Inhibition of the human O-linked β-N-acetylglucosaminidase (hOGA, GH84) enzyme is pharmacologically relevant in several diseases such as neurodegenerative and cardiovascular disorders, type 2 diabetes, and cancer. Human lysosomal hexosaminidases (hHexA and hHexB, GH20) are mechanistically related enzymes; therefore, selective inhibition of these enzymes is crucial in terms of potential applications. In order to extend the structure-activity relationships of OGA inhibitors, a series of 2-acetamido-2-deoxy-d-glucono-1,5-lactone sulfonylhydrazones was prepared from d-glucosamine. The synthetic sequence involved condensation of N-acetyl-3,4,6-tri-O-acetyl-d-glucosamine with arenesulfonylhydrazines, followed by MnO2 oxidation to the corresponding glucono-1,5-lactone sulfonylhydrazones. Removal of the O-acetyl protecting groups by NH3/MeOH furnished the test compounds. Evaluation of these compounds by enzyme kinetic methods against hOGA and hHexB revealed potent nanomolar competitive inhibition of both enzymes, with no significant selectivity towards either. The most efficient inhibitor of hOGA was 2-acetamido-2-deoxy-d-glucono-1,5-lactone 1-naphthalenesulfonylhydrazone (5f, Ki = 27 nM). This compound had a Ki of 6.8 nM towards hHexB. To assess the binding mode of these inhibitors to hOGA, computational studies (Prime protein-ligand refinement and QM/MM optimizations) were performed, which suggested the binding preference of the glucono-1,5-lactone sulfonylhydrazones in an s-cis conformation for all test compounds.

• MeSH
• antigeny nádorové chemie   metabolismus   MeSH
• beta-hexosaminidasa, beta řetězec chemie   metabolismus   MeSH
• histonacetyltransferasy chemie   metabolismus   MeSH
• hyaluronoglukosaminidasa chemie   metabolismus   MeSH
• hydrazony chemická syntéza   chemie   farmakologie   MeSH
• inhibitory enzymů chemická syntéza   chemie   farmakologie   MeSH
• laktony chemie   MeSH
• lidé MeSH
• molekulární konformace MeSH
• molekulární modely MeSH
• oxidy chemie   MeSH
• sloučeniny manganu chemie   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Seven previously undescribed sesquiterpene lactones, three known sesquiterpene lactones (ixerin D, 15-p-hydroxyphenylacetyllactucin, and 15-p-hydroxyphenylacetyllactucin-8-sulfate), and two known quinic acid derivatives (3-O-feruloylquinic acid and 3,5-di-O-caffeoylquinic acid) were isolated from Sonchus palustris L. roots. Four formerly undescribed compounds were elucidated to be 3β,14-dihydroxycostunolide-3-O-β-D-glucopyranosyl-(2-O-p-hydroxyphenylacetyl)-14-O-p-hydroxyphenylacetate, 15-p-methoxyphenylacetyllactucin, 15-p-methoxyphenylacetyllactucin-8-sulfate, and 8-p-hydroxyphenylacetyllactucin-15-sulfate. Additionally, three undescribed conjugates of lactucin and a eudesmanolide type sesquiterpenic acid, sonchpalustrin, 4″-O-methylsonchpalustrin, and isosonchpalustrin, were characterized. The structures of the newly discovered natural products were elucidated using 1D and 2D NMR spectroscopy and UHPLC-HRMS. 15-p-Hydroxyphenylacetyllactucin and 15-p-methoxyphenylacetyllactucin showed significant in vitro cytotoxicity against CEM and BJ cells with IC50 values ranging from 3.9 to 9.8 μM. Compounds 3 and 4 showed also strong anti-inflammatory activity in vitro.

• MeSH
• antitumorózní látky fytogenní chemie   izolace a purifikace   farmakologie   MeSH
• Asteraceae chemie   MeSH
• fytonutrienty chemie   izolace a purifikace   farmakologie   MeSH
• kultivované buňky MeSH
• laktony chemie   izolace a purifikace   farmakologie   MeSH
• léky antitumorózní - screeningové testy MeSH
• lidé MeSH
• proliferace buněk účinky léků   MeSH
• seskviterpeny chemie   izolace a purifikace   farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

This paper describes the synthesis of a new A-homo lactam D-homo lactone androstane derivative from dehydroepiandrosterone. To evaluate the impact of the introduction of nitrogen in the parental scaffold on biological activity, a new androstane enamide-type lactam derivative was prepared and characterized. The new compound as well as starting compounds were screened for cytotoxic, anti-angiogenic and anti-inflammatory activities using several human cancer cell lines (MCF-7, MDA-MB-231, PC3, CEM, G-361, HeLa), endothelial (HUVEC) and non-tumour (MRC-5 and BJ) cell lines. Strong cytotoxic and anti-inflammatory activity with a broad therapeutical window was demonstrated by the A-homo lactam D-homo lactone androstane derivative. The induction of apoptosis in treated PC3 cultures was confirmed using apoptotic morphology screening and a fluorescent double-staining method. New A-homo lactam D-homo lactone androstane derivative induced apoptosis more than the tested reference compounds, Formestane and Doxorubicin. An in silico ADME analysis showed that the compounds possess drug-like properties.

• MeSH
• androstany chemie   izolace a purifikace   farmakologie   MeSH
• antiflogistika chemie   izolace a purifikace   farmakologie   MeSH
• antitumorózní látky fytogenní chemie   izolace a purifikace   farmakologie   MeSH
• apoptóza účinky léků   MeSH
• E-selektin antagonisté a inhibitory   biosyntéza   MeSH
• kultivované buňky MeSH
• laktony chemie   izolace a purifikace   farmakologie   MeSH
• léky antitumorózní - screeningové testy MeSH
• lidé MeSH
• molekulární konformace MeSH
• optické zobrazování MeSH
• proliferace buněk účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Actinomycete strain YIM PH20520, isolated from the rhizosphere soil sample of Panax notoginseng collected in Wenshang, Yunnan Province, China, exhibited antifungal activity against root-rot pathogens of the Panax notoginseng. The structures of bioactive molecules, isolated from the ethyl acetate extract of the fermentation broth of the strain, were identified as echinosporin (1) and 7-deoxyechinosporin (2) based on extensive spectroscopic analyses. 1 exhibited antifungal activity against four tested root-rot pathogens of Panax notoginseng include Fusarium oxysporum, Fusarium solani, Alternaria panax, and Phoma herbarum with the MIC value at 64, 64, 32, and 64 μg/mL, respectively. 2 exhibited antifungal activities against F. oxysporum, F. solani, A. panax, and P. herbarum with the MIC value at 128, 128, 64, and 128 μg/mL, respectively. Based on the phylogenetic analyses, the closest phylogenetic relative of strain YIM PH20520 is Amycolatopsis speibonae JS72T (97.69%), so strain YIM PH20520 was identified as Amycolatopsis strain. To the best of our knowledge, this is the first report of echinosporin antibiotics isolated from Amycolatopsis strain besides Streptomyces strain and their antifungal activity against four tested root-rot pathogens of the Panax notoginseng. The results provide a reliable evidence for the following related biosynthetic investigations on Amycolatopsis strain YIM PH20520 due to echinosporins antibiotics' unique tricyclic acetal-lactone structures.

• MeSH
• Actinobacteria chemie   klasifikace   genetika   MeSH
• antifungální látky chemie   izolace a purifikace   farmakologie   MeSH
• fylogeneze MeSH
• houby účinky léků   MeSH
• kořeny rostlin mikrobiologie   MeSH
• laktony chemie   izolace a purifikace   farmakologie   MeSH
• mikrobiální testy citlivosti MeSH
• molekulární struktura MeSH
• nemoci rostlin mikrobiologie   MeSH
• Panax notoginseng mikrobiologie   MeSH
• rhizosféra MeSH
• RNA ribozomální 16S genetika   MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Čína MeSH

Strigolactones (SLs) constitute a new class of plant hormones of increasing importance in plant science. The structure of natural SLs is too complex for ready access by synthesis. Therefore, much attention is being given to design of SL analogues and mimics with a simpler structure but with retention of bioactivity. Here new hybrid type SL mimics have been designed derived from auxins, the common plant growth regulators. Auxins were simply coupled with the butenolide D-ring using bromo (or chloro) butenolide. D-rings having an extra methyl group at the vicinal C-3' carbon atom, or at the C-2' carbon atom, or at both have also been studied. The new hybrid type SL mimics were bioassayed for germination activity of seeds of the parasitic weeds S. hermonthica, O. minor and P. ramosa using the classical method of counting germinated seeds and a colorimetric method. For comparison SL mimics derived from phenyl acetic acid were also investigated. The bioassays revealed that mimics with a normal D-ring had appreciable to good activity, those with an extra methyl group at C-2' were also appreciably active, whereas those with a methyl group in the vicinal C-3' position were inactive (S. hermonthica) or only slightly active. The new hybrid type mimics may be attractive as potential suicidal germination agents in agronomic applications.

• MeSH
• biomimetické materiály chemická syntéza   chemie   farmakologie   MeSH
• klíčení účinky léků   MeSH
• kyseliny indoloctové chemická syntéza   chemie   farmakologie   MeSH
• laktony chemická syntéza   chemie   farmakologie   MeSH
• molekulární struktura MeSH
• plevel účinky léků   růst a vývoj   MeSH
• racionální návrh léčiv MeSH
• regulátory růstu rostlin chemická syntéza   chemie   farmakologie   MeSH
• stabilita léku MeSH
• Publikační typ
• časopisecké články MeSH

The past decade may be considered as revolutionary in the research field focused on the physiological function of macrophages. Unknown subtypes of these cells involved in pathological mechanisms were described recently, and they are considered as potential drug delivery targets. The innate ability to internalize foreign bodies exhibited by macrophages can be employed as a therapeutic strategy. The efficiency of this uptake depends on the size, shape and surface physiochemical properties of the phagocyted objects. Here, we propose a method of preparation and preliminary evaluation of drug-polymer conjugate-based microspheres for macrophage targeted drug delivery. The aim of the study was to identify crucial uptake-enhancing parameters for solid, surface modified particles. A model drug molecule-lamivudine-was conjugated with poly-ε-caprolactone via ring opening polymerization. The conjugate was utilized in a solvent evaporation method technique to form solid particles. Interactions between particles and a model rat alveolar cell line were evaluated by flow cytometry. The polymerization product was characterized by a molecular weight of 3.8 kDa. The surface of the obtained solid drug-loaded cores of a hydrodynamic diameter equal to 2.4 µm was modified with biocompatible polyelectrolytes via a layer-by-layer assembly method. Differences in the internalization efficiency of four particle batches by the model RAW 264.7 cell line suggest that particle diameter and surface hydrophobicity are the most influential parameters in terms of phagocytic uptake.

• MeSH
• fagocytóza MeSH
• fixní kombinace léků MeSH
• kapronáty aplikace a dávkování   chemie   MeSH
• laktony aplikace a dávkování   chemie   MeSH
• lamivudin aplikace a dávkování   chemie   MeSH
• látky proti HIV aplikace a dávkování   chemie   MeSH
• magnetická rezonanční spektroskopie MeSH
• makrofágy imunologie   metabolismus   MeSH
• mikrosféry MeSH
• myši MeSH
• nosiče léků chemie   MeSH
• polymery metabolismus   MeSH
• RAW 264.7 buňky MeSH
• spektrální analýza MeSH
• systémy cílené aplikace léků * MeSH
• viabilita buněk účinky léků   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Dermatophytes are the etiological agents of cutaneous mycoses, including the prevalent nail infections and athlete's foot. Candida spp. are opportunistic and emerging pathogens, causing superficial to deeper infections related to high mortality rates. As a consequence of prolonged application of antifungal drugs, the treatment failures combined with multidrug-resistance have become a serious problem in clinical practice. Therefore, novel alternative antifungals are required urgently. δ-Lactones have attracted great interest owing to their wide range of biological activity. This article describes the antifungal activity of synthetic δ-lactones against yeasts of the genus Candida spp. and dermatophytes (through the broth microdilution method), discusses the pathways by which the compounds exert this action (toward the fungal cell wall and/or membrane), and evaluates the toxicity to human leukocytes and chorioallantoic membrane (by the hen's egg test-chorioallantoic membrane). Two of the compounds in the series presented broader spectrum of antifungal activity, including against resistant fungal species. The mechanism of action was related to damage in the fungal cell wall and membrane, with specific target action dependent on the type of substituent present in the δ-lactone structure. The damage in the fungal cell was corroborated by electron microscopy images, which evidenced lysed and completely altered cells after in vitro treatment with δ-lactones. Toxicity was dose dependent for the viability of human leukocytes, but none of the compounds was mutagenic, genotoxic, or membrane irritant when evaluated at higher concentrations than MIC. In this way, δ-lactones constitute a class with excellent perspectives regarding their potential applications as antifungals.

• MeSH
• antifungální látky chemie   farmakologie   toxicita   MeSH
• Arthrodermataceae účinky léků   MeSH
• buněčná stěna účinky léků   MeSH
• Candida účinky léků   MeSH
• laktony chemie   farmakologie   toxicita   MeSH
• leukocyty účinky léků   MeSH
• lidé MeSH
• mikrobiální testy citlivosti MeSH
• vyvíjení léků MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Strigolactones (SLs) are plant hormones that play various roles in plant development. The chemical stability of SLs depends on the solvent, the pH, and the presence of nucleophiles. Hydrolysis leads to detachment of the butenolide ring, and plays a crucial role in the initial stages of the signal-transduction process occurring between the receptor and the SL signaling molecule. RESULTS: To date, two different mechanisms have been proposed for SL hydrolysis. Results obtained from kinetic, thermodynamic, and mass spectral data for the reaction between the widely used synthetic SL analog GR24 and seven different nucleophiles demonstrate that the reaction proceeds via the Michael addition-elimination mechanism. CONCLUSION: This study provides valuable information on the chemical stability of GR24 in different plant growth media and buffers. Such information is valuable for scientists using GR24 treatments to study SL-regulated processes in plants. © 2017 Society of Chemical Industry.

• MeSH
• heterocyklické sloučeniny tricyklické chemie   MeSH
• hmotnostní spektrometrie MeSH
• hydrolýza MeSH
• kinetika MeSH
• laktony chemie   MeSH
• regulátory růstu rostlin chemie   MeSH
• termodynamika MeSH
• vývoj rostlin MeSH
• Publikační typ
• časopisecké články MeSH

Strigolactones are a particular class of plant metabolites with diverse biological functions starting from the stimulation of parasitic seed germination to phytohormonal activity. The expansion of parasitic weeds in the fields of developing countries is threatening the food supply and calls for simple procedures to combat these weeds. Strigolactone analogues represent a promising approach for such control through suicidal germination, i.e., parasitic seed germination without the presence of the host causing parasite death. In the present work, the synthesis of resorcinol-type strigolactone mimics related to debranones is reported. These compounds were highly stable even at alkaline pH levels and able to induce seed germination of parasitic plants Striga hermonthica and Phelipanche ramosa at low concentrations, EC50 ≈ 2 × 10-7 M ( Striga) and EC50 ≈ 2 × 10-9 M ( Phelipanche). On the other hand, the mimics had no significant effect on root architecture of Arabidopsis plants, suggesting a selective activity for parasitic seed germination, making them a primary target as suicidal germinators.

• MeSH
• klíčení účinky léků   MeSH
• laktony chemie   farmakologie   MeSH
• Orobanchaceae embryologie   fyziologie   MeSH
• regulátory růstu rostlin farmakologie   MeSH
• resorcinoly chemie   MeSH
• semena rostlinná účinky léků   fyziologie   MeSH
• Striga embryologie   fyziologie   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The high interest in polymers from natural resources prompted us to investigate the use of enzymatically synthesized polyglobalide (PGL) in the preparation of polymer networks with potential applications as biomaterials for drug delivery devices. Polymer networks were obtained under mild conditions by photoinitiated thiol-ene coupling between PGL and a poly(ethylene glycol- co-thiomalate) (PEG-SH) copolymer obtained by polycondensation. The obtained polymer networks were thoroughly characterized by Raman spectroscopy, scanning electron microscopy, titration of thiol groups and elemental analysis. Our study took into consideration the synthesis parameters for the polymer networks, such as the total polymer concentration and the SH/C=C functionality molar ratio. Swelling in both THF and water was assessed, and the potential of the materials for drug delivery was determined. The scanning electron microscopy images showed that the prepared polymer networks may have different morphologies ranging from homogeneous polymer materials to macroporous structures. Additionally, the prepared materials were found to be suitable from a cytotoxicity point of view, enabling their application as biomaterials for drug delivery devices.

• MeSH
• buňky 3T3 MeSH
• estery chemie   MeSH
• hydrogely škodlivé účinky   chemická syntéza   chemie   MeSH
• laktony chemie   MeSH
• myši MeSH
• polyethylenglykoly chemie   MeSH
• sloučeniny síry chemie   MeSH
• ultrafialové záření MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH