7-(2-Thienyl)-7-deazaadenosine (AB61) showed nanomolar cytotoxic activities against various cancer cell lines but only mild (micromolar) activities against normal fibroblasts. The selectivity of AB61 was found to be due to inefficient phosphorylation of AB61 in normal fibroblasts. The phosphorylation of AB61 in the leukemic CCRF-CEM cell line proceeds well and it was shown that AB61 is incorporated into both DNA and RNA, preferentially as a ribonucleotide. It was further confirmed that a triphosphate of AB61 is a substrate for both RNA and DNA polymerases in enzymatic assays. Gene expression analysis suggests that AB61 affects DNA damage pathways and protein translation/folding machinery. Indeed, formation of large 53BP1 foci was observed in nuclei of AB61-treated U2OS-GFP-53BP1 cells indicating DNA damage. Random incorporation of AB61 into RNA blocked its translation in an in vitro assay and reduction of reporter protein expression was also observed in mice after 4-hour treatment with AB61. AB61 also significantly reduced tumor volume in mice bearing SK-OV-3, BT-549, and HT-29 xenografts. The results indicate that AB61 is a promising compound with unique mechanism of action and deserves further development as an anticancer agent. Mol Cancer Ther; 15(5); 922-37. ©2016 AACR.

• MeSH
• analýza přežití MeSH
• DNA genetika   metabolismus   MeSH
• fibroblasty MeSH
• lidé MeSH
• messenger RNA genetika   metabolismus   MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory farmakoterapie   genetika   metabolismus   patologie   MeSH
• permeabilita buněčné membrány účinky léků   MeSH
• poškození DNA účinky léků   MeSH
• proliferace buněk účinky léků   MeSH
• proteosyntéza účinky léků   MeSH
• protinádorové látky chemie   metabolismus   farmakologie   MeSH
• regulace genové exprese u nádorů MeSH
• sbalování proteinů účinky léků   MeSH
• tubercidin analogy a deriváty   chemie   metabolismus   farmakologie   MeSH
• výsledek terapie MeSH
• xenogenní modely - testy protinádorové aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• DNA MeSH
• messenger RNA MeSH
• protinádorové látky MeSH
• tubercidin 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
• 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
• Názvy látek
• antivirové látky MeSH
• prekurzory léčiv MeSH
• protinádorové látky MeSH
• purinové nukleosidy MeSH
• purinové nukleotidy MeSH

A series of 6-(hetero)aryl- or 6-methyl-7-deazapurine ribonucleosides bearing a substituent at position 2 (Cl, F, NH2, or CH3) were prepared by cross-coupling reactions at position 6 and functional group transformations at position 2. Cytostatic, antiviral, and antimicrobial activity assays were performed. The title compounds were observed to be potent and selective inhibitors of Mycobacterium tuberculosis adenosine kinase (ADK), but not human ADK; moreover, they were found to be non-cytotoxic. The antimycobacterial activities against M. tuberculosis, however, were only moderate. The reason for this could be due to either poor uptake through the cell wall or to parallel biosynthesis of adenosine monophosphate by the salvage pathway.

• Klíčová slova
• antimycobacterial agents, cytostatics, nucleosides, purines, pyrrolopyrimidines,
• MeSH
• adenosinkinasa antagonisté a inhibitory   MeSH
• antituberkulotika chemická syntéza   farmakologie   MeSH
• inhibitory enzymů chemická syntéza   farmakologie   MeSH
• kultivované buňky MeSH
• lidé MeSH
• puriny chemie   MeSH
• ribonukleosidy chemie   farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 7-deazapurine MeSH Prohlížeč
• adenosinkinasa MeSH
• antituberkulotika MeSH
• inhibitory enzymů MeSH
• puriny MeSH
• ribonukleosidy MeSH

Adenosine kinase (ADK) from Mycobacterium tuberculosis (Mtb) was selected as a target for design of antimycobacterial nucleosides. Screening of 7-(het)aryl-7-deazaadenine ribonucleosides with Mtb and human (h) ADKs and testing with wild-type and drug-resistant Mtb strains identified specific inhibitors of Mtb ADK with micromolar antimycobacterial activity and low cytotoxicity. X-ray structures of complexes of Mtb and hADKs with 7-ethynyl-7-deazaadenosine showed differences in inhibitor interactions in the adenosine binding sites. 1D (1)H STD NMR experiments revealed that these inhibitors are readily accommodated into the ATP and adenosine binding sites of Mtb ADK, whereas they bind preferentially into the adenosine site of hADK. Occupation of the Mtb ADK ATP site with inhibitors and formation of catalytically less competent semiopen conformation of MtbADK after inhibitor binding in the adenosine site explain the lack of phosphorylation of 7-substituted-7-deazaadenosines. Semiempirical quantum mechanical analysis confirmed different affinity of nucleosides for the Mtb ADK adenosine and ATP sites.

• MeSH
• adenin analogy a deriváty   chemie   MeSH
• adenosinkinasa antagonisté a inhibitory   chemie   metabolismus   MeSH
• adenosintrifosfát metabolismus   MeSH
• antituberkulotika chemie   farmakologie   MeSH
• konformace proteinů MeSH
• krystalografie rentgenová MeSH
• lidé MeSH
• mikrobiální testy citlivosti MeSH
• Mycobacterium tuberculosis účinky léků   enzymologie   MeSH
• nukleární magnetická rezonance biomolekulární MeSH
• preklinické hodnocení léčiv MeSH
• ribonukleosidy chemie   farmakologie   MeSH
• vazebná místa MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 7-deazaadenine MeSH Prohlížeč
• adenin MeSH
• adenosinkinasa MeSH
• adenosintrifosfát MeSH
• antituberkulotika MeSH
• ribonukleosidy 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 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
• Názvy látek
• antivirové látky MeSH
• arabinonukleosidy MeSH
• deoxyribonukleosidy MeSH
• protinádorové látky MeSH
• sacharidy MeSH

A series of 7-aryl- and 7-hetaryl-7-deazaadenosines was prepared by the cross-coupling reactions of unprotected or protected 7-iodo-7-deazaadenosines with (het)arylboronic acids, stannanes, or zinc halides. Nucleosides bearing 5-membered heterocycles at the position 7 exerted potent in vitro antiproliferative effects against a broad panel of hematological and solid tumor cell lines. Cell cycle analysis indicated profound inhibition of RNA synthesis and induction of apoptosis in treated cells. Intracellular conversion to triphosphates has been detected with active compounds. The triphosphate metabolites showed only a weak inhibitory effect on human RNA polymerase II, suggesting potentially other mechanisms for the inhibition of RNA synthesis and quick onset of apoptosis. Initial in vivo evaluation demonstrated an effect of 7-(2-thienyl)-7-deazaadenine ribonucleoside on the survival rate in syngeneic P388D1 mouse leukemia model.

• MeSH
• adenosinkinasa antagonisté a inhibitory   MeSH
• apoptóza účinky léků   MeSH
• cytostatické látky chemická syntéza   farmakologie   MeSH
• lidé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• protinádorové látky chemická syntéza   farmakologie   MeSH
• RNA-polymerasa II antagonisté a inhibitory   MeSH
• tubercidin analogy a deriváty   chemická syntéza   farmakologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adenosinkinasa MeSH
• cytostatické látky MeSH
• protinádorové látky MeSH
• RNA-polymerasa II MeSH
• tubercidin MeSH

A series of cycloSal-phosphate prodrugs of a recently described new class of nucleoside cytostatics (6-hetaryl-7-deazapurine ribonucleosides) was prepared. The corresponding 2',3'-isopropylidene 6-chloro-7-deazapurine nucleosides were converted into 5-O'-cycloSal-phosphates. These underwent a series of Stille or Suzuki cross-couplings with diverse (het)arylstannanes or -boronic acids to yield the protected 6-(het)aryl-7-deazapurine pronucleotides that were subsequently deprotected to give 12 derivatives of free pronucleotides. The in vitro cytostatic effect of the pronucleotides was compared with parent nucleoside analogues. In most cases, the activity of the pronucleotide was similar to or somewhat lower than that of the corresponding parent nucleosides, with the exception of 7-fluoro pronucleotides 13 a, 13 b, and 13 d, which had exhibited GIC(50) values that were improved by one order of magnitude (to the low nanomolar range). The presence of a cycloSal-phosphate group also influenced selectivity toward various cell lines. Several pronucleotides were found which strongly inhibit human adenosine kinase but only weakly inhibit the MTB adenosine kinase.

• MeSH
• adenosinkinasa antagonisté a inhibitory   metabolismus   MeSH
• cytostatické látky chemická syntéza   chemie   farmakologie   MeSH
• fosfáty chemie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• prekurzory léčiv chemická syntéza   chemie   farmakologie   MeSH
• purinové nukleotidy chemická syntéza   chemie   farmakologie   MeSH
• puriny chemie   MeSH
• ribonukleosidy chemická syntéza   chemie   farmakologie   MeSH
• screeningové testy protinádorových léčiv MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 7-deazapurine MeSH Prohlížeč
• adenosinkinasa MeSH
• cyclo-(3-methylsaligenyl)ribofuranosyl-4-(2-furyl)-5-fluoro-7'H-pyrrolo(2,3-d)pyrimidine-5'-O-phosphate MeSH Prohlížeč
• cyclo-(3-methylsaligenyl)ribofuranosyl-4-(3-furyl)-5-fluoro-7'H-pyrrolo(2,3-d)pyrimidine-5'-O-phosphate MeSH Prohlížeč
• cyclo-(3-methylsaligenyl)ribofuranosyl-4-(3-thienyl)-5-fluoro-7'H-pyrrolo(2,3-d)pyrimidine-5'-O-phosphate MeSH Prohlížeč
• cytostatické látky MeSH
• fosfáty MeSH
• prekurzory léčiv MeSH
• purinové nukleotidy MeSH
• puriny MeSH
• ribonukleosidy 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
• buněčný cyklus účinky léků   MeSH
• cytostatické látky chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky chemická syntéza   chemie   farmakologie   MeSH
• puriny chemická syntéza   chemie   farmakologie   MeSH
• ribonukleosidy chemická syntéza   chemie   farmakologie   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
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 7-deazapurine MeSH Prohlížeč
• cytostatické látky MeSH
• protinádorové látky MeSH
• puriny 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
• antivirové látky chemická syntéza   chemie   farmakologie   MeSH
• Hepacivirus účinky léků   MeSH
• lidé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• protinádorové látky chemická syntéza   chemie   farmakologie   MeSH
• purinové nukleosidy chemická syntéza   chemie   farmakologie   MeSH
• ribonukleosidy chemická syntéza   chemie   farmakologie   MeSH
• screeningové testy protinádorových léčiv 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
• protinádorové látky MeSH
• purinové nukleosidy MeSH
• ribonukleosidy MeSH