Modification of the carbohydrate scaffold is an important theme in drug and vaccine discovery. Therefore, the preparation of novel types of glycomimetics is of interest in synthetic carbohydrate chemistry. In this manuscript, we present an early investigation of the synthesis, structure, and conformational behaviour of (1→1)-Si-disaccharides as a novel type of glycomimetics arising from the replacement of interglycosidic oxygen with a dimethyl-, methylpropyl-, or diisopropylsilyl linkage. We accomplished the preparation of this unusual group of umpoled compounds by the reaction of lithiated glycal or 2-oxyglycal units with dialkyldichlorosilanes. We demonstrated the good stability of the "Si-glycosidic" linkage under acidic conditions even at elevated temperatures. Next, we described the conformational landscape of these compounds by the combination of in silico modelling with spectroscopic and crystallographic methods. Finally, we explained the observed conformational flexibility of these compounds by the absence of gauche stabilizing effects that are typically at play in natural carbohydrates.
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
- antitumorózní látky chemie farmakologie MeSH
- hmotnostní spektrometrie s elektrosprejovou ionizací MeSH
- lidé MeSH
- magnetická rezonanční spektroskopie MeSH
- nádorové buněčné linie MeSH
- purinové nukleosidy chemie farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
A series of novel sugar-modified derivatives of cytostatic 6-hetaryl-7-deazapurine ribonucleosides: 2′-C-methylribonucleosides, arabinonucleosides and 2′-deoxy-2′-fluoroarabinonucleosides bearing an alkyl, aryl and hetaryl group in position 6 were prepared by palladium catalyzed cross-coupling reactions of corresponding (protected) 6-chloro-(7-fluoro)-7-deazapurine nucleosides with (het)arylboronic, hetarylstannanes and trimethylaluminium eventually followed by deprotection. Key intermediate 6-chloro-7-deazapurine 2′-C-methyl-β-D-ribofuranoside was prepared via a stereoselective nucleobase anion glycosylation with toluoyl-protected 1,2-anhydro-2-C-methylribofuranose. The 1,2-anhydro sugar was synthesized in 3 steps starting from readily available 2-C-methylribonolactone. The 6-chloro-7-deazapurine arabinofuranoside intermediate was obtained by epimerization from 3′,5′-protected 6-chloro-7-deazapurine ribofuranoside via 2′-hydroxyl oxidation followed by reduction. None of the prepared compounds showed any considerable cytostatic or antiviral activity.
- MeSH
- inhibitory enzymů chemická syntéza chemie farmakologie MeSH
- molekulární struktura MeSH
- organické sloučeniny křemíku chemická syntéza chemie farmakologie MeSH
- restrikční endonukleasy typu II antagonisté a inhibitory metabolismus MeSH
- štěpení DNA účinky léků MeSH
- stereoizomerie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
A series of six pyrimidine-modified dNTPs--5-ethynyl-, 5-phenyl-, and 5-(3-nitrophenyl)deoxycitidine and -deoxyuridine triphosphates--were prepared and incorporated by primer extension with Vent (exo-)polymerase to specific DNA sequences within or next to the recognition sequences of selected restriction endonucleases. The cleavage of these pyrimidine-modified DNA sequences by 13 restriction enzymes was then studied. Whereas the presence of any modified C within the target sequence completely prevented any restriction cleavage, most enzymes tolerated the presence of 5-ethynylU and two of them even the presence of 5-phenyl- and 5-(3-nitrophenyl)U. Modifications outside the recognition sequence were tolerated except in the case of phenyl derivatives with the PvuII enzyme. 5-EthynylC was used for protection of the recognition sequence from cleavage in the presence of the second unmodified copy of the same sequence that was cleaved.
Aqueous Sonogashira cross-coupling reactions of 5-iodopyrimidine or 7-iodo-7-deazaadenine nucleosides with bile acid-derived terminal acetylenes linked via an ester or amide tether gave the corresponding bile acid-nucleoside conjugates. Analogous reactions of halogenated nucleoside triphosphates gave directly bile acid-modified dNTPs. Enzymatic incorporation of these modified nucleotides to DNA was successfully performed using Phusion polymerase for primer extension. One of the dNTPs (dCTP bearing cholic acid) was also efficient for PCR amplification.
- MeSH
- denaturace nukleových kyselin MeSH
- DNA-dependentní DNA-polymerasy metabolismus MeSH
- DNA chemie metabolismus MeSH
- nukleosidy chemická syntéza chemie MeSH
- nukleotidy chemická syntéza chemie metabolismus MeSH
- Thermococcaceae enzymologie MeSH
- žlučové kyseliny a soli chemie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Novel direct C-H borylations of 7-deazapurines to position 8 by B2pin2 under Ir catalysis were followed by Suzuki cross-couplings with aryl halides and other functional group transformations to give diverse 8-substituted 7-deazaadenines.
Modified 2'-deoxynucleoside triphosphates (dNTPs) bearing [Ru(bpy)(3)](2+) and [Os(bpy)(3)](2+) complexes attached via an acetylene linker to the 5-position of pyrimidines (C and U) or to the 7-position of 7-deazapurines (7-deaza-A and 7-deaza-G) have been prepared in one step by aqueous cross-couplings of halogenated dNTPs with the corresponding terminal acetylenes. Polymerase incorporation by primer extension using Vent (exo-) or Pwo polymerases gave DNA labeled in specific positions with Ru(2+) or Os(2+) complexes. Square-wave voltammetry could be efficiently used to detect these labeled nucleic acids by reversible oxidations of Ru(2+/3+) or Os(2+/3+). The redox potentials of the Ru(2+) complexes (1.1-1.25 V) are very close to that of G oxidation (1.1 V), while the potentials of Os(2+) complexes (0.75 V) are sufficiently different to enable their independent detection. On the other hand, Ru(2+)-labeled DNA can be independently analyzed by luminescence. In combination with previously reported dNTPs bearing ferrocene, aminophenyl, and nitrophenyl tags, the Os-labeled dATP has been successfully used for "multicolor" redox labeling of DNA and for DNA minisequencing.
- MeSH
- barva MeSH
- barvení a značení metody MeSH
- DNA-dependentní DNA-polymerasy chemie MeSH
- DNA chemie MeSH
- elektrochemie MeSH
- luminiscence MeSH
- oligonukleotidy chemie MeSH
- osmium chemie MeSH
- oxidace-redukce MeSH
- reagencia zkříženě vázaná chemie MeSH
- ruthenium chemie MeSH
- Publikační typ
- práce podpořená grantem MeSH
An efficient and facile synthesis of a large series of diverse 6-(N-substituted aminomethyl)-, 6-(O-substituted hydroxymethyl)- and 6-(S-substituted sulfanylmethyl)purine nucleosides (55 examples of both ribo- and 2'-deoxyribonucleosides), aimed at identifying novel homologues of natural nucleosides, was developed. The key transformation involved nucleophilic substitutions of Tol-protected 6-(mesyloxymethyl)purine nucleosides by primary or secondary amines, alcoholates or thiolates. While the 2'-deoxyribonucleosides were inactive, the ribonucleosides exerted considerable cytostatic effects and some anti-HCV activity with low selectivity.
- MeSH
- aminace MeSH
- antivirové látky farmakologie chemická syntéza chemie MeSH
- cytostatické látky farmakologie chemická syntéza chemie MeSH
- financování organizované MeSH
- Hepacivirus účinky léků MeSH
- hydroxylace MeSH
- lidé MeSH
- methansulfonáty chemie MeSH
- metylace MeSH
- molekulární struktura MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- purinové nukleosidy farmakologie chemická syntéza chemie MeSH
- sloučeniny síry farmakologie chemická syntéza chemie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
A series of N(3)-substituted thymine acyclic nucleoside phosphonates bearing a number of (phosphonomethoxy)alkyl groups were synthesized and investigated for their ability to inhibit the human thymidine phosphorylase expressed in V79 Chinese hamster cells, as well as thymidine phosphorylase from SD-lymphoma, Escherichia coli and human placenta. In comparison to N(1)- substituted analogues which possess a considerable inhibitory activity towards thymidine phosphorylase from SD-lymphoma, the results showed a marginal inhibitory effect of these compounds. None of the presented N(3)-substituted derivatives possess a significant cytostatic activity.
- MeSH
- Cricetulus MeSH
- financování organizované MeSH
- inhibitory enzymů farmakologie chemická syntéza MeSH
- křečci praví MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- lymfom T-buněčný enzymologie MeSH
- organofosfonáty farmakologie chemická syntéza MeSH
- placenta enzymologie MeSH
- pyrimidinové nukleosidy farmakologie chemická syntéza MeSH
- thymidinfosforylasa antagonisté a inhibitory MeSH
- thymin analogy a deriváty farmakologie chemická syntéza MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- křečci praví MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- zvířata MeSH
