A series of new pyrimidine-pyrazole hybrid molecules were designed as inhibitors of cyclin-dependent kinase 2. Designed compounds were docked using Glide and the compounds showing good score values and encouraging interactions with the residues were selected for synthesis. They were then evaluated using CDK2-CyclinA2 enzyme inhibition by a luminescent ADP detection assay. We show that of the 26 compounds synthesized and evaluated, at least 5 compounds were found to be highly potent (IC50  < 20 nm); which can be further optimized to have selectivity over other kinase isoforms.

• MeSH
• cyklin-dependentní kinasa 2 antagonisté a inhibitory   metabolismus   MeSH
• inhibiční koncentrace 50 MeSH
• inhibitory proteinkinas chemická syntéza   metabolismus   MeSH
• lidé MeSH
• protein - isoformy antagonisté a inhibitory   metabolismus   MeSH
• pyrazoly chemie   metabolismus   MeSH
• pyrimidiny chemie   MeSH
• racionální návrh léčiv * MeSH
• simulace molekulového dockingu MeSH
• terciární struktura proteinů MeSH
• vazebná místa MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Quinacrine-the drug based on 9-aminoacridine-failed in clinical trials for prion diseases, whereas it was active in in vitro studies. We hypothesize that aromatic nucleophilic substitution at C9 could be contributing factor responsible for this failure because of the transfer of acridine moiety from quinacrine to abundant glutathione. Here, we described the semi-large-scale synthesis of the acridinylated glutathione and the consequences of its formation on biological and biophysical activities. The acridinylated glutathione is one order of magnitude weaker prion protein binder than the parent quinacrine. Moreover, according to log DpH 7.4 , the glutathione conjugate is two orders of magnitude more hydrophilic than quinacrine. Its higher hydrophilicity and higher dsDNA binding potency will significantly decrease its bioavailability in membrane-like environment. The glutathione deactivates quinacrine not only directly but also decreases its bioavailability. Furthermore, the conjugate can spontaneously decompose to practically insoluble acridone, which is precipitated out from the living systems.

• MeSH
• biologická dostupnost MeSH
• chinakrin chemická syntéza   chemie   farmakologie   MeSH
• glutathion chemie   farmakologie   MeSH
• hodnocení léčiv MeSH
• hydrofobní a hydrofilní interakce MeSH
• lidé MeSH
• molekulární struktura MeSH
• prionové nemoci farmakoterapie   MeSH
• priony antagonisté a inhibitory   účinky léků   MeSH
• rozpustnost MeSH
• vazba proteinů MeSH
• voda chemie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Gluten promotes type 1 diabetes in nonobese diabetic (NOD) mice and likely also in humans. In NOD mice and in non-diabetes-prone mice, it induces inflammation in the pancreatic lymph nodes, suggesting that gluten can initiate inflammation locally. Further, gliadin fragments stimulate insulin secretion from beta cells directly. We hypothesized that gluten fragments may cross the intestinal barrier to be distributed to organs other than the gut. If present in pancreas, gliadin could interact directly with the immune system and the beta cells to initiate diabetes development. We orally and intravenously administered 33-mer and 19-mer gliadin peptide to NOD, BALB/c, and C57BL/6 mice and found that the peptides readily crossed the intestinal barrier in all strains. Several degradation products were found in the pancreas by mass spectroscopy. Notably, the exocrine pancreas incorporated large amounts of radioactive label shortly after administration of the peptides. The study demonstrates that, even in normal animals, large gliadin fragments can reach the pancreas. If applicable to humans, the increased gut permeability in prediabetes and type 1 diabetes patients could expose beta cells directly to gliadin fragments. Here they could initiate inflammation and induce beta cell stress and thus contribute to the development of type 1 diabetes.

• MeSH
• aplikace orální MeSH
• beta-buňky imunologie   sekrece   MeSH
• chromatografie kapalinová MeSH
• diabetes mellitus 1. typu imunologie   MeSH
• elektroforéza v polyakrylamidovém gelu MeSH
• gliadin imunologie   farmakokinetika   MeSH
• hmotnostní spektrometrie MeSH
• inzulin sekrece   MeSH
• myši inbrední BALB C MeSH
• myši inbrední C57BL MeSH
• myši inbrední NOD MeSH
• pankreas exokrinní metabolismus   sekrece   MeSH
• pankreas metabolismus   sekrece   MeSH
• peptidové fragmenty farmakokinetika   MeSH
• permeabilita MeSH
• spektrometrie hmotnostní - ionizace laserem za účasti matrice MeSH
• střeva metabolismus   MeSH
• zánět MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

The lipophilic nature of allopregnanolone prevents its user-friendly application in human medicine. On inspiration by previously prepared allopregnanolone with a 16alpha-bound tetraethylammonium salt, an attempt was made to produce allopregnanolone analogues with polar groups introduced into position 16alpha with the goal of increasing water solubility, brain accessibility, and potency of neuroactive steroids. The Michael addition to derivatives of pregn-16-en-20-one was the key reaction step. The link between the steroid skeleton and the new side chain was either a methylene group (when diethyl malonate was added) or an oxygen atom (when a hydroxy derivative was added). [(35)S]TBPS displacement was used to evaluate the products. Several carbamates (but not their parent alcohols) displaced TBPS from the picrotoxin binding site on GABA(A) receptors. Although none of them was more potent than the above ammonium salt, which stimulated this study, their nonionic nature should not prevent their passage into the brain.

• MeSH
• financování organizované MeSH
• GABA modulátory farmakologie   chemická syntéza   MeSH
• krysa rodu rattus MeSH
• mozek metabolismus   MeSH
• potkani Wistar MeSH
• pregnanolon analogy a deriváty   farmakologie   chemická syntéza   MeSH
• radioligandová zkouška MeSH
• receptory GABA-A metabolismus   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH

Mouse mammary tumor virus (MMTV) is the prototypical member of the Betaretrovirus genus, but the processes of its morphogenesis are poorly characterized. In this report, we describe an unusual intracellular processing of MMTV Gag polyprotein in human 293T cells transiently expressing MMTV from heterologous promoter. The same specific cleavage products of the viral protease were seen for the wild type as well as for nonmyristylated mutant of MMTV Gag polyprotein completely defective in the particle release. Inactivation of the viral protease resulted in more stable Gag polyprotein and in accumulation of intracytoplasmic particles for nonmyristylated Gag. The intracellular processing of nonmyristylated MMTV Gag indicates that protease activation in betaretrovirus can occur independently of budding.

• MeSH
• dexamethason farmakologie   MeSH
• experimentální nádory mléčných žláz virologie   MeSH
• financování organizované MeSH
• genové produkty gag genetika   metabolismus   MeSH
• kinetika MeSH
• lidé MeSH
• mléčné žlázy zvířat virologie   MeSH
• myši MeSH
• nádory mléčné žlázy u zvířat virologie   MeSH
• promotorové oblasti (genetika) MeSH
• proteasy genetika   metabolismus   MeSH
• proviry genetika   MeSH
• restrikční mapování MeSH
• substituce aminokyselin MeSH
• T-lymfocyty účinky léků   virologie   MeSH
• transfekce MeSH
• virus myšího tumoru prsní žlázy genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH

Retroviral integrase participates in two catalytic reactions, which require interactions with the two ends of the viral DNA in the 3'processing reaction, and with a targeted host DNA in the strand transfer reaction. The 3'-hydroxyl group of 2'-deoxyadenosine resulting from the specific removing of GT dinucleotide from the viral DNA in the processing reaction provides the attachment site for the host DNA in a transesterification reaction. We synthesized oligonucleotides (ONs) of various lengths that mimic the processed HIV-1 U5 terminus of the proviral long terminal repeat (LTR) and are ended by 2'-deoxyadenosine containing a 3'-O-phosphonomethyl group. The duplex stability of phosphonomethyl ONs was increased by covalent linkage of the modified strand with its complementary strand by a triethylene glycol loop (TEG). Modified ONs containing up to 10 bases inhibited in vitro the strand transfer reaction catalyzed by HIV-1 integrase at nanomolar concentrations.

• MeSH
• financování organizované MeSH
• HIV - dlouhá koncová repetice genetika   MeSH
• HIV-integrasa účinky léků   MeSH
• inhibitory HIV-integrasy farmakologie   chemická syntéza   MeSH
• konformace nukleové kyseliny MeSH
• kyseliny fosforu MeSH
• molekulární mimikry MeSH
• oligonukleotidy farmakologie   chemická syntéza   MeSH

Glycopeptide dendrimers containing different types of tumor associated-carbohydrate antigens (T(N), TF, sialyl-T(N), sialyl-TF, sialyl-Le(x), sialyl-Le(a) etc.) were used in diagnosis and therapy of different sorts of cancer. These dendrimeric structures with incorporated T-cell epitopes and adjuvants can be used as antitumor vaccines. Best results were obtained with multiantigenic vaccines, containing, e.g. five or six different TAAs. The topic of TAAs and their dendrimeric forms at molecular level are reviewed, including structure, syntheses, and biological activities. Use of glycopeptide dendrimers as antiviral vaccines against HIV and influenza is also described. Their syntheses, physico-chemical properties, and biological activities are given with many examples.

• MeSH
• adjuvancia imunologická terapeutické užití   MeSH
• antigeny sacharidové asociované s nádorem chemie   klasifikace   MeSH
• dendrimery diagnostické užití   chemie   terapeutické užití   MeSH
• financování organizované MeSH
• glykopeptidy diagnostické užití   chemie   terapeutické užití   MeSH
• HIV infekce terapie   MeSH
• imunoterapie metody   MeSH
• lidé MeSH
• molekulární sekvence - údaje MeSH
• nádory diagnóza   terapie   MeSH
• protinádorové vakcíny chemie   terapeutické užití   MeSH
• sacharidové sekvence MeSH
• syntetické vakcíny diagnostické užití   chemie   terapeutické užití   MeSH
• vakcíny proti AIDS chemie   terapeutické užití   MeSH
• vakcíny proti chřipce chemie   terapeutické užití   MeSH
• virové nemoci diagnóza   terapie   MeSH
• virové vakcíny chemie   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• přehledy MeSH