Racionální syntéza a molekulární mechanismus účinku acyklických nukleotydů odvozených od PMEDAP -potencionálního léčiva proti hematologickým malignitám.; Rational desing, synthesis and molecular mode of action of acyclic nucleotides derived from PMEDAP - potential drugs againsthaematological malignancies.

• MeSH
• protinádorové látky chemická syntéza   MeSH
• purinové nukleosidy chemická syntéza   MeSH
• screeningové testy protinádorových léčiv MeSH

• Konspekt
• Farmacie. Farmakologie
• NLK Obory
• farmacie a farmakologie
• farmacie a farmakologie
• NLK Publikační typ
• závěrečné zprávy o řešení grantu IGA MZ ČR

Studium inhibičního účinku nových analogů nukleotidů na nádorové buňky. XXX XXX XXX

• MeSH
• protinádorové látky farmakologie   MeSH

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• onkologie
• biochemie
• NLK Publikační typ
• závěrečné zprávy o řešení grantu IGA MZ ČR

• Publikační typ
• abstrakt z konference MeSH

BACKGROUND: 9-[2-(phosphonomethoxy)ethyl] guanine (PMEG) is a nucleotide analogue with anticancer activity. Here we investigate the role of ERK, p38, JNK and AKT kinases in PMEG-induced apoptosis. MATERIALS AND METHODS: CCRF-CEM and HL-60 leukemia cells were used to assess MAPK mRNA and protein expression in PMEG-treated cells. MAPK activation was measured using phospho-specific antibodies. Apoptosis was evaluated by caspase-3 and PARP cleavage. RESULTS: Up-regulation of p38β, γ and δ mRNA were observed following PMEG treatment of CCRF-CEM cells, however, the total protein expression remained unchanged. Neither PMEG nor its analogue 9-[2-(phosphonomethoxy) ethyl]-2,6-diaminopurine (PMEDAP) induced p38 kinase phosphorylation in CCRF-CEM cells, whereas increased p38 phosphorylation was observed in HL-60 cells. The ERK pathway was also activated by these compounds. Pretreatment of the cells with the p38 inhibitor SB203580 diminished drug-induced apoptosis whereas inhibition of ERK, JNK or AKT pathways did not. [corrected]. CONCLUSION: PMEG- and PMEDAP-induced. [corrected].

• MeSH
• adenin analogy a deriváty   farmakologie   MeSH
• aktivace enzymů účinky léků   MeSH
• extracelulárním signálem regulované MAP kinasy antagonisté a inhibitory   metabolismus   MeSH
• guanin analogy a deriváty   farmakologie   MeSH
• HL-60 buňky MeSH
• kaspasa 3 metabolismus   MeSH
• lidé MeSH
• MAP kinasa-kinasa 4 antagonisté a inhibitory   metabolismus   MeSH
• MAP kinasový signální systém účinky léků   MeSH
• messenger RNA biosyntéza   genetika   MeSH
• mitogenem aktivované proteinkinasy p38 antagonisté a inhibitory   biosyntéza   genetika   metabolismus   MeSH
• mitogenem aktivované proteinkinasy antagonisté a inhibitory   biosyntéza   genetika   metabolismus   MeSH
• nádorové buněčné linie MeSH
• organofosforové sloučeniny farmakologie   MeSH
• protinádorové látky farmakologie   MeSH
• protoonkogenní proteiny c-akt antagonisté a inhibitory   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

A series of O-phenyl methyl-, ethyl- and benzylalanyl phosphoramidate pronucleotides derived from cytostatic 6-aryl-7-deazapurine ribonucleosides were prepared by the cross-coupling reactions of the 2',3'-isopropylidene protected 6-chloro-7-deazapurine ribonucleoside phosphoramidates with (het)arylboronic acids or -stannanes followed by deprotection. Most of the prepared prodrugs exerted in vitro cytostatic effects against both solid tumor and lymphoid cancer cells within low micromolar range of concentrations. These activities were in general weaker or comparable to the activities of the parent nucleosides. Additional testing of selected prodrugs suggests that the lack of activity improvement over parent nucleosides is not due to the lack of permeability or inefficient catabolism of alanyl-ester by intracellular hydrolases. More likely, active efflux of prodrugs may play a role in their weak cytotoxic activity.

• MeSH
• hmotnostní spektrometrie s elektrosprejovou ionizací MeSH
• lidé MeSH
• magnetická rezonanční spektroskopie MeSH
• nádorové buněčné linie MeSH
• protinádorové látky chemie   farmakologie   MeSH
• purinové nukleosidy chemie   farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The antiviral effect of the acyclic nucleoside phosphonate tenofovir (R)-PMPA on double-stranded DNA Cauliflower mosaic virus (CaMV) in Brassica pekinensis plants grown in vitro on liquid medium was evaluated. Double antibody sandwich ELISA and PCR were used for relative quantification of viral protein and detecting nucleic acid in plants. (R)-PMPA at concentrations of 25 and 50 mg/l significantly reduced CaMV titers in plants within 6-9 weeks to levels detectable neither by ELISA nor by PCR. Virus-free plants were obtained after 3-month cultivation of meristem tips on semisolid medium containing 50 mg/l (R)-PMPA and their regeneration to whole plants in the greenhouse. Studying the metabolism of (R)-PMPA in B. pekinensis revealed that mono- and diphosphate, structural analogs of NDP and/or NTP, are the only metabolites formed. The data indicate very low substrate activity of the enzymes toward (R)-PMPA as substrate. The extent of phosphorylation in the plant's leaves represents only 4.5% of applied labeled (R)-PMPA. In roots, we detected no radioactive peaks of phosphorylated metabolites of (R)-PMPAp or (R)-PMPApp.

• MeSH
• adenin analogy a deriváty   metabolismus   farmakologie   MeSH
• antivirové látky metabolismus   farmakologie   MeSH
• biotransformace MeSH
• Brassica metabolismus   virologie   MeSH
• Caulimovirus účinky léků   růst a vývoj   MeSH
• DNA virů analýza   MeSH
• ELISA metody   MeSH
• kyseliny fosforité metabolismus   farmakologie   MeSH
• polymerázová řetězová reakce metody   MeSH
• virová nálož MeSH
• virové proteiny analýza   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

A series of simple desmethoxy analogues of coruscanone A was prepared via a novel version of Ti(iPrO)(4)-mediated Knoevenagel condensation of cyclopentenedione with substituted benzaldehydes and cinnamic aldehydes, and the compounds were evaluated for antifungal activity and cytotoxicity. The most potent 2-benzylidenecyclopent-4-ene-1,3-dione possessed antifungal effect comparable to coruscanone A and a somewhat broader spectrum of activity against Candida species. The compound was also superior to fluconazole against several non-albicans Candida sp. Evaluation of the ability of the compound to influence cell proliferation using two different assays showed that 2-benzylidenecyclopent-4-ene-1,3-dione has lower cytotoxicity compared to the natural product.

• MeSH
• antifungální látky chemická syntéza   chemie   farmakologie   MeSH
• buněčné linie MeSH
• Candida účinky léků   MeSH
• cyklopentany chemická syntéza   chemie   farmakologie   MeSH
• gama-butyrolakton analogy a deriváty   chemická syntéza   chemie   farmakologie   MeSH
• kandidóza farmakoterapie   MeSH
• lidé MeSH
• mikrobiální testy citlivosti MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

A novel and efficient method for the one-pot synthesis of diamide (bis-amidate) prodrugs of acyclic nucleoside phosphonates, starting from free phosphonic acids or phosphonate diesters is reported. The approach from phosphonate diesters via their bis(trimethylsilyl) esters is highly convenient, eliminates isolation and tedious purification of the phosphonic acids, and affords the corresponding bis-amidates in excellent yields (83-98%) and purity. The methodology has been applied to the synthesis of the potent anticancer agent GS-9219, and symmetrical bis-amidates of other biologically active phosphonic acids. Anti-HIV, antiproliferative, and immunomodulatory activities of the compounds are discussed including the bis-amidate prodrugs 14 and 17 that exhibited anti-HIV activity at submicromolar concentrations with minimal cytotoxicity.

• MeSH
• adjuvancia imunologická chemická syntéza   chemie   farmakologie   MeSH
• buněčné linie MeSH
• diamid chemická syntéza   chemie   farmakologie   MeSH
• hmotnostní spektrometrie s elektrosprejovou ionizací MeSH
• kyseliny fosforité chemie   MeSH
• látky proti HIV chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• magnetická rezonanční spektroskopie MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nukleosidy chemie   MeSH
• preklinické hodnocení léčiv MeSH
• prekurzory léčiv chemická syntéza   chemie   farmakologie   MeSH
• proliferace buněk účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Developmental processes are closely connected to certain states of epigenetic information which, among others, rely on methylation of chromatin. S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) are key cofactors of enzymes catalyzing DNA and histone methylation. To study the consequences of altered SAH/SAM levels on plant development we applied 9-(S)-(2,3-dihydroxypropyl)-adenine (DHPA), an inhibitor of SAH-hydrolase, on tobacco seeds during a short phase of germination period (6 days). The transient drug treatment induced: (1) dosage-dependent global DNA hypomethylation mitotically transmitted to adult plants; (2) pleiotropic developmental defects including decreased apical dominance, altered leaf and flower symmetry, flower whorl malformations and reduced fertility; (3) dramatic upregulation of floral organ identity genes NTDEF, NTGLO and NAG1 in leaves. We conclude that temporal SAH-hydrolase inhibition deregulated floral genes expression probably via chromatin methylation changes. The data further show that plants might be particularly sensitive to accurate setting of SAH/SAM levels during critical developmental periods.

• MeSH
• adenin analogy a deriváty   toxicita   MeSH
• adenosylhomocysteinasa antagonisté a inhibitory   metabolismus   MeSH
• DNA primery genetika   MeSH
• epigeneze genetická účinky léků   fyziologie   MeSH
• klíčení účinky léků   fyziologie   MeSH
• komplementární DNA genetika   MeSH
• květy anatomie a histologie   fyziologie   MeSH
• metylace DNA MeSH
• neparametrická statistika MeSH
• pyl fyziologie   MeSH
• regulace genové exprese u rostlin účinky léků   genetika   fyziologie   MeSH
• rostlinné proteiny metabolismus   MeSH
• Southernův blotting MeSH
• tabák enzymologie   fyziologie   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

A series of 3-aryl-5-acyloxymethyl-5,6-dihydro-2H-pyran-2-ones, related to highly antifungally active butenolides, was synthesized via cyclization of substituted δ-hydroxy acids as the key step, and evaluated for their in vitro antifungal activity and cytostatic activity. While the extension of the furanone ring to pyranone led to a complete loss of the antifungal effect, some of the compounds displayed promising effect against several cell lines, including the resistant colorectal carcinoma cells.

• MeSH
• antifungální látky chemická syntéza   chemie   farmakologie   MeSH
• cytostatické látky chemická syntéza   chemie   farmakologie   MeSH
• furany chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• pyrany chemie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH