Aktuální platná úhradová kritéria umožňují lékařům zahájit vysoce efektivní imunomodulační terapii, tzv. HET (high‐efficacy treatment), již od první ataky za předpokladu splnění nepříznivých prognostických známek, kterými jsou přítomnost T1 gadolinium enhancující nebo infratentoriální léze a/nebo spinální léze. Tato možnost poskytuje pacientům obrovskou výhodu, která vede prokazatelně k oddálení nebo minimalizaci rizika progrese nezávislé na relapsech, stejně tak významně redukuje i riziko relapsu a v neposlední řadě taktéž i riziko radiologické progrese. Efektivita vysoce účinné terapie je v rámci článku prezentována v kazuistice pacientky, u níž se pomocí HET podařilo dosáhnout klinické i radiologické stability, a tedy i statusu NEDA‐3.

Current reimbursement rules make it possible for physicians to start the highly effective immunomodulatory therapy (so called HET) of multiple sclerosis since the first attack of the disease when unfavorable prognostic traits are present, i.e. gadolinium‐enhancing T1 or infratentorial and/or spinal lesions. This fact represents an enormous advantage for the patients, clearly postponing or minimizing progression independent of relapses and also reducing significantly the risk of relapse or, last but not least, of radiological progression. In this article, the effectiveness of highly effective therapy is demonstrated by a case study of a female patient in whom both clinical and radiological stability, i.e. NEDA‐3 status, were achieved using HET.

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

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

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

• MeSH
• veterinární lékařství dějiny   MeSH
• Publikační typ
• periodika MeSH

• Konspekt
• Veterinární lékařství
• NLK Obory
• veterinární lékařství

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
• léky antitumorózní - screeningové testy 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
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• Publikační typ
• abstrakty 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

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 metabolismus   MeSH
• HeLa buňky MeSH
• Hepacivirus účinky léků   genetika   MeSH
• HL-60 buňky MeSH
• inhibitory syntézy nukleových kyselin 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

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.

• MeSH
• cytostatické látky MeSH
• klinická chemie MeSH
• nukleosidy MeSH
• puriny MeSH
• pyrimidiny MeSH
• vztahy mezi strukturou a aktivitou MeSH