Purine nucleosides represent an interesting group of nitrogen heterocycles, showing a wide range of biological effects. In this study, we designed and synthesized a series of 6,9-disubstituted and 2,6,9-trisubstituted purine ribonucleosides via consecutive nucleophilic aromatic substitution, glycosylation, and deprotection of the ribofuranose unit. We prepared eight new purine nucleosides bearing unique adamantylated aromatic amines at position 6. Additionally, the ability of the synthesized purine nucleosides to form stable host-guest complexes with β-cyclodextrin (β-CD) was confirmed using nuclear magnetic resonance (NMR) and mass spectrometry (ESI-MS) experiments. The in vitro antiproliferative activity of purine nucleosides and their equimolar mixtures with β-CD was tested against two types of human tumor cell line. Six adamantane-based purine nucleosides showed an antiproliferative activity in the micromolar range. Moreover, their effect was only slightly suppressed by the presence of β-CD, which was probably due to the competitive binding of the corresponding purine nucleoside inside the β-CD cavity.

• Klíčová slova
• adamantane, antiproliferative activity, glycosylation, nucleoside, purine, β-cyclodextrin,
• MeSH
• adamantan * farmakologie   MeSH
• beta-cyklodextriny * farmakologie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nukleosidy farmakologie   chemie   MeSH
• purinové nukleosidy farmakologie   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• adamantan * MeSH
• beta-cyklodextriny * MeSH
• nukleosidy MeSH
• purinové nukleosidy MeSH

Cytokinins are naturally occurring substances that act as plant growth regulators promoting plant growth and development, including shoot initiation and branching, and also affecting apical dominance and leaf senescence. Aromatic cytokinin 6-benzylaminopurine (BAP) has been widely used in micropropagation systems and biotechnology. However, its 9-glucoside (BAP9G) accumulates in explants, causing root inhibition and growth heterogenity. To overcome BAP disadvantages, a series of ring-substituted 2'-deoxy-9-(β)-d-ribofuranosylpurine derivatives was prepared and examined in different classical cytokinin bioassays. Amaranthus, senescence and tobacco callus bioassays were employed to provide details of cytokinin activity of 2'-deoxy-9-(β)-d-ribosides compared to their respective free bases and ribosides. The prepared derivatives were also tested for their recognition by cytokinin receptors of Arabidopsis thaliana AHK3 and CRE1/AHK4. The ability of aromatic N6-substituted adenine-2'-deoxy-9-(β)-d-ribosides to promote plant growth and delay senescence was increased considerably and, in contrast to BAP, no loss of cytokinin activity at higher concentrations was observed. The presence of a 2'-deoxyribosyl moiety at the N9-position led to an increase in cytokinin activities in comparison to the free bases and ribosides. The antioxidant capacity, cytotoxicity and effect on the MHV-68 gammaherpesvirus strain were also examined.

• Klíčová slova
• 2′-Deoxyribosides, Antioxidative capacity, Antiviral testing, Aromatic cytokinins, Plant growth regulator, Purine derivatives,
• MeSH
• antioxidancia chemická syntéza   chemie   farmakologie   MeSH
• Arabidopsis účinky léků   metabolismus   MeSH
• Cercopithecus aethiops MeSH
• molekulární struktura MeSH
• purinové nukleosidy chemická syntéza   chemie   farmakologie   MeSH
• regulátory růstu rostlin chemická syntéza   chemie   farmakologie   MeSH
• Vero buňky MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antioxidancia MeSH
• purinové nukleosidy MeSH
• regulátory růstu rostlin 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.

• Klíčová slova
• 4′-C-Methyl-ribonucleosides, Branched nucleosides, Nucleoside antivirals, Nucleosides, Prodrugs,
• 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
• Názvy látek
• antitumorózní látky MeSH
• antivirové látky MeSH
• prekurzory léčiv MeSH
• purinové nukleosidy MeSH
• purinové nukleotidy 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
• Názvy látek
• antibakteriální látky MeSH
• antituberkulotika MeSH
• antivirové látky MeSH
• cytostatické látky MeSH
• cytotoxiny MeSH
• purinové nukleosidy MeSH
• ribonukleosidy 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
• Názvy látek
• antitumorózní látky MeSH
• purinové nukleosidy MeSH

Synthesis of novel purine bases and nucleosides bearing unsubstituted or substituted cyclopropyl rings in position 6 is reported. Unsubstituted 6-cyclopropylpurines were efficiently prepared by cross-coupling reactions of 6-chloropurines with cyclopropylzinc chloride. 6-Vinylpurines underwent Cu-mediated cyclopropanations with ethyl diazoacetate to give 6-[(ethoxycarbonyl)cyclopropyl]purines that were further transformed to carboxylic acids, amides and alcohols. 6-Cyclopropylpurine ribonucleoside exerted a significant cytostatic effect while all substituted derivatives were inactive.

• MeSH
• cyklopropany chemie   MeSH
• krystalografie rentgenová MeSH
• lidé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• proliferace buněk účinky léků   MeSH
• purinové nukleosidy chemická syntéza   chemie   farmakologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cyklopropany MeSH
• purinové nukleosidy 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 chemická syntéza   chemie   farmakologie   MeSH
• cytostatické látky chemická syntéza   chemie   farmakologie   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 chemická syntéza   chemie   farmakologie   MeSH
• sloučeniny síry chemická syntéza   chemie   farmakologie   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antivirové látky MeSH
• cytostatické látky MeSH
• methansulfonáty MeSH
• purinové nukleosidy MeSH
• sloučeniny síry MeSH

An efficient and facile synthesis of a large series of diverse 6-[2-(dialkylamino)vinyl]-, 6-[2-(dialkylamino)ethyl]-, 6-(2-alkoxyethyl)-, and 6-[2-(alkylsulfanyl)ethyl]purine nucleosides (35 examples of both ribo- and 2'-deoxyribonucleosides) was developed. The key transformations involved conjugate nucleophilic additions of amines, alcoholates, or thiolates to Tol-protected 6-alkylylpurine or 6-vinylpurine nucleosides. 6-[(2-Dialkylamino)vinyl]- and some 6-[(2-dialkylamino)ethyl]purine ribonucleosides exerted significant cytostatic effects and some anti-HCV activity with low selectivity.

• MeSH
• alkylace MeSH
• aminace MeSH
• antivirové látky MeSH
• buněčné linie MeSH
• Hepacivirus účinky léků   MeSH
• lidé MeSH
• molekulární struktura MeSH
• myši MeSH
• purinové nukleosidy chemická syntéza   chemie   farmakologie   MeSH
• viabilita buněk účinky léků   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antivirové látky MeSH
• purinové nukleosidy MeSH

A series of purine l-ribonucleosides 2a-2i bearing diverse C-substituents (alkyl, aryl, hetaryl or hydroxymethyl) in the position 6 were prepared by Pd-catalyzed cross-coupling reactions of 6-chloro-9-(2,3,5-tri-O-acetyl-beta-l-ribofuranosyl)purine with the corresponding organometallics followed by deprotection. Unlike their d-ribonucleoside enantiomers that possess strong cytostatic and anti-HCV activity, the l-ribonucleosides were inactive except for 6-benzylpurine nucleoside 2h showing moderate anti-HCV effect in replicon assay. A triphosphate of 2h did not inhibit HCV RNA polymerase.

• MeSH
• antitumorózní látky chemická syntéza   chemie   farmakologie   MeSH
• antivirové látky 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
• myši MeSH
• nádorové buněčné linie MeSH
• proliferace buněk účinky léků   MeSH
• purinové nukleosidy chemická syntéza   chemie   farmakologie   MeSH
• ribonukleosidy chemická syntéza   chemie   farmakologie   MeSH
• techniky in vitro MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antitumorózní látky MeSH
• antivirové látky MeSH
• purinové nukleosidy MeSH
• ribonukleosidy MeSH

Significant anti-HCV activity of 6-hetarylpurine ribonucleosides has been discovered and is reported here for the first time and compared with cytostatic effect. An extended series of 6-hetarylpurine nucleosides has been prepared by heterocyclizations in position 6 of purine nucleosides or by cross-couplings of 6-chloropurine nucleosides with hetarylboronic acids, -stannanes, or -zinc halides. The most anti-HCV active were purine ribonucleosides bearing pyrrol-3-yl or 2-furyl groups exerting EC(90) = 0.14 and 0.4 microM, respectively.

• MeSH
• antitumorózní látky chemická syntéza   chemie   farmakologie   MeSH
• antivirové látky chemická syntéza   chemie   farmakologie   MeSH
• Hepacivirus účinky léků   MeSH
• léky antitumorózní - screeningové testy MeSH
• lidé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• purinové nukleosidy chemická syntéza   chemie   farmakologie   MeSH
• ribonukleosidy chemická syntéza   chemie   farmakologie   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antitumorózní látky MeSH
• antivirové látky MeSH
• purinové nukleosidy MeSH
• ribonukleosidy MeSH