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 α.
- MeSH
- adenin analogy a deriváty chemie MeSH
- antitumorózní látky chemická syntéza chemie farmakologie MeSH
- antivirové látky chemická syntéza chemie farmakologie MeSH
- buňky Hep G2 MeSH
- cytostatické látky chemická syntéza chemie farmakologie MeSH
- DNA-dependentní DNA-polymerasy antagonisté a inhibitory metabolismus MeSH
- HeLa buňky MeSH
- Hepacivirus účinky léků genetika MeSH
- HL-60 buňky MeSH
- léky antitumorózní - screeningové testy MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- molekulární struktura MeSH
- nádorové buněčné linie MeSH
- proliferace buněk účinky léků MeSH
- ribonukleosidy chemická syntéza chemie farmakologie MeSH
- viabilita buněk účinky léků 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
This study is a thorough examination of the effects of the DNA polymerase inhibitor aphidicolin on the nuclear cycle and cell cycle progression characteristics, as well as their reversibility, in Giardia intestinalis. Giardia trophozoites are arrested in the G1/S-junction after aphidicolin treatment according to their DNA content. However, cell growth continues and trophozoites arrested with aphidicolin resemble cells in the G2 phase and trophozoites in ageing cultures. Extensive treatment with aphidicolin causes side effects and we detected positive signals for phosphorylated histone H2A, which, in mammalian cells, is involved in a signalling pathway triggered as a reaction to double stranded DNA breaks. These results suggest that aphidicolin causes dissociation of the nuclear and cytoplasmic cycles, a phenomenon that has also been described for other inhibitors in mammalian cell lines. Thus, if aphidicolin is used for synchronization of Giardia trophozoites, this fact must be accounted for, and treatment with aphidicolin must be minimal. Copyright 2009 Elsevier Inc. All rights reserved.
- MeSH
- afidikolin farmakologie MeSH
- bromodeoxyuridin metabolismus MeSH
- buněčný cyklus účinky léků MeSH
- časové faktory MeSH
- cyklin B analýza MeSH
- DNA-dependentní DNA-polymerasy antagonisté a inhibitory MeSH
- fluorescenční protilátková technika MeSH
- fosforylace účinky léků MeSH
- Giardia lamblia cytologie genetika účinky léků MeSH
- histony metabolismus MeSH
- inhibitory enzymů farmakologie MeSH
- mitotický index MeSH
- poškození DNA účinky léků MeSH
- protozoální DNA biosyntéza účinky léků MeSH
- průtoková cytometrie MeSH
- replikace DNA účinky léků MeSH
- trofozoiti cytologie účinky léků MeSH
- Publikační typ
- práce podpořená grantem MeSH
- MeSH
- Chlamydia trachomatis patogenita MeSH
- DNA-dependentní DNA-polymerasy antagonisté a inhibitory krev moč MeSH
- lidé MeSH
- Neisseria gonorrhoeae patogenita MeSH
- odběr biologického vzorku metody přístrojové vybavení MeSH
- polymerázová řetězová reakce MeSH
- reagenční diagnostické soupravy MeSH
- zmrazování MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
