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Find video protocols related to scientific articles indexed in Pubmed.
Rational design of urea-based glutamate carboxypeptidase II (GCPII) inhibitors as versatile tools for specific drug targeting and delivery.
Bioorg. Med. Chem.
PUBLISHED: 01-20-2014
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Glutamate carboxypeptidase II (GCPII), also known as prostate specific membrane antigen (PSMA), is an established prostate cancer marker and is considered a promising target for specific anticancer drug delivery. Low-molecular-weight inhibitors of GCPII are advantageous specific ligands for this purpose. However, they must be modified with a linker to enable connection of the ligand with an imaging molecule, anticancer drug, and/or nanocarrier. Here, we describe a structure-activity relationship (SAR) study of GCPII inhibitors with linkers suitable for imaging and drug delivery. Structure-assisted inhibitor design and targeting of a specific GCPII exosite resulted in a 7-fold improvement in Ki value compared to the parent structure. X-ray structural analysis of the inhibitor series led to the identification of several inhibitor binding modes. We also optimized the length of the inhibitor linker for effective attachment to a biotin-binding molecule and showed that the optimized inhibitor could be used to target nanoparticles to cells expressing GCPII.
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Synthesis, cytostatic, antimicrobial, and anti-HCV activity of 6-substituted 7-(het)aryl-7-deazapurine ribonucleosides.
J. Med. Chem.
PUBLISHED: 01-16-2014
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A series of 80 7-(het)aryl- and 7-ethynyl-7-deazapurine ribonucleosides bearing a methoxy, methylsulfanyl, methylamino, dimethylamino, methyl, or oxo group at position 6, or 2,6-disubstituted derivatives bearing a methyl or amino group at position 2, were prepared, and the biological activity of the compounds was studied and compared with that of the parent 7-(het)aryl-7-deazaadenosine series. Several of the compounds, in particular 6-substituted 7-deazapurine derivatives bearing a furyl or ethynyl group at position 7, were significantly cytotoxic at low nanomolar concentrations whereas most were much less potent or inactive. Promising activity was observed with some compounds against Mycobacterium bovis and also against hepatitis C virus in a replicon assay.
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Pyrrolidine nucleotide analogs with a tunable conformation.
Beilstein J Org Chem
PUBLISHED: 01-01-2014
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Conformational preferences of the pyrrolidine ring in nucleotide analogs 7-14 were investigated by means of NMR and molecular modeling. The effect of the relative configuration of hydroxy and nucleobase substituents as well as the effect of the alkylation or acylation of the pyrrolidine nitrogen atom on the conformation of the pyrrolidine ring were studied. The results of a conformational analysis show that the alkylation/acylation can be effectively used for tuning the pyrrolidine conformation over the whole pseudorotation cycle.
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Synthesis of 2,6-disubstituted pyridin-3-yl C-2-deoxyribonucleosides through chemoselective transformations of bromo-chloropyridine C-nucleosides.
Org. Biomol. Chem.
PUBLISHED: 06-12-2013
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2-Bromo-6-chloro- and 6-bromo-2-chloropyridin-3-yl deoxyribonucleosides were prepared by the Heck coupling of bromo-chloro-iodopyridines with TBS-protected deoxyribose glycal. Some of their Pd-catalyzed cross-coupling reactions proceeded chemoselectively at the position of the bromine, whereas nucleophilic substitutions were unselective and gave mixtures of products. The mono-substituted intermediates were used for another coupling or nucleophilic substitution giving rise to a small library of title 2,6-disubstituted pyridine C-deoxyribonucleosides. The title nucleosides did not exert antiviral or cytostatic effects.
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Acyclic nucleoside phosphonates containing a second phosphonate group are potent inhibitors of 6-oxopurine phosphoribosyltransferases and have antimalarial activity.
J. Med. Chem.
PUBLISHED: 03-19-2013
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Acyclic nucleoside phosphonates (ANPs) that contain a 6-oxopurine base are good inhibitors of the Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) 6-oxopurine phosphoribosyltransferases (PRTs). Chemical modifications based on the crystal structure of 2-(phosphonoethoxy)ethylguanine (PEEG) in complex with human HGPRT have led to the design of new ANPs. These novel compounds contain a second phosphonate group attached to the ANP scaffold. {[(2-[(Guanine-9H-yl)methyl]propane-1,3-diyl)bis(oxy)]bis(methylene)}diphosphonic acid (compound 17) exhibited a Ki value of 30 nM for human HGPRT and 70 nM for Pf HGXPRT. The crystal structure of this compound in complex with human HGPRT shows that it fills or partially fills three critical locations in the active site: the binding sites of the purine base, the 5-phosphate group, and pyrophosphate. This is the first HG(X)PRT inhibitor that has been able to achieve this result. Prodrugs have been synthesized resulting in IC50 values as low as 3.8 ?M for Pf grown in cell culture, up to 25-fold lower compared to the parent compounds.
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Synthesis and cytostatic and antiviral activities of 2-deoxy-2,2-difluororibo- and 2-deoxy-2-fluororibonucleosides derived from 7-(Het)aryl-7-deazaadenines.
ChemMedChem
PUBLISHED: 01-31-2013
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A series of sugar-modified derivatives of cytostatic 7-heteroaryl-7-deazaadenosines (2-deoxy-2-fluororibo- and 2-deoxy-2,2-difluororibonucleosides) bearing an aryl or heteroaryl group at position?7 was prepared and screened for biological activity. The difluororibonucleosides were prepared by non- stereoselective glycosidation of 6-chloro-7-deazapurine with benzoyl-protected 2-deoxy-2,2-difluoro-D-erythro-pentofuranosyl-1-mesylate, followed by amination and aqueous Suzuki cross-couplings with (het)arylboronic acids. The fluororibo derivatives were prepared by aqueous palladium-catalyzed cross-coupling reactions of the corresponding 7-iodo-7-deazaadenine 2-deoxy-2-fluororibonucleoside 20 with (het)arylboronic acids. The key intermediate 20 was prepared by a six-step sequence from the corresponding arabinonucleoside by selective protection of 3- and 5-hydroxy groups with acid-labile groups, followed by stereoselective SN 2 fluorination and deprotection. Some of the title nucleosides and 7-iodo-7-deazaadenine intermediates showed micromolar cytostatic or anti-HCV activity. The most active were 7-iodo and 7-ethynyl derivatives. The corresponding 2-deoxy-2,2-difluororibonucleoside 5-O-triphosphates were found to be good substrates for bacterial DNA polymerases, but are inhibitors of human polymerase??.
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General and modular synthesis of isomeric 5-substituted pyridin-2-yl and 6-substituted pyridin-3-yl C-ribonucleosides bearing diverse alkyl, aryl, hetaryl, amino, carbamoyl, and hydroxy groups.
J. Org. Chem.
PUBLISHED: 07-25-2011
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A general modular and practical methodology for preparation of diverse 5-substituted pyridin-2-yl and 6-substituted pyridin-3-yl C-ribonucleosides was developed. Regioselective lithiation of 2,5-dibromopyridine proceeded at position 5 or 2 depending on the solvent, and the resulting bromopyridyl lithium species underwent additions to TBS-protected ribonolactone and follow-up transformations to corresponding acetylated hemiketal intermediates 7 and 10 that were diastereoselectively reduced to give either 5-bromopyridin-2-yl or 6-bromopyridin-3-yl silyl-protected C-ribonucleosides 8 or 11 in 68% and 77% overall yields as pure ?-anomers. These bromopyridyl C-nucleoside intermediates were then subjected to a series of palladium-catalyzed cross-coupling reactions, aminations, aminocarbonylations, and hydroxylations to give a series of protected 1?-(5-alkyl-, 5-aryl-, 5-amino-, 5-carbamoyl-, and 5-hydroxypyridin-2-yl)-C-ribonucleosides 13a-i and ?-(6-alkyl-, 6-aryl-, 6-amino-, 6-carbamoyl-, and 6-hydroxypyridin-3-yl)-C-ribonucleosides 15a-i. Deprotection of silylated nucleosides by Et(3)N·3HF, TBAF, or TFA gave a series of free C-nucleosides 14a-i and 16a-i.
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The observed and calculated 1H and 13C chemical shifts of tertiary amines and their N-oxides.
Magn Reson Chem
PUBLISHED: 01-25-2011
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A series of model tertiary amines were oxidized in situ in an NMR tube to amine N-oxides and their (1)H and (13)C NMR spectra were recorded. Next, the chemical shifts induced by oxidation (??) were calculated using different GIAO methods investigating the influence of the method [Hartree-Fock (HF), Moeller-Plesset perturbation, density functional theory (DFT)], the functional applied in the DFT (B3LYP, BPW, OPBE, OPW91) and the basis set used [6-31G*, 6-311G**, 6-311 + + G** and 6-311 + + G(3df,3pd)]. The best results were obtained with the HF/6-311 + + G** and OPBE/6-311 + + G** methods. The computation/experiment comparison approach was used for the configuration prediction of chiral amine N-oxides-(R) and (S)-agroclavine-6-N-oxide.
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Observed and calculated 1H and 13C chemical shifts induced by the in situ oxidation of model sulfides to sulfoxides and sulfones.
Magn Reson Chem
PUBLISHED: 07-28-2010
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A series of model sulfides was oxidized in the NMR sample tube to sulfoxides and sulfones by the stepwise addition of meta-chloroperbenzoic acid in deuterochloroform. Various methods of quantum chemical calculations have been tested to reproduce the observed (1)H and (13)C chemical shifts of the starting sulfides and their oxidation products. It has been shown that the determination of the energy-minimized conformation is a very important condition for obtaining realistic data in the subsequent calculation of the NMR chemical shifts. The correlation between calculated and observed chemical shifts is very good for carbon atoms (even for the cheap DFT B3LYP/6-31G* method) and somewhat less satisfactory for hydrogen atoms. The calculated chemical shifts induced by oxidation (the Delta delta values) agree even better with the experimental values and can also be used to determine the oxidation state of the sulfur atom (-S-, -SO-, -SO(2)-).
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Cyclodextrin carriers of positively charged porphyrin sensitizers.
Org. Biomol. Chem.
PUBLISHED: 07-20-2009
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The cationic sensitizer 5,10,15,20-tetrakis(N-methylpyridinium-4-yl)porphyrin (TMPyP) forms supramolecular complexes with native, per-methylated, sulfonated and dimethyl-sulfonated cyclodextrins (CDs). Binding interactions were proved by NMR, mass spectra, capillary zone electrophoresis, UV-Vis and fluorescence spectroscopy. The 2D-NMR experiments on native CDs indicate that the interaction of TMPyP with the external CD surface is the dominant binding mode. The high binding affinity of TMPyP towards sulfonated CDs is due to electrostatic interactions. Binding is accompanied by an increase of the TMPyP basicity. Whereas betaCD does not affect the lifetime of the TMPyP triplet states, binding with sulfonated CDs causes the protonation of the TMPyP triplet states even in neutral solution. The diprotonated anionic sensitizer 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrin (TPPSH(2)(2+)) forms host-guest complexes with native betaCD and gammaCD, similarly as in its non-protonated state. The positive charge of pyrrole nitrogen atoms does not significantly influence the mode of the interaction. In contrast to TMPyP, the lifetimes of the triplet states of bound TPPSH(2)(2+) to native CDs increase.
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Sugar-modified derivatives of cytostatic 7-(het)aryl-7-deazaadenosines: 2-C-methylribonucleosides, 2-deoxy-2-fluoroarabinonucleosides, arabinonucleosides and 2-deoxyribonucleosides.
Bioorg. Med. Chem.
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A series of novel sugar-modified derivatives of cytostatic 7-hetaryl-7-deazaadenosines (2-C-methylribonucleosides, 2-deoxy-2-fluoroarabinonucleosides, arabinonucleosides and 2-deoxyribonucleosides) was prepared and screened for biological activity. The synthesis consisted of preparation of the corresponding sugar-modified 7-iodo-7-deazaadenine nucleosides and their aqueous-phase Suzuki-Miyaura cross-coupling reactions with (het)arylboronic acids or Stille couplings with hetarylstannanes in DMF. The synthesis of 7-iodo-7-deazaadenine nucleosides was based on a glycosidation of 6-chloro-7-iodo-7-deazapurine with a suitable sugar synthon or on an interconversion of 2-OH stereocenter (for arabinonucleosides). Several examples of 2-C-Me-ribonucleosides showed moderate anti-HCV activities in a replicon assay accompanied by cytotoxicity. Several 7-hetaryl-7-deazaadenine fluoroarabino- and arabinonucleosides exerted moderate micromolar cytostatic effects. The most active was 7-ethynyl-7-deazaadenine fluoroarabinonucleoside which showed submicromolar antiproliferative activity. However, all the sugar-modified derivatives were less active than the parent ribonucleosides.
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13C GIAO DFT calculation as a tool for configuration prediction of N-O group in saturated heterocyclic N-oxides.
Magn Reson Chem
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Tropane, tropinone, pseudopelletierine and cocaine were oxidized in situ in a nuclear magnetic resonance (NMR) tube providing mixtures of exo/endo N-oxides. Observed (13)C chemical shifts were correlated with values calculated by gauge-including atomic orbitals density functional theory (DFT) OPBE/6-31G* method using DFT B3LYP/6-31G* optimized geometries. The same method of (13)C chemical shift calculation was applied on series of methyl-substituted 1-methylpiperidines and their epimeric N-oxides described in literature. The results show that using this undemanding calculation method enables assignment of configuration of N-O group in N-epimeric saturated heterocyclic N-oxides. The approach enables assigning of the configuration with high degree of certainty even if NMR data of only one isomer are available. An improved method of in situ oxidation of starting amines in an NMR tube is also described.
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