Pfleiderer, Wolfgang

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Pteridines Part CXXI : Protection of (6R)-5,6,7,8-Tetrahydro-L-biopterin

2015, Yao, Qizheng, Pfleiderer, Wolfgang

A series of new (6R)-5,6,7,8-tetrahydo-l-biopterin derivatives have been synthesised and characterised by elemental analyses and UV and NMR spectroscopy.

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Synthesis and in vitro evaluation of 2-amino-4-N-piperazinyl-6-(3,4-dimethoxyphenyl)-pteridines as dual immunosuppressive and anti-inflammatory agents

2011-01-01, Jonghe, Steven De, Marchand, Arnaud, Gao, Ling-Jie, Calleja, Agnes, Cuveliers, Eva, Sienaert, Ilse, Herman, Jean, Clydesdale, Gavin, Sefrioui, Hassane, Lin, Yuan, Pfleiderer, Wolfgang, Waer, Mark, Herdewijn, Piet

Screening of a pteridine-based compound library led to the identification of compounds exhibiting immunosuppressive as well as anti-inflammatory activity. Optimization afforded a series of 2-amino-4-N-piperazinyl-6-(3,4-dimethoxyphenyl)pteridine analogues. The most potent congeners in this series displayed low nM IC50 values in the Mixed Lymphocyte Reaction (MLR) assay. In addition, these compounds also have potent anti-inflammatory activity as measured in the Tumor Necrosis Factor (TNF) assay.

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Nitrosation of N-Methyl Derivatives of Uric Acid and Their Transnitrosation Ability to N-Acetylcysteine

2010, Suzuki, Toshinori, Yamamoto, Hiroshi, Pfleiderer, Wolfgang

When 1,3-dimethyluric acid was treated with a nitric oxide donor, diethylamine NONOate, in an aerobic neutral solution and the reaction was analyzed by HPLC, 1,3-dimethyluric acid was consumed to yield a nitrosated derivative, which decomposed with a half-life of 17.9 min at pH 7.4 and 37 °C. When 1,3,7-trimethyluric acid was treated with diethylamine NONOate, no consumption of 1,3,7-trimethyluric acid was observed. However, in the reaction of N-acetylcysteine with diethylamine NONOate, the yield of N-acetyl-S-nitrosocysteine increased by the addition of 1,3,7-trimethyluric acid as well as 1,3-dimethyluric acid. For 1,3,7,9-tetramethyluric acid, no consumption in the reaction with diethylamine NONOate and no effect on the S-nitrosation were observed. These results suggest that 1,3-dimethyluric and 1,3,7-trimethyluric acids are both nitrosated by diethylamine NONOate on the nitrogen atom of their oxoimidazole ring, although the half-life of the nitrosated 1,3,7-trimethyluric acid is too short to detect by HPLC. Consequently, these two acids can act as vehicles of nitric oxide.

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Plasma cytokine concentration changes induced by the antitumor agents dipterinyl calcium pentahydrate (DCP) and related calcium pterins

2009, Moheno, Phillip, Pfleiderer, Wolfgang, Fuchs, Dietmar

Analysis of plasma cytokine concentration changes determined that oral dosing with the antitumor agent (1:4 mol:mol) calcium pterin (CaPterin) increased plasma IL-10, decreased plasma IL-6, and decreased plasma IFN-γ concentrations in nude mice with MDA-MB-231 xenograph tumors [Moheno, P., Pfleiderer, W., Dipasquale, A.G., Rheingold, A.L., Fuchs, D., 2008. Cytokine and IDO metabolite changes effected by calcium pterin during inhibition of MDA-MB-231 xenograph tumors in nude mice. Int. J. Pharm. 355, 238–248]. A further analysis, reported here, of plasma cytokine concentration changes in nude mice with the same tumor xenographs treated with dipterinyl calcium pentahydrate (DCP), (1:2 mol:mol) calcium pterin, and CaCl2·2H2O has been carried out. The measured cytokines included: IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12, IFN-γ, and TNF-α. The major preliminary findings from the analyses of these data are that (1) the overall relative tumor volumes for the treatments correlated significantly with a full study antitumor plasma cytokine pattern (fsAPCP), a composite measure consisting of decreased plasma IL-6 and increased IL-4 concentrations, and (2) DCP induces a significant threshold antitumor response strongly correlated to a derived DCP antitumor plasma cytokine pattern (DCP/APCP) consisting of plasma IL-12, IL-6, and IL-4 concentration changes. This DCP/APCP composite measure identifies plasma IL-12 concentration increases, plasma IL-6 concentration decreases, and plasma IL-4 concentration increases correlated to relative tumor volume decreases caused by DCP dosing. The finding that the novel calcium pterins and CaCl2·2H2O treatments decrease plasma IL-6 concentrations corroborates the previous finding that CaPterin dosing decreases plasma IL-6 concentrations in this mouse/tumor system [Moheno, P., Pfleiderer, W., Dipasquale, A.G., Rheingold, A.L., Fuchs, D., 2008. Cytokine and IDO metabolite changes effected by calcium pterin during inhibition of MDA-MB-231 xenograph tumors in nude mice. Int. J. Pharm. 355, 238–248].

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Nitroimidazoles Part 7 : Synthesis and Anti-HIV Activity of New 4-Nitroimidazole Derivatives

2012, Al-Masoudi, Najim A., Pfleiderer, Wolfgang, Pannecouque, Christophe

Reverse transcriptase enzyme (RT) is an attractive target for the development of new drugs useful in AIDS therapy and HIV non-nucleoside reverse transcriptase inhibitors (NNRTIs), and offers the possibility of generating structures of increased potency. On this basis, a series of 4-oxo-3-phenyl-2-(phenylimino)thiazolidin-5-ylidene, 3-hydroxypropyl, 3-azidopropyl, and 3-aminopropyl derivatives of 1-benzyl-2-ethyl-4-nitroimidazoles 6–8, as well as the substituted 1,2,3-triazolo analogs 12–14, the diazepam 15 and carboxamide derivatives 16 and 17 were synthesized. All compounds have been evaluated for their anti-HIV activity.

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Nucleotides : Part LXXIX ; New building blocks for photolithographic syntheses of oligoribonucleotides

2011, Hermann, Christoph, Kvassiouk, Evgeny, Pfleiderer, Wolfgang

Two series of new ribonucleoside 3′-phosphoramidites (see 36–42) carrying the photolabile [2-(2-nitrophenyl)propoxy]carbonyl group at the 5′-O-position were synthesized and characterized as monomeric building blocks for photolithographic syntheses of RNA chips. Base protection was achieved in the well-known manner by the 2-(4-nitrophenyl)ethyl (npe) and the [2-(4-nitrophenyl)ethoxy]carbonyl (npeoc) group. The carbohydrate moiety carried in addition the 2′-O-(tetrahydro-4-methoxy-2H-pyran-4-yl) group for blocking the 2′-OH function.

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Nucleotides: Part LXXVI : Synthesis and Properties of New Isoalloxazine (=Benzo[g]pteridine‐2,4(1H,3H)‐dione) Derivatives as Labels for Oligonucleotides

2010, Kvassiouk, Evgeny, Charubala, Ramamurthy, Pfleiderer, Wolfgang

A series of new fluorescing 8‐(6‐hydroxyhexyl)isoalloxazine (=8‐(6‐hydroxyhexyl)benzo[g]pteridine‐2,4(1H,3H)‐dione) derivatives 4–13 were synthesized from 6‐[(6‐hydroxyhexyl)amino]uracil (2) with 1‐chloro‐4‐nitrosobenzene via 8‐chloro‐10‐(6‐hydroxyhexyl)isoalloxazine (3) and subsequent substitution of the Cl‐atom of 3 by various amines (Scheme). Analogously, 8‐substituted 10‐{3‐[(2,2‐dimethyl‐1,3‐dioxolan‐4‐yl)methoxy]propyl}isoalloxazines 19, 20, and 23–25 were prepared which yielded on deprotection the corresponding 10‐[3‐(2,3‐dihydroxypropoxy)propyl]alloxazines 21, 22, and 26–28. Their conversion into the 3″‐O‐(4,4′‐dimethoxytrityl) derivatives 29–33 and subsequent transformation into the corresponding 2″‐(2‐cyanoethyl N,N‐diisopropylphosphoramidites) 34–38 led to new building blocks for oligonucleotide synthesis. A series of 21‐mer oligodeoxyribonucleotides carrying the fluorescing isoalloxazine 37 in various positions of the chain were assembled in a DNA synthesizer. Combination with the complementary sequence yielded the stable duplexes 40–54 showing by the melting temperatures Tm that the fluorophor (F) does not harm the stability of the unmodified duplex 39 (Table).

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Nucleotides part LXXX : Synthesis of 3′-O fluorescence labeled thymidine derivatives and their 5′-O-triphosphates

2011-07, Prykota, Tamara I., Pfleiderer, Wolfgang

A new labeling technique attaching a fluorescent pteridine derivative (3, 5) via a linker onto the 3′-OH group of 5′-O-dimethoxytritylthymidine (7) was developed to lead to the conjugates 8 and 11. After detritylation to give 9 and 12, the final conversion into the corresponding 5′-triphosphates (13, 14), which were isolated as sodium salts, was performed by known methods.

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Nucleotides: Part LXXVIII : Double Labeling of Nucleosides and Nucleotides

2010-12-15, Maier, Thomas, Pfleiderer, Wolfgang

Several N(‐hydroxyalkyl)‐2,4‐dinitroanilines were transformed into their phosphoramidites (see 5 and 6 in Scheme 1) in view of their use as fluorescence quenchers, and modified 2‐aminobenzamides (see 9, 10, 18, and 19 in Scheme 1) were applied in model reactions as fluorophors to determine the relative fluorescence quantum yields of the 3′‐Aba and 5′‐Dnp‐3′‐Aba conjugates (Aba=aminobenzamide, Dnp=dinitroaniline). Thymidine was alkylated with N‐(2‐chloroethyl)‐2,4‐dinitroaniline (24) to give 25 which was further modified to the building blocks 27 and 28 (Scheme 3). The 2‐amino group in 29 was transformed by diazotation into the 2‐fluoroinosine derivative 30 used as starting material for several reactions at the pyrimidine nucleus (→31, 33, and 35; Scheme 4). The 3′,5′‐di‐O‐acetyl‐2′‐deoxy‐N2‐[(dimethylamino)methylene]guanosine (37) was alkylated with methyl and ethyl iodide preferentially at N(1) to 43 and 44, and similarly reacted N‐(2‐chloroethyl)‐2,4‐dinitroaniline (24) to 38 and the N‐(2‐iodoethyl)‐N‐methyl analog 50 to 53 (Scheme 5). The 2′‐deoxyguanosine derivative 53 was transformed into 3′,5′‐di‐O‐acetyl‐2‐fluoro‐1‐{2‐[(2,4‐dinitrophenyl)methylamino]ethyl}inosine (54; Scheme 5) which reacted with 2,2′‐[ethane‐1,2‐diylbis(oxy)]bis[ethanamine] to modify the 2‐position with an amino spacer resulting in 56 (Scheme 6). Attachment of the fluorescein moiety 55 at 56 via a urea linkage led to the doubly labeled 2′‐deoxyguanosine derivative 57 (Scheme 6). Dimethoxytritylation to 58 and further reaction to the 3′‐succinate 59 and 3′‐phosphoramidite 60 afforded the common building blocks for the oligonucleotide synthesis (Scheme 6). Similarly, 30 reacted with N‐(2‐aminoethyl)‐2,4‐dinitroaniline (61) thus attaching the quencher at the 2‐position to yield 62 (Scheme 7). The amino spacer was again attached at the same site via a urea bridge to form 64. The labeling of 64 with the fluorescein derivative 55 was straigthforward giving 65. and dimethoxytritylation to 66 and further phosphitylation to 67 followed known procedures (Scheme 7). Several oligo‐2′‐deoxynucleotides containing the doubly labeled 2′‐deoxyguanosines at various positions of the chain were formed in a DNA synthesizer, and their fluorescence properties and the Tms in comparison to their parent duplexes were measured (Tables 1–5).

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Purines: Part XVI : Syntheses, Properties, and Reactions of 8-Aminoxanthines

2010, Mosselhi, Mosselhi A., Pfleiderer, Wolfgang

A series of N‐substituted 8‐aminoxanthines (=8‐amino‐3,7(or 3,9)‐dihydro‐1H‐purine‐2,6‐diones) 8–16 and 34–37 were synthesized from the corresponding 8‐nitroxanthines 1–7, 30–33, and 8‐(phenylazo)xanthines 17 and 18 by catalytic reduction. Another approach was derived from 6‐amino‐5‐(cyanoamino)uracils (=N‐(6‐amino‐1,2,3,4‐tetrahydro‐2,4‐dioxopyrimidin‐5‐yl)cyanamides) 23, 24, and 27 by base‐catalyzed cyclization yielding 25–28. All 8‐aminoxanthines 8–29 and 34–37 were acetylated to the corresponding 8‐(acetylamino)xanthines 40–57, and prolonged heating led to 8‐(diacetylamino)xanthines 58 and 59. Several 8‐aminoxanthines 8–13 were diazotized forming 8‐diazoxanthines 60–64. Coupling reactions of isolated 62 and 64 and intermediary formed 8‐diazoxanthines with 1,3‐dimethylbarbituric acid (=1,3‐dimethylpyrimidine‐2,4,6(1H,3H,5H)‐trione; 66) resulted in 5‐[(xanthin‐8‐yl)diazenyl]‐1,3‐dimethylbarbituric acids=3,7(or 3,9)‐dihydro‐8‐[2‐(1,2,3,4‐tetrahydro‐1,3‐dimethyl‐2,4‐dioxopyrimidin‐5‐yl)diazenyl]‐1H‐purine‐2,6‐diones) 67–80. The newly synthesized xanthine derivatives were characterized by the determination of their pKa values, the UV‐ and NMR spectra, as well as elemental analyses.