3 in relation to the structurally related ALR1 was comparable to that for epalrestat. SAR conclusions suggest possible modifications to improve further inhibition efficacy, selectivity, and biological availability in the group of rhodanine carboxylic acids.
- MeSH
- aldehydreduktasa antagonisté a inhibitory metabolismus MeSH
- buňky Hep G2 MeSH
- inhibitory enzymů chemická syntéza chemie farmakologie MeSH
- kyselina octová chemická syntéza chemie farmakologie MeSH
- lidé MeSH
- ligandy MeSH
- oční čočka účinky léků enzymologie MeSH
- potkani Wistar MeSH
- rhodanin analogy a deriváty chemie farmakologie MeSH
- thiazolidiny chemie farmakologie MeSH
- vazebná místa MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: The possible use of acridines as anticancer agents was first considered in the 1920´s. Since then, a large number of acridine drugs have been tested as antitumour agents, including compounds containing sulphur on the acridine chromophore. In this review, we will discuss recent studies which have investigated the anticancer activity of this class of acridine derivatives. METHODS: We present the results both of our own decade-long research and also of existing research literature into the anticancer activity of acridine derivatives containing sulphur. The evidence of specific tumor-cell killing properties displayed by these compounds suggest the potential of using such molecules as anticancer therapeutics. RESULTS: During the last decade, a number of acridine analogs have been developed by modifying the position and the nature of the substituent on the acridine core. In this paper, we published results on the anticancer activity of acridine derivatives containing sulfur (acridine thioureas, acridine thiazolidine/thiazoidinone, and acridine thiosemicarbazones/ thiosemicarbazides). In cancer chemotherapy, the mechanism of the drugs is complex, although the study of the anticancer activity of acridines has yielded exciting results. CONCLUSION: In this review we have summarized recent literature on the anticancer activity of acridine derivatives containing sulfur. A considerable amount of published data suggests that these compounds exhibit promising anticancer activity against selected cancer cell lines. The obtained results can be helpful in the development of new pharmaceutical agents.
- MeSH
- akridiny farmakologie MeSH
- antitumorózní látky farmakologie MeSH
- léky antitumorózní - screeningové testy MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- thiazolidiny farmakologie MeSH
- thiomočovina analogy a deriváty farmakologie MeSH
- thiosemikarbazony farmakologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
The mitotic kinase Aurora-A and its partner protein TPX2 (Targeting Protein for Xenopus kinesin-like protein 2) are overexpressed in cancers, and it has been proposed that they work together as an oncogenic holoenzyme. TPX2 is responsible for activating Aurora-A during mitosis, ensuring proper cell division. Disruption of the interface with TPX2 is therefore a potential target for novel anticancer drugs that exploit the increased sensitivity of cancer cells to mitotic stress. Here, we investigate the interface using coprecipitation assays and isothermal titration calorimetry to quantify the energetic contribution of individual residues of TPX2. Residues Tyr8, Tyr10, Phe16, and Trp34 of TPX2 are shown to be crucial for robust complex formation, suggesting that the interaction could be abrogated through blocking any of the three pockets on Aurora-A that complement these residues. Phosphorylation of Aurora-A on Thr288 is also necessary for high-affinity binding, and here we identify arginine residues that communicate the phosphorylation of Thr288 to the TPX2 binding site. With these findings in mind, we conducted a high-throughput X-ray crystallography-based screen of 1255 fragments against Aurora-A and identified 59 hits. Over three-quarters of these hits bound to the pockets described above, both validating our identification of hotspots and demonstrating the druggability of this protein-protein interaction. Our study exemplifies the potential of high-throughput crystallography facilities such as XChem to aid drug discovery. These results will accelerate the development of chemical inhibitors of the Aurora-A/TPX2 interaction.
- MeSH
- aurora kinasa A chemie metabolismus MeSH
- jaderné proteiny chemie metabolismus MeSH
- krystalografie rentgenová MeSH
- lidé MeSH
- ligandy MeSH
- mapy interakcí proteinů účinky léků MeSH
- objevování léků MeSH
- proteiny asociované s mikrotubuly chemie metabolismus MeSH
- proteiny buněčného cyklu chemie metabolismus MeSH
- simulace molekulového dockingu MeSH
- thiazolidiny chemie farmakologie MeSH
- vazba proteinů účinky léků MeSH
- vazebná místa účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Actin cytoskeleton is a vital cellular structure primarily known for controlling cell integrity, division and expansion. Here we present a proteomic dissection of Arabidopsis roots treated by actin depolymerizing agent latrunculin B. Pharmacological disintegration of the actin cytoskeleton by latrunculin B caused downregulation of several proteins involved in the actin organization and dynamics. Moreover, this approach helped to identify new protein candidates involved in gene transcription, due to the altered abundance of proteins involved in mRNA nuclear export. Finally, latrunculin B negatively affected the abundance of abscisic acid (ABA) responsive proteins. SIGNIFICANCE: This article substantially contributes to the current knowledge about the importance of actin organization and dynamics in proteome remodelling. We employed gel based and gel free proteomic analyses and identified several new protein candidates and protein networks linking actin dynamics to the gene transcription and to the ABA response in Arabidopsis.
- MeSH
- aktiny chemie metabolismus MeSH
- Arabidopsis chemie MeSH
- bicyklické sloučeniny heterocyklické farmakologie MeSH
- kořeny rostlin chemie MeSH
- kyselina abscisová fyziologie MeSH
- mikrofilamenta účinky léků MeSH
- polymerizace účinky léků MeSH
- proteiny huseníčku analýza chemie metabolismus MeSH
- proteom analýza účinky léků MeSH
- proteomika metody MeSH
- thiazolidiny farmakologie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND: We investigated the targeting of microtubules (MT) and F-actin cytoskeleton (AC) of the human pathogenic yeast Cryptococcus neoformans with agents for cancer therapy, in order to examine whether this yeast cytoskeleton could become a new antifungal target for the inhibition of cell division. METHODS: Cells treated with 10 cytoskeleton inhibitors in yeast extract peptone dextrose medium were investigated by phase-contrast and fluorescence microscopy, and growth inhibition was estimated by cell counts using a Bürker chamber and measuring absorbance for 6 days. RESULTS: Docetaxel, paclitaxel, vinblastine sulfate salt, cytochalasin D and chlorpropham [isopropyl N-(3-chlorophenyl) carbamate] did not inhibit proliferation. The MT inhibitors methyl benzimidazole-2-ylcarbamate (BCM), nocodazole, thiabendazole (TBZ) and vincristine (VINC) disrupted MT and inhibited mitoses, but anucleated buds emerged on cells that increased in size, vacuolated and seemed to die after 2 days. The response of the cells to the presence of the actin inhibitor latrunculin A (LA) included the disappearance of actin patches, actin cables and actin rings; this arrested budding and cell division. However, in 3-4 days, resistant budding cells appeared in all 5 inhibitors. Disruption of the MT and AC and inhibition of cell division and budding persisted only when the MT and AC inhibitors were combined, i.e. VINC + LA, BCM + LA or TBZ + LA. CONCLUSION: The MT and AC of C. neoformans are new antifungal targets for the persistent inhibition of cell division by combined F-actin and MT inhibitors.
- MeSH
- aktiny antagonisté a inhibitory MeSH
- antifungální látky farmakologie MeSH
- antitumorózní látky farmakologie MeSH
- bicyklické sloučeniny heterocyklické farmakologie MeSH
- buněčné dělení účinky léků MeSH
- Cryptococcus neoformans účinky léků MeSH
- fluorescenční mikroskopie MeSH
- lidé MeSH
- mikrofilamenta účinky léků MeSH
- mikrotubuly účinky léků MeSH
- racionální návrh léčiv MeSH
- thiazolidiny farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Our basic cell biology research was aimed at investigating the effect on eukaryotic cells of the sudden loss of the F-actin cytoskeleton. Cells treated with latrunculin A (LA) in yeast extract peptone dextrose (YEPD) medium were examined using phase-contrast and fluorescent microscopy, freeze-substitution, transmission and scanning electron microscopy, counted using a Bürker chamber and their absorbance measured. The cells responded to the presence of LA, an F-actin inhibitor, with the disappearance of actin patches, actin cables and actin rings. This resulted in the formation of larger spherical cells with irregular morphology in the cell walls and ultrastructural disorder of the cell organelles and secretory vesicles. Instead of buds, LA-inhibited cells formed only 'table-mountain-like' wide flattened swellings without apical growth with a thinner glucan cell-wall layer containing β-1,3-glucan microfibrils. The LA-inhibited cells lysed. Actin cables and patches were required for bud formation and bud growth. In addition, actin patches were required for the formation of β-1,3-glucan microfibrils in the bud cell wall. LA has fungistatic, fungicidal and fungilytic effects on the budding yeast Saccharomyces cerevisiae.
- MeSH
- aktiny antagonisté a inhibitory MeSH
- antifungální látky farmakologie MeSH
- bicyklické sloučeniny heterocyklické farmakologie MeSH
- mikrobiální viabilita účinky léků MeSH
- mikroskopie MeSH
- počet mikrobiálních kolonií MeSH
- Saccharomyces cerevisiae cytologie účinky léků fyziologie MeSH
- Saccharomycetales cytologie účinky léků fyziologie MeSH
- thiazolidiny farmakologie MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: This basic research aimed to investigate the effects of the actin inhibitor latrunculin A (LA) on the human pathogen Cryptococcus neoformans, by freeze-substitution (FS) and electron microscopy (EM), to determine whether the actin cytoskeleton can become a new antifungal target for inhibition of cell division. METHODS: Cells treated with LA for 20 h in yeast-extract peptone dextrose medium were investigated by phase-contrast and fluorescent microscopy, FS and transmission EM, counted in a Bürker chamber and the absorbance was then measured. RESULTS: The disappearance of actin patches, actin cables and actin rings demonstrated the response of the cells of C. neoformans to the presence of the actin inhibitor LA. The removal of actin cables and patches arrested proliferation and led to the production of cells that had ultrastructural disorder, irregular morphology of the mitochondria and thick aberrant cell walls. Budding cells lysed in the buds and septa. CONCLUSION: LA exerts fungistatic, fungicidal and fungilytic effects on the human pathogenic yeast C. neoformans.
- MeSH
- aktiny antagonisté a inhibitory MeSH
- antifungální látky farmakologie MeSH
- bicyklické sloučeniny heterocyklické farmakologie MeSH
- buněčná stěna účinky léků metabolismus MeSH
- buněčné dělení účinky léků MeSH
- Cryptococcus neoformans účinky léků metabolismus MeSH
- elektronová mikroskopie metody MeSH
- fluorescenční mikroskopie metody MeSH
- kryptokokóza farmakoterapie metabolismus mikrobiologie MeSH
- lidé MeSH
- mikrofilamenta účinky léků metabolismus MeSH
- proliferace buněk účinky léků MeSH
- thiazolidiny farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The F-actin cytoskeleton of Cryptococcus neoformans is known to comprise actin cables, cortical patches and cytokinetic ring. Here, we describe a new F-actin structure in fungi, a perinuclear F-actin collar ring around the cell nucleus, by fluorescent microscopic imaging of rhodamine phalloidin-stained F-actin. Perinuclear F-actin rings form in Cryptococcus neoformans treated with the microtubule inhibitor Nocodazole or with the drug solvent dimethyl sulfoxide (DMSO) or grown in yeast extract peptone dextrose (YEPD) medium, but they are absent in cells treated with Latrunculin A. Perinuclear F-actin rings may function as 'funicular cabin' for the cell nucleus, and actin cables as intracellular 'funicular' suspending nucleus in the central position in the cell and moving nucleus along the polarity axis along actin cables.
- MeSH
- aktiny analýza MeSH
- bicyklické sloučeniny heterocyklické farmakologie MeSH
- buněčné jádro ultrastruktura MeSH
- Cryptococcus neoformans účinky léků fyziologie ultrastruktura MeSH
- dimethylsulfoxid farmakologie MeSH
- elektronová mikroskopie MeSH
- faloidin analogy a deriváty MeSH
- fluorescenční mikroskopie MeSH
- mikrofilamenta ultrastruktura MeSH
- mikrotubuly účinky léků MeSH
- modulátory tubulinu farmakologie MeSH
- mořské toxiny farmakologie MeSH
- nokodazol farmakologie MeSH
- rhodaminy MeSH
- scavengery volných radikálů farmakologie MeSH
- thiazolidiny farmakologie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The unique long-neck yeast Fellomyces fuzhouensis has F-actin cables and cortical patches. Here, we describe a new F-actin structure present in fungi, a perinuclear F-actin collar ring around the cell nucleus. This F-actin structure can be visualized by fluorescent microscopic imaging of rhodamine-phalloidin-stained F-actin in cells treated with the mitotic drug isopropyl N-(3-chlorophenyl) carbamate or the microtubule inhibitor thiabendazol or when cells were grown in cut dried radish medium or yeast extract pepton dextrose (YEPD) medium. In contrast, these structures were absent in cells treated with Latrunculin A. The hypothetical functions of the F-actin ring are discussed.
- MeSH
- aktiny metabolismus MeSH
- Basidiomycota účinky léků růst a vývoj metabolismus ultrastruktura MeSH
- bicyklické sloučeniny heterocyklické farmakologie MeSH
- buněčné jádro metabolismus MeSH
- fluorescenční mikroskopie MeSH
- mikrofilamenta metabolismus ultrastruktura MeSH
- thiazolidiny farmakologie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
