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
- antivirové látky chemická syntéza farmakologie MeSH
- Hepacivirus účinky léků MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- prekurzory léčiv chemická syntéza farmakologie MeSH
- protinádorové látky 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 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 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
- 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
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- molekulární struktura MeSH
- protinádorové látky chemická syntéza chemie farmakologie MeSH
- replikace viru účinky léků MeSH
- sacharidy chemie MeSH
- screeningové testy protinádorových léčiv 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 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.
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
- buněčný cyklus účinky léků MeSH
- cytostatické látky farmakologie chemická syntéza chemie MeSH
- lidé MeSH
- molekulární struktura MeSH
- nádorové buněčné linie MeSH
- proliferace buněk účinky léků MeSH
- protinádorové látky farmakologie chemická syntéza chemie MeSH
- puriny farmakologie chemická syntéza chemie MeSH
- ribonukleosidy farmakologie chemická syntéza chemie MeSH
- screeningové testy protinádorových léčiv 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
A series of 3-deazapurine ribonucleosides 5a-5l bearing diverse C-substituents (alkyl, aryl and heteroaryl) in the position 6 were prepared by Pd-catalyzed cross-coupling reactions of either free 6-chloro-3-deazapurine ribonucleoside 4 or its acetyl protected congener 3 followed by deprotection. An improved synthesis of the starting 4-chloro-1-(2,3,5-tri-O-acetyl-ß-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridine (3) was developed by the application of Vorbrüggen glycosylation of silylated nucleobase with 1,2,3,5-tetra-O-acetyl-ß-D-ribofuranose (2). None of compounds 5a-5l showed any considerable cytostatic or antiviral activity.
- MeSH
- alkyny chemie metabolismus MeSH
- dimerizace MeSH
- leukemie farmakoterapie MeSH
- lidé MeSH
- nukleosidy chemická syntéza chemie metabolismus MeSH
- párování bází genetika MeSH
- protinádorové látky farmakologie chemie metabolismus MeSH
- puriny metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
