The RNA binding protein Human Antigen R (HuR) has been identified as a main regulator of the innate immune response and its inhibition can lead to beneficial anti-inflammatory effects. To this aim, we previously synthesized a novel class of small molecules named Tanshinone Mimics (TMs) able to interfere with HuR-RNA binding, and that dampen the LPS-induced immune response. Herein, we present a novel series of TMs, encompassing thiophene 3/TM9 and 4/TM10, furan 5/TM11 and 6/TM12, pyrrole 7b/TM13, and pyrazole 8. The furan-containing 5(TM11) showed the greatest inhibitory effect of the series on HuR-RNA complex formation, as suggested by RNA Electromobility Shift Assay and Time-Resolved FRET. Molecular Dynamics Calculation of HuR - 5/TM11 interaction, quantum mechanics approaches and Surface Plasmon Resonance data, all indicates that, within the novel heteroaryl substituents, the furan ring better recapitulates the chemical features of the RNA bound to HuR. Compound 5/TM11 also showed improved aqueous solubility compared to previously reported TMs. Real-time monitoring of cell growth and flow cytometry analyses showed that 5/TM11 preferentially reduced cell proliferation rather than apoptosis in murine macrophages at immunomodulatory doses. We observed its effects on the innate immune response triggered by lipopolysaccharide (LPS) in macrophages, showing that 5/TM11 significantly reduced the expression of proinflammatory cytokines as Cxcl10 and Il1b.

• Klíčová slova
• Anti-inflammatory agents, ELAVL1, HuR, HuR inhibitors, LPS, Tanshinone mimics,
• MeSH
• antiflogistika farmakologie   chemie   MeSH
• apoptóza účinky léků   MeSH
• chemokin CXCL10 metabolismus   MeSH
• diterpeny abietanové * farmakologie   chemie   MeSH
• furany farmakologie   chemie   MeSH
• HuR protein metabolismus   MeSH
• lidé MeSH
• lipopolysacharidy farmakologie   MeSH
• makrofágy * účinky léků   metabolismus   MeSH
• myši MeSH
• RAW 264.7 buňky MeSH
• rozpustnost MeSH
• simulace molekulární dynamiky MeSH
• zánět farmakoterapie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antiflogistika MeSH
• chemokin CXCL10 MeSH
• diterpeny abietanové * MeSH
• furany MeSH
• HuR protein MeSH
• lipopolysacharidy MeSH
• tanshinone MeSH Prohlížeč

In spite of the impressing cytotoxicity of thapsigargin (Tg), this compound cannot be used as a chemotherapeutic drug because of general toxicity, causing unacceptable side effects. Instead, a prodrug targeted towards tumors, mipsagargin, was brought into clinical trials. What substantially reduces the clinical potential is the limited access to Tg and its derivatives and cost-inefficient syntheses with unacceptably low yields. Laser trilobum, which contains a structurally related sesquiterpene lactone, trilobolide (Tb), is successfully cultivated. Here, we report scalable isolation of Tb from L. trilobum and a transformation of Tb to 8-O-(12-aminododecanoyl)-8-O-debutanoylthapsigargin in seven steps. The use of cultivated L. trilobum offers an unlimited source of the active principle in mipsagargin.

• Klíčová slova
• 8-O-(12-aminododecanoyl)-8-O-debutanoylthapsigargin, Laser trilobum cultivation, chemical synthesis, extraction, mipsagargin, optimization and scale-up, sarco/endoplasmic reticulum calcium ATPase (SERCA), sesquiterpene lactones, thapsigargin, trilobolide, trilobolide isolation from fruits,
• MeSH
• antitumorózní látky fytogenní chemie   izolace a purifikace   MeSH
• Apiaceae chemie   metabolismus   MeSH
• butyráty chemie   izolace a purifikace   MeSH
• furany chemie   izolace a purifikace   MeSH
• lidé MeSH
• molekulární struktura MeSH
• nádory farmakoterapie   patologie   MeSH
• ovoce chemie   metabolismus   MeSH
• oxid uhličitý chemie   MeSH
• rostlinné extrakty chemie   MeSH
• sarkoplazmatická Ca2+-ATPáza antagonisté a inhibitory   metabolismus   MeSH
• superkritická fluidní chromatografie metody   MeSH
• techniky syntetické chemie * MeSH
• thapsigargin analogy a deriváty   izolace a purifikace   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antitumorózní látky fytogenní MeSH
• butyráty MeSH
• furany MeSH
• oxid uhličitý MeSH
• rostlinné extrakty MeSH
• sarkoplazmatická Ca2+-ATPáza MeSH
• thapsigargin MeSH
• trilobolide MeSH Prohlížeč

Cystic echinococcosis (CE) remains an important challenge both in humans and animals. There is no safe and suitable remedy for CE, so the discovery of new compounds with promising scolicidal effects, particularly from herbal sources, is of great importance for therapeutic uses in the treatment and prevention of CE reappearance. Sesquiterpenes are C15 organic compounds made up of three isoprene units and mostly occurring as fragrant components of essential oils. They are of economic importance for the cosmetic and pharmaceutical industry, and recently attracted the attention of the scientific community for their remarkable parasiticidal properties. In the present study, we have focused on three known sesquiterpenes, isofuranodiene (IFD), α-bisabolol (BSB), and farnesol (FOH), as important phytoconstituents of the essential oils of wild celery (Smyrnium olusatrum), chamomile (Matricaria chamomilla), and acacia farnese (Vachellia farnesiana), respectively. Protoscoleces were recovered from fertile hydatid cysts and were exposed to different concentrations of the three tested compounds for different exposure times. The viability of protoscoleces was confirmed by 0.1% eosin staining. Results of scolicidal activity evaluations showed that IFD possessed the best effect against Echinococcus granulosus protoscoleces (LC50 and LC90 values of 8.87 and 25.48 µg/mL, respectively), followed by BSB (LC50 of 103.2 µg/mL) and FOH (LC50 of 113.68 µg/mL). The overall toxicity of IFD differed significantly from those of FOH and BSB, while there was no significant difference in toxicity between the latter compounds (p > 0.05). The present study showed that IFD seems to be a promising scolicidal agent and can be further tested to become a candidate for CE treatment.

• Klíčová slova
• cystic echinococcosis, farnesol, isofuranodiene, protoscolex, α-bisabolol,
• MeSH
• antiparazitární látky farmakologie   MeSH
• Echinococcus granulosus účinky léků   MeSH
• farnesol farmakologie   MeSH
• furany chemie   farmakologie   MeSH
• LD50 MeSH
• monocyklické seskviterpeny farmakologie   MeSH
• seskviterpeny chemie   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antiparazitární látky MeSH
• bisabolol MeSH Prohlížeč
• farnesol MeSH
• furany MeSH
• isofuranodiene MeSH Prohlížeč
• monocyklické seskviterpeny MeSH
• seskviterpeny MeSH

Two novel coordination compounds containing heterocyclic bidentate N,N-donor ligand 2-(furan-2-yl)-5-(pyridin-2-yl)-1,3,4-oxadiazole (fpo) were synthesized. A general formula for compounds originating from perchlorates of iron, cobalt, and fpo can be written as: [M(fpo)2(H2O)2](ClO4)2 (M = Fe(II) for (1) Co(II) for (2)). The characterization of compounds was performed by general physico-chemical methods-elemental analysis (EA), Fourier transform infrared spectroscopy (FT-IR), nuclear magnetic resonance (NMR) in case of organics, and single crystal X-ray diffraction (sXRD). Moreover, magneto-chemical properties were studied employing measurements in static field (DC) for 1 and X-band EPR (Electron paramagnetic resonance), direct current (DC), and alternating current (AC) magnetic measurements in case of 2. The analysis of DC magnetic properties revealed a high spin arrangement in 1, significant rhombicity for both complexes, and large magnetic anisotropy in 2 (D = -21.2 cm-1). Moreover, 2 showed field-induced slow relaxation of the magnetization (Ueff = 65.3 K). EPR spectroscopy and ab initio calculations (CASSCF/NEVPT2) confirmed the presence of easy axis anisotropy and the importance of the second coordination sphere.

• Klíčová slova
• 1,3,4-oxadiazole, second coordination sphere, single-molecule magnet,
• MeSH
• anizotropie MeSH
• elektronová paramagnetická rezonance MeSH
• furany chemie   MeSH
• kobalt chemie   MeSH
• komplexní sloučeniny chemie   MeSH
• krystalografie rentgenová MeSH
• magnetická rezonanční spektroskopie MeSH
• molekulární modely MeSH
• oxadiazoly chemie   MeSH
• spektroskopie infračervená s Fourierovou transformací MeSH
• spektroskopie Mossbauerova MeSH
• železnaté sloučeniny chemie   MeSH
• železo chemie   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 1,3,4-oxadiazole MeSH Prohlížeč
• furan MeSH Prohlížeč
• furany MeSH
• kobalt MeSH
• komplexní sloučeniny MeSH
• oxadiazoly MeSH
• železnaté sloučeniny MeSH
• železo MeSH

Smoke derived karrikinolide and trimethylbutenolide exerted neuroprotective effects against monoamine oxidase and acetylcholinesterase. Synthesis of potent analogs was achieved. Sulphur substitution in the bicyclic ring structure of KAR1 displayed the most encouraging activity returning IC50 values of 13.75 ± 0.001 μM and 0.03 ± 0.02 μM for monoamine oxidase A and B and 0.08 ± 0.006 μM for acetylcholinesterase. Neuroprotective butenolides may be particularly useful in the treatment of depressive disorders, Alzheimer's and Parkinson's diseases.

• Klíčová slova
• Acetylcholinesterase, Karrikinolide, Monoamine oxidase, Smoke, Synthesis, Trimethylbutenolide,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• depresivní poruchy farmakoterapie   MeSH
• furany chemická syntéza   chemie   farmakologie   MeSH
• gama-butyrolakton analogy a deriváty   chemická syntéza   chemie   farmakologie   MeSH
• inhibitory MAO chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• molekulární struktura MeSH
• monoaminoxidasa metabolismus   MeSH
• neurodegenerativní nemoci farmakoterapie   MeSH
• neuroprotektivní látky chemická syntéza   chemie   farmakologie   MeSH
• pyrany chemická syntéza   chemie   farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 3-methyl-2H-furo(2,3-c)pyran-2-one MeSH Prohlížeč
• 3,4,5-trimethylfuran-2(5H)-one MeSH Prohlížeč
• acetylcholinesterasa MeSH
• butenolide MeSH Prohlížeč
• furany MeSH
• gama-butyrolakton MeSH
• inhibitory MAO MeSH
• monoaminoxidasa MeSH
• neuroprotektivní látky MeSH
• pyrany MeSH

• MeSH
• Apiaceae chemie   MeSH
• butyráty chemie   farmakologie   MeSH
• cytokiny imunologie   MeSH
• furany chemie   farmakologie   MeSH
• kultivované buňky MeSH
• lidé MeSH
• molekulární struktura MeSH
• myši MeSH
• oxid dusnatý imunologie   MeSH
• peritoneum cytologie   MeSH
• potkani Wistar MeSH
• semena rostlinná chemie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• butyráty MeSH
• cytokiny MeSH
• furany MeSH
• oxid dusnatý MeSH
• trilobolide MeSH Prohlížeč

Reported is the identification of the furo[3,2-b]pyridine core as a novel scaffold for potent and highly selective inhibitors of cdc-like kinases (CLKs) and efficient modulators of the Hedgehog signaling pathway. Initially, a diverse target compound set was prepared by synthetic sequences based on chemoselective metal-mediated couplings, including assembly of the furo[3,2-b]pyridine scaffold by copper-mediated oxidative cyclization. Optimization of the subseries containing 3,5-disubstituted furo[3,2-b]pyridines afforded potent, cell-active, and highly selective inhibitors of CLKs. Profiling of the kinase-inactive subset of 3,5,7-trisubstituted furo[3,2-b]pyridines revealed sub-micromolar modulators of the Hedgehog pathway.

• Klíčová slova
• biological activity, chemical probes, heterocycles, inhibitors, kinases,
• MeSH
• furany chemie   MeSH
• inhibiční koncentrace 50 MeSH
• inhibitory proteinkinas chemická syntéza   chemie   farmakologie   MeSH
• knihovny malých molekul chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• MFC-7 buňky MeSH
• molekulární struktura MeSH
• proteiny hedgehog chemie   MeSH
• pyridiny chemie   MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• furany MeSH
• furo(3,2-b)pyridine MeSH Prohlížeč
• inhibitory proteinkinas MeSH
• knihovny malých molekul MeSH
• proteiny hedgehog MeSH
• pyridiny MeSH

Three series of isomeric pyrrolo- and furo-fused 7-deazapurine ribonucleosides were synthesized and screened for cytostatic and antiviral activity. The synthesis was based on heterocyclizations of hetaryl-azidopyrimidines to form the tricyclic heterocyclic bases, followed by glycosylation and final derivatizations through cross-coupling reactions or nucleophilic substitutions. The pyrrolo[2',3':4,5]pyrrolo[2,3- d]pyrimidine and furo[2',3':4,5]pyrrolo[2,3- d]pyrimidine ribonucleosides were found to be potent cytostatics, whereas the isomeric pyrrolo[3',2',4,5]pyrrolo[2,3- d]pyrimidine nucleosides were inactive. The most active were the methyl, methoxy, and methylsulfanyl derivatives exerting submicromolar cytostatic effects and good selectivity toward cancer cells. We have shown that the nucleosides are activated by intracellular phosphorylation and the nucleotides get incorporated to both RNA and DNA, where they cause DNA damage. They represent a new type of promising candidates for preclinical development toward antitumor agents.

• MeSH
• antitumorózní látky chemická syntéza   chemie   farmakologie   MeSH
• antivirové látky chemická syntéza   chemie   farmakologie   MeSH
• furany chemie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• puriny chemie   MeSH
• pyrroly chemie   MeSH
• ribonukleosidy chemická syntéza   chemie   farmakologie   MeSH
• techniky syntetické chemie MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 7-deazapurine MeSH Prohlížeč
• antitumorózní látky MeSH
• antivirové látky MeSH
• furan MeSH Prohlížeč
• furany MeSH
• puriny MeSH
• pyrroly MeSH
• ribonukleosidy MeSH

A very short three-step approach to trans,trans,trans-2,5-diaryl-3,4-dimethyltetrahydrofuran lignans is reported. The carbon skeleton is assembled in a single step based on an unprecedented tandem reaction consisting of 1,2-addition of aryllithium reagents to α,β-unsaturated aldehydes, ruthenium-catalyzed redox isomerization of the resulting alkoxides to enolates and their dimerization triggered by single electron oxidation. The resulting 2,3-dialkyl-1,4-diketones form with moderate to good d/l-diastereoselectivity and are transformed to the target tetrahydrofuran lignans by reduction and diastereoselective cycloetherification.

• MeSH
• aldehydy chemická syntéza   chemie   MeSH
• biomimetika MeSH
• cyklizace MeSH
• furany chemická syntéza   chemie   MeSH
• isomerie MeSH
• katalýza MeSH
• krystalografie rentgenová MeSH
• lignany chemická syntéza   chemie   MeSH
• molekulární modely MeSH
• oxidace-redukce MeSH
• oxidační párování MeSH
• ruthenium chemie   MeSH
• techniky syntetické chemie MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• aldehydy MeSH
• furany MeSH
• lignany MeSH
• ruthenium MeSH
• tetrahydrofuran MeSH Prohlížeč

A library of thirty two 3,4-diphenylfuranones related to both combretastatin A-4 and antifungal 5-(acyloxymethyl)-3-(halophenyl)-2,5-dihydrofuran-2-ones was prepared. Cytotoxic effects on a panel of cancer and normal cell lines and antiinfective activity were evaluated, and the data were complemented with tests for the activation of caspase 3 and 7. High cytotoxicity was observed in some of the halogenated analogues, eg. 3-(3,4-dichlorophenyl)-4-(4-methylphenyl)-2,5-dihydrofuran-2-one with IC50 0.12-0.23 μM, but the compounds were also highly toxic against non-malignant control cells. More importantly, notable antibacterial activity indicating G+ selectivity has been found in the 3,4-diarylfuranone class of compounds for the first time. Hydroxymethylation of furanone C5 knocked out cytotoxic effects (up to 40 μM) while maintaining significant activity against Staphylococcus strains in some derivatives. MIC95 of the most promising compound, 3-(4-bromophenyl)-5,5-bis(hydroxymethyl)-4-(4-methylphenyl)-2,5-dihydrofuran-2-one against S. aureus strain ATCC 6538 was 0.98 μM (0.38 μg/mL) and 3.9 μM (1.52 μg/mL) after 24 and 48 h, respectively.

• Klíčová slova
• Antibacterial, Combretafuranone, Combretastatin analogue, Cytotoxic, Furanone, Synthesis,
• MeSH
• antibakteriální látky chemická syntéza   chemie   farmakologie   MeSH
• antifungální látky chemická syntéza   chemie   farmakologie   MeSH
• apoptóza účinky léků   MeSH
• Bacteria účinky léků   MeSH
• furany chemická syntéza   chemie   farmakologie   MeSH
• houby účinky léků   MeSH
• kultivované buňky MeSH
• lidé MeSH
• mikrobiální testy citlivosti MeSH
• molekulární struktura MeSH
• proliferace buněk účinky léků   MeSH
• viabilita 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
• Názvy látek
• antibakteriální látky MeSH
• antifungální látky MeSH
• furany MeSH