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2 Fluoroadenosine

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Hiroshi Ohrui – One of the best experts on this subject based on the ideXlab platform.

Krzysztof W Pankiewicz – One of the best experts on this subject based on the ideXlab platform.

  • NAD-analogues as potential anticancer agents: conformational restrictions as basis for selectivity.
    Acta biochimica Polonica, 1996
    Co-Authors: Krzysztof W Pankiewicz, Andrzej Zatorski, Kyoichi A. Watanabe
    Abstract:

    Cofactor type inhibitors (NAD-analogues) of IMP-dehydrogenase (IMPDH) were synthesized and their application as potential anticancer agents are discussed. C-nucleoside isosteres of NAD, C-NAD and C-PAD, showed an effective competitive inhibition of IMPDH, C-NAD but not C-PAD caused extremely potent inhibition of alcohol dehydrogenase. We also synthesized compounds in which nicotinamide riboriboside was replaced with tiazofurin (TAD-analogues) and the 2‘ and 3’-positions of adenosine part were fluorinated. The ribose ring of 2‘-deoxy-2‘-Fluoroadenosine is in the C3′-endo conformation whereas 3′-deoxy-3′-Fluoroadenosine favors the C2‘-endo sugar pucker. These derivatives are good inhibitors of IMPDH type II, the isoenzyme dominant in neoplastic cells. In contrast, all these analogues showed rather week inhibitory activity against alcohol dehydrogenase. Nicotinamide riboriboside derivatives in which the base and the sugar are linked through an oxygen or a methylene bridge were synthesized. NAD-analogues containing such conformationally restricted nicotinamide nucleoside moiety (syn or anti) are expected to be selective inhibitors of B-specific (IMPDH) or A-specific dehydrogenases, respectively.

  • Potent inhibitors of human inosine monophosphate dehydrogenase type II. Fluorine-substituted analogues of thiazole-4-carboxamide adenine dinucleotide.
    Journal of Medicinal Chemistry, 1995
    Co-Authors: Andrzej Zatorski, Barry M. Goldstein, T.d. Colby, Jeffery P. Jones, Krzysztof W Pankiewicz
    Abstract:

    : Three analogues of thiazole-4-carboxamide adenine dinucleotide (TAD) (1-3) containing a fluorine atom at the C2‘ of the adenine nucleoside (in the ribo and arabino configuration) and at the C3′ (in the ribo configuration) were synthesized in high yield from the corresponding 5′-monophosphates of 2‘-deoxy-2‘-Fluoroadenosine (9), 9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-adenine (17), and 3′-deoxy-3′-Fluoroadenosine (14), respectively. Pure 2‘,3′-O-isopropylidene-tiazofurin 5’-phosphorimidazolide (8) was obtained by phosphorylation of the protected tiazofurin followed by treatment with carbonyldiimidazole and HPLC purification. Reaction of 8 with 9 in DMF-d7 (monitored by 1H and 31P NMR) afforded the desired dinucleotide 12, which after deisopropylidenation gave 1 in 82% yield. Small amounts of symmetrical dinucleotides AppA (10, 7.2%) and TRppTR (11, 8.0%) were also isolated during HPLC purification of the major product 12. In a similar manner, compounds 2 and 3 were obtained by coupling of 8 with 14 and 17 in 80% and 76% yield, respectively. All newly prepared fluoro-substituted compounds as well as beta-CF2-TAD, earlier synthesized by us, showed good inhibitory activity against inosine monophosphate dehydrogenase type II, the isozyme which is predominant in neoplastic cells. Binding of 1 (Kis = 0.5 microM), 2 (Kis = 0.7 microM), and 3 (Kis = 2.9 microM) was comparable to that of TAD (Ki = 0.2 microM). The difluoromethylene bisphosphonate analogue, beta-CF2-TAD (Ki = 0.17 microM), was found to be equally effective as the best cofactor-type inhibitor, beta-CH2-TAD (Ki = 0.11 microM). Interestingly, the level of inhibition of horse liver alcohol dehydrogenase by these compounds was found to be much lower (0.1 mM for 1 and 2 and no inhibition up to 10 mM for 3). These findings show that inhibition of tumor-induced inosine monophosphate dehydrogenase type II is selective and may be of therapeutic interest.

  • Synthesis of thiazole-4-carboxamide-adenine difluoromethylenediphosphonates substituted with fluorine at C-2‘ of the adenosine.
    Carbohydrate research, 1993
    Co-Authors: Andrzej Zatorski, Barry M. Goldstein, Pawell Lipla, Nevena Mollova, Karl H. Schram, Kyoichi A. Watanabe, Krzysztof W Pankiewicz
    Abstract:

    Abstract Synthesis of an analogue 3 of thiazole-4-carboxamide adeninedinucleotide (TAD) in which the α-oxygen atom of the pyrophosphate bridge is replaced by a difluoromethylene group has been achieved. Likewise, 2′-deoxy-2′-Fluoroadenosine containing analogues of TAD (4) and its difluoromethylenediphosphonate congener (5 have been synthesized. Adenosine 5′-difluoromethylenediphosphonate (8) was prepared from 5′-O-tosyladenosine (6) and tris-tetra-n-butylammonium)difluoromethylene-diphosphonate (7) by a modified procedure of Poulter’s.2 Compound 8 was converted into the 2′-3′-cyclic carbonate 9 by treatment with triethyl orthoformate. Treatment of 9 with 2′-3′-O-isopro-pylidenetiazofurin (10) in pyridine in the presence of DCC gave a mixture of dinucleotide 11 and the isopropylidene-protected diadenosine tetraphosphonate 12. After deprotection of 11, the desired β-difluoromethylene TAD (3_ was separated by HPLC as the minor product. The diadenosine tetraphosphonate 12, an analogue of Ap4A, was obtained as the major component. Alternatively, 2′-3′-O-isopropylidenetiazofurin (10) was tosylated, and the product 13 was further converted into the corresponding difluoromethylenediphosphonate 14 by coupling with 7. DCC-catalyzed coupling of 14 with 2′-deoxy-2′-Fluoroadenosine (15) followed by deisopropylidenation afforded the anlogue 5. Again the corresponding tetraphosphonate analogue of tiazofurin 17 was the predominant product. Dinucleotide 4 was obtained by coupling of the carbonyldiimidazole-activated tiazofurin 5′-monophosphate with 2′-deoxy-2′-Fluoroadenosine 5′-monophosphate. 2′-Deoxy-2′-Fluoroadenosine (′15) was prepared efficiently from the known N6-benzoyl-3′-O-tetrahydropyranyladenosine (18), which was converted into 3′-O-tetrahydropyranyl-2′-O-triflyl-5′-O-trityladenosine (20) by tritylation and triflation. Treatment of 20 with sodium acetacetate in hexamethylphosphoric triamide, followed by deaceltylation afforded 9-(3-O-tetrahydropyranyl-5-O-trityl-β- d -arabinofuranosyl)-N6-benzoyladenine (22), which was then treated with DAST. After deprotection of the product, 15 was obtained in good yield.

Andrzej Zatorski – One of the best experts on this subject based on the ideXlab platform.

  • NAD-analogues as potential anticancer agents: conformational restrictions as basis for selectivity.
    Acta biochimica Polonica, 1996
    Co-Authors: Krzysztof W Pankiewicz, Andrzej Zatorski, Kyoichi A. Watanabe
    Abstract:

    Cofactor type inhibitors (NAD-analogues) of IMP-dehydrogenase (IMPDH) were synthesized and their application as potential anticancer agents are discussed. C-nucleoside isosteres of NAD, C-NAD and C-PAD, showed an effective competitive inhibition of IMPDH, C-NAD but not C-PAD caused extremely potent inhibition of alcohol dehydrogenase. We also synthesized compounds in which nicotinamide riboside was replaced with tiazofurin (TAD-analogues) and the 2‘ and 3’-positions of adenosine part were fluorinated. The ribose ring of 2‘-deoxy-2‘-Fluoroadenosine is in the C3′-endo conformation whereas 3′-deoxy-3′-Fluoroadenosine favors the C2‘-endo sugar pucker. These derivatives are good inhibitors of IMPDH type II, the isoenzyme dominant in neoplastic cells. In contrast, all these analogues showed rather week inhibitory activity against alcohol dehydrogenase. Nicotinamide riboside derivatives in which the base and the sugar are linked through an oxygen or a methylene bridge were synthesized. NAD-analogues containing such conformationally restricted nicotinamide nucleoside moiety (syn or anti) are expected to be selective inhibitors of B-specific (IMPDH) or A-specific dehydrogenases, respectively.

  • Potent inhibitors of human inosine monophosphate dehydrogenase type II. Fluorine-substituted analogues of thiazole-4-carboxamide adenine dinucleotide.
    Journal of Medicinal Chemistry, 1995
    Co-Authors: Andrzej Zatorski, Barry M. Goldstein, T.d. Colby, Jeffery P. Jones, Krzysztof W Pankiewicz
    Abstract:

    : Three analogues of thiazole-4-carboxamide adenine dinucleotide (TAD) (1-3) containing a fluorine atom at the C2‘ of the adenine nucleoside (in the ribo and arabino configuration) and at the C3′ (in the ribo configuration) were synthesized in high yield from the corresponding 5’-monophosphates of 2‘-deoxy-2‘-Fluoroadenosine (9), 9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-adenine (17), and 3′-deoxy-3′-Fluoroadenosine (14), respectively. Pure 2‘,3′-O-isopropylidene-tiazofurin 5’-phosphorimidazolide (8) was obtained by phosphorylation of the protected tiazofurin followed by treatment with carbonyldiimidazole and HPLC purification. Reaction of 8 with 9 in DMF-d7 (monitored by 1H and 31P NMR) afforded the desired dinucleotide 12, which after deisopropylidenation gave 1 in 82% yield. Small amounts of symmetrical dinucleotides AppA (10, 7.2%) and TRppTR (11, 8.0%) were also isolated during HPLC purification of the major product 12. In a similar manner, compounds 2 and 3 were obtained by coupling of 8 with 14 and 17 in 80% and 76% yield, respectively. All newly prepared fluoro-substituted compounds as well as beta-CF2-TAD, earlier synthesized by us, showed good inhibitory activity against inosine monophosphate dehydrogenase type II, the isozyme which is predominant in neoplastic cells. Binding of 1 (Kis = 0.5 microM), 2 (Kis = 0.7 microM), and 3 (Kis = 2.9 microM) was comparable to that of TAD (Ki = 0.2 microM). The difluoromethylene bisphosphonate analogue, beta-CF2-TAD (Ki = 0.17 microM), was found to be equally effective as the best cofactor-type inhibitor, beta-CH2-TAD (Ki = 0.11 microM). Interestingly, the level of inhibition of horse liver alcohol dehydrogenase by these compounds was found to be much lower (0.1 mM for 1 and 2 and no inhibition up to 10 mM for 3). These findings show that inhibition of tumor-induced inosine monophosphate dehydrogenase type II is selective and may be of therapeutic interest.

  • Synthesis of thiazole-4-carboxamide-adenine difluoromethylenediphosphonates substituted with fluorine at C-2‘ of the adenosine.
    Carbohydrate research, 1993
    Co-Authors: Andrzej Zatorski, Barry M. Goldstein, Pawell Lipla, Nevena Mollova, Karl H. Schram, Kyoichi A. Watanabe, Krzysztof W Pankiewicz
    Abstract:

    Abstract Synthesis of an analogue 3 of thiazole-4-carboxamide adenine-dinucleotide (TAD) in which the α-oxygen atom of the pyrophosphate bridge is replaced by a difluoromethylene group has been achieved. Likewise, 2′-deoxy-2′-Fluoroadenosine containing analogues of TAD (4) and its difluoromethylenediphosphonate congener (5 have been synthesized. Adenosine 5′-difluoromethylenediphosphonate (8) was prepared from 5′-O-tosyladenosine (6) and tris-tetra-n-butylammonium)difluoromethylene-diphosphonate (7) by a modified procedure of Poulter’s.2 Compound 8 was converted into the 2′-3′-cyclic carbonate 9 by treatment with triethyl orthoformate. Treatment of 9 with 2′-3′-O-isopro-pylidenetiazofurin (10) in pyridine in the presence of DCC gave a mixture of dinucleotide 11 and the isopropylidene-protected diadenosine tetraphosphonate 12. After deprotection of 11, the desired β-difluoromethylene TAD (3_ was separated by HPLC as the minor product. The diadenosine tetraphosphonate 12, an analogue of Ap4A, was obtained as the major component. Alternatively, 2′-3′-O-isopropylidenetiazofurin (10) was tosylated, and the product 13 was further converted into the corresponding difluoromethylenediphosphonate 14 by coupling with 7. DCC-catalyzed coupling of 14 with 2′-deoxy-2′-Fluoroadenosine (15) followed by deisopropylidenation afforded the anlogue 5. Again the corresponding tetraphosphonate analogue of tiazofurin 17 was the predominant product. Dinucleotide 4 was obtained by coupling of the carbonyldiimidazole-activated tiazofurin 5′-monophosphate with 2′-deoxy-2′-Fluoroadenosine 5′-monophosphate. 2′-Deoxy-2′-Fluoroadenosine (′15) was prepared efficiently from the known N6-benzoyl-3′-O-tetrahydropyranyladenosine (18), which was converted into 3′-O-tetrahydropyranyl-2′-O-triflyl-5′-O-trityladenosine (20) by tritylation and triflation. Treatment of 20 with sodium acetate in hexamethylphosphoric triamide, followed by deaceltylation afforded 9-(3-O-tetrahydropyranyl-5-O-trityl-β- d -arabinofuranosyl)-N6-benzoyladenine (22), which was then treated with DAST. After deprotection of the product, 15 was obtained in good yield.

Jesús Fernández-lucas – One of the best experts on this subject based on the ideXlab platform.

H. Schwalbe – One of the best experts on this subject based on the ideXlab platform.

  • ^19F-labeling of the adenine H2-site to study large RNAs by NMR spectroscopy
    Journal of Biomolecular NMR, 2016
    Co-Authors: F. Sochor, R. Silvers, D. Müller, C. Richter, B. Fürtig, H. Schwalbe
    Abstract:

    In comparison to proteins and protein complexes, the size of RNA amenable to NMR studies is limited despite the development of new isotopic labeling strategies including deuteration and ligation of differentially labeled RNAs. Due to the restricted chemical shift dispersion in only four different nucleotides spectral resolution remains limited in larger RNAs. Labeling RNAs with the NMR-active nucleus ^19F has previously been introduced for small RNAs up to 40 nucleotides (nt). In the presented work, we study the natural occurring RNA aptamer domain of the guanine-sensing riboswitch comprising 73 nucleotides from Bacillus subtilis . The work includes protocols for improved in vitro transcription of 2Fluoroadenosine-5′-triphosphat (2F-ATP) using the mutant P266L of the T7 RNA polymerase. Our NMR analysis shows that the secondary and tertiary structure of the riboswitch is fully maintained and that the specific binding of the cognate ligand hypoxanthine is not impaired by the introduction of the ^19F isotope. The thermal stability of the ^19F-labeled riboswitch is not altered compared to the unmodified sequence, but local base pair stabilities, as measured by hydrogen exchange experiments, are modulated. The characteristic change in the chemical shift of the imino resonances detected in a ^1H,^15N-HSQC allow the identification of Watson–Crick base paired uridine signals and the ^19F resonances can be used as reporters for tertiary and secondary structure transitions, confirming the potential of ^19F-labeling even for sizeable RNAs in the range of 70 nucleotides.

  • (19)F-labeling of the adenine H2-site to study large RNAs by NMR spectroscopy.
    Journal of biomolecular NMR, 2015
    Co-Authors: F. Sochor, R. Silvers, D. Müller, C. Richter, B. Fürtig, H. Schwalbe
    Abstract:

    In comparison to proteins and protein complexes, the size of RNA amenable to NMR studies is limited despite the development of new isotopic labeling strategies including deuteration and ligation of differentially labeled RNAs. Due to the restricted chemical shift dispersion in only four different nucleotides spectral resolution remains limited in larger RNAs. Labeling RNAs with the NMR-active nucleus 19F has previously been introduced for small RNAs up to 40 nucleotides (nt). In the presented work, we study the natural occurring RNA aptamer domain of the guanine-sensing riboswitch comprising 73 nucleotides from Bacillus subtilis. The work includes protocols for improved in vitro transcription of 2Fluoroadenosine-5′-triphosphat (2F-ATP) using the mutant P266L of the T7 RNA polymerase. Our NMR analysis shows that the secondary and tertiary structure of the riboswitch is fully maintained and that the specific binding of the cognate ligand hypoxanthine is not impaired by the introduction of the 19F isotope. The thermal stability of the 19F-labeled riboswitch is not altered compared to the unmodified sequence, but local base pair stabilities, as measured by hydrogen exchange experiments, are modulated. The characteristic change in the chemical shift of the imino resonances detected in a 1H,15N-HSQC allow the identification of Watson–Crick base paired uridine signals and the 19F resonances can be used as reporters for tertiary and secondary structure transitions, confirming the potential of 19F-labeling even for sizeable RNAs in the range of 70 nucleotides.