Four 6-substituted 4-amino-pyrimido[4,5-b]indole 2'-deoxyribonucleoside triphosphates (dA(BX)TPs) were prepared by glycosylation of 4,6-dichloropyrimidoindole followed by ammonolysis, cross-coupling and triphosphorylation. They were found to be moderate to good substrates for DNA polymerases in primer extension. They also exerted fluorescence with emission maxima 335-378nm. When incorporated to oligonucleotide probes, they did not show significant mismatch discrimination but the 6-benzofuryl 4-amino-pyrimido[4,5-b]indole nucleotide displayed a useful sensitivity to protein binding in experiment with SSB protein.
- MeSH
- chybné párování bází MeSH
- deoxyadeninnukleotidy chemická syntéza chemie metabolismus MeSH
- deoxyribonukleosidy chemická syntéza chemie metabolismus MeSH
- DNA vazebné proteiny chemie metabolismus MeSH
- DNA-dependentní DNA-polymerasy metabolismus MeSH
- Escherichia coli chemie metabolismus MeSH
- fluorescenční barviva chemická syntéza chemie metabolismus MeSH
- fluorescenční spektrometrie MeSH
- indoly chemická syntéza chemie metabolismus MeSH
- oligonukleotidové sondy chemická syntéza chemie metabolismus MeSH
- proteiny z Escherichia coli chemie metabolismus MeSH
- sekvence nukleotidů MeSH
- Publikační typ
- časopisecké články MeSH
New types of double-headed 2'-deoxycytidine 5'-O-triphosphates (dC(XC)TPs) bearing another cytosine or 5-fluorocytosine linked through a flexible propargyl, homopropargyl or pent-1-ynyl linker to position 5 were prepared by the aqueous Sonogashira cross-coupling reactions of 5-iodo-dCTP with the corresponding (fluoro)cytosine-alkynes. The modified dC(XC)TPs were good substrates for DNA polymerases and were used for enzymatic synthesis of cytosine-functionalized DNA by primer extension or PCR. The cytosine- or fluorocytosine-linked DNA probes did not significantly inhibit DNA methyltransferases and did not cross-link to these proteins.
- MeSH
- cytosin chemie metabolismus farmakologie MeSH
- deoxycytosinnukleotidy chemická syntéza chemie metabolismus farmakologie MeSH
- DNA-(cytosin-5-)methyltransferasa antagonisté a inhibitory chemie metabolismus MeSH
- DNA-dependentní DNA-polymerasy metabolismus MeSH
- DNA biosyntéza chemie metabolismus MeSH
- molekulární modely MeSH
- molekulární struktura MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The synthesis and biological activity profiling of a large series of diverse pyrrolo[2,3-d]pyrimidine 4'-C-methylribonucleosides bearing an (het)aryl group at position 4 or 5 is reported as well as the synthesis of several phosphoramidate prodrugs. These compounds are 4'-C-methyl derivatives of previously reported cytostatic hetaryl-7-deazapurine ribonucleosides. The synthesis is based on glycosylation of halogenated 7-deazapurine bases with 1,2-di-O-acetyl-3,5-di-O-benzyl-4-C-methyl-β-d-ribofuranose followed by cross-coupling and nucleophilic substitution reactions. The final compounds showed low cytotoxicity and several derivatives exerted antiviral activity against HCV or Dengue viruses at micromolar concentrations.
- MeSH
- antitumorózní látky chemická syntéza farmakologie MeSH
- antivirové látky chemická syntéza farmakologie MeSH
- Hepacivirus účinky léků MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- prekurzory léčiv chemická syntéza farmakologie MeSH
- purinové nukleosidy chemická syntéza farmakologie MeSH
- purinové nukleotidy chemická syntéza farmakologie MeSH
- virus dengue účinky léků MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
A systematic study of the cleavage of DNA sequences containing 5-fluorocytosine or 5-fluorouracil by type II restriction endonucleases (REs) was performed and the results compared with the same sequences containing natural pyrimidine bases, uracil or 5-methylcytosine. The results show that some REs recognize fluorine as a hydrogen on cytosine and cleave the corresponding sequences where the presence of m5dC leads to blocking of the cleavage. However, on uracil, the same REs recognize the F as a methyl surrogate and cleave the sequences which are not cleaved if uracil is incorporated instead of thymine. These results are interesting for understanding the recognition of DNA sequences by REs and for manipulation of the specific DNA cutting.
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.
- MeSH
- antibakteriální látky chemická syntéza chemie farmakologie MeSH
- antituberkulotika chemická syntéza chemie farmakologie MeSH
- antivirové látky chemická syntéza chemie farmakologie MeSH
- cytostatické látky chemická syntéza chemie farmakologie MeSH
- cytotoxiny chemická syntéza chemie farmakologie MeSH
- Hepacivirus účinky léků fyziologie MeSH
- lidé MeSH
- Mycobacterium bovis účinky léků MeSH
- nádorové buněčné linie MeSH
- purinové nukleosidy chemická syntéza chemie farmakologie MeSH
- replikace viru účinky léků MeSH
- ribonukleosidy chemická syntéza chemie farmakologie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
A series of new pyrimido[4,5-b]indole ribonucleosides bearing phenyl or hetaryl group at position 4 has been prepared by selective Pd-catalyzed cross-coupling reactions of the corresponding protected 4,6-dichloropyrimido[4,5-b]indole ribonucleoside with (het)arylboronic acids or stannanes followed by deprotection. Further cross-couplings under harsher conditions and employing X-Phos ligand proceeded at the position 6 leading to 4,6-disubstituted pyrimido[4,5-b]indole ribonucleosides. Some of these compounds displayed antiviral activity against Dengue virus.
- MeSH
- antivirové látky chemická syntéza farmakologie toxicita MeSH
- buňky Hep G2 MeSH
- Hepacivirus účinky léků metabolismus MeSH
- indoly chemie MeSH
- katalýza MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- palladium MeSH
- proliferace buněk účinky léků MeSH
- pyrimidiny chemie MeSH
- replikace viru účinky léků MeSH
- ribonukleosidy chemická syntéza farmakologie toxicita MeSH
- virus dengue účinky léků metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
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.
- MeSH
- antitumorózní látky chemická syntéza chemie farmakologie MeSH
- antivirové látky chemická syntéza chemie farmakologie MeSH
- arabinonukleosidy chemická syntéza chemie farmakologie MeSH
- deoxyribonukleosidy chemická syntéza chemie farmakologie MeSH
- HeLa buňky MeSH
- Hepacivirus účinky léků MeSH
- HL-60 buňky MeSH
- léky antitumorózní - screeningové testy MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- molekulární struktura MeSH
- replikace viru účinky léků MeSH
- sacharidy chemie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou 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
- 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 7-deazapurine ribonucleosides bearing an alkyl, aryl, or hetaryl group in position 6 and H, F, or Cl atom in position 7 has been prepared either by Pd-catalyzed cross-coupling reactions of the corresponding protected 6-chloro-(7-halogenated-)7-deazapurine ribonucleosides with alkyl- or (het)arylorganometallics followed by deprotection, or by single-step aqueous phase cross-coupling reactions of unprotected 6-chloro-(7-halogenated-)7-deazapurine ribonucleosides with (het)arylboronic acids. Significant cytostatic effect was detected with a substantial proportion of the prepared compounds. The most potent were 7-H or 7-F derivatives of 6-furyl- or 6-thienyl-7-deazapurines displaying cytostatic activity in multiple cancer cell lines with a geometric mean of 50% growth inhibition concentration ranging from 16 to 96 nM, a potency comparable to or better than that of the nucleoside analogue clofarabine. Intracellular phosphorylation to mono- and triphosphates and the inhibition of total RNA synthesis was demonstrated in preliminary study of metabolism and mechanism of action studies.
- MeSH
- antitumorózní látky farmakologie chemická syntéza chemie MeSH
- buněčný cyklus účinky léků MeSH
- cytostatické látky farmakologie chemická syntéza chemie MeSH
- léky antitumorózní - screeningové testy MeSH
- lidé MeSH
- molekulární struktura MeSH
- nádorové buněčné linie MeSH
- proliferace buněk účinky léků MeSH
- puriny farmakologie chemická syntéza chemie MeSH
- ribonukleosidy farmakologie chemická syntéza chemie MeSH
- stereoizomerie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
