7 research outputs found
Preparation of Nucleosides Derived from 2-Nitroimidazole and d-Arabinose, d-Ribose, and d-Galactose by the Vorbrüggen Method and Their Conversion to Potential Precursors for Tracers To Image Hypoxia
Get PDFPreparation of Nucleosides Derived from 2-Nitroimidazole and d-Arabinose, d-Ribose, and d-Galactose by the Vorbrüggen Method and Their Conversion to Potential Precursors for Tracers To Image Hypoxia
No full text2-Nitroimidazole was silylated using hexaethyldisilazane and then reacted with 1-<i>O</i>-acetyl derivatives of d-arabinose, d-ribose, and d-galactose in acetonitrile at mild temperatures (−20 °C to rt), catalyzed by triethylsilyl triflate (Vorbrüggen conditions). The α-anomer was formed in the former case and the β-anomers in the latter two cases (highly) selectively. When d-arabinose and d-ribose were silylated with <i>tert</i>-butyldiphenylsilyl chloride in pyridine at the hydroxyl groups at C-5 and acetylated at the other ones in a one-pot reaction, mixtures of anomeric 1-<i>O</i>-acetyl derivatives were obtained. These were coupled by the Vorbrüggen method and then deblocked at C-5 and tosylated to give precursors for tracers to image hypoxia in four steps without using Hg(CN)<sub>2</sub> necessary for other methods. The Vorbrüggen conditions enable a shorter route to azomycin nucleoside analogues than the previous coupling procedures
Stereochemical Course of Methyl Transfer by Cobalamin-Dependent Radical SAM Methyltransferase in Fosfomycin Biosynthesis
No full textThe
methyl groups of [<i>methyl</i>-(<i>S</i>)]- and
[<i>methyl</i>-(<i>R</i>)]-[<i>methyl</i>-D,T]-l-methionine fed to <i>Streptomyces fradiae</i> were incorporated into fosfomycin, which was chemically degraded
to chiral AcONa. The enzymatic test gave the (<i>S</i>)-configuration
for the chiral AcONa derived from methionine with the (<i>S</i>)-[D,T]Âmethyl group (<i>F</i> = 31.7) and (<i>R</i>) for the one derived from methionine with the (<i>R</i>)-[D,T]Âmethyl group (<i>F</i> = 83.0). The radical SAM
methyltransferase transfers the methyl group of MeCbl to HEP-CMP with
inversion of configuration
2-Nitroimidazole-Furanoside Derivatives for Hypoxia Imaging—Investigation of Nucleoside Transporter Interaction, 18F-Labeling and Preclinical PET Imaging
No full text2-Nitroimidazole-Furanoside Derivatives for Hypoxia Imaging—Investigation of Nucleoside Transporter Interaction, <sup>18</sup>F-Labeling and Preclinical PET Imaging
No full textThe benefits of PET imaging of tumor hypoxia in patient management has been demonstrated in many examples and with various tracers over the last years. Although, the optimal hypoxia imaging agent has yet to be found, 2-nitroimidazole (azomycin) sugar derivatives—mimicking nucleosides—have proven their potential with [18F]FAZA ([18F]fluoro-azomycin-α-arabinoside) as a prominent representative in clinical use. Still, for all of these tracers, cellular uptake by passive diffusion is postulated with the disadvantage of slow kinetics and low tumor-to-background ratios. We recently evaluated [18F]fluoro-azomycin-β-deoxyriboside (β-[18F]FAZDR), with a structure more similar to nucleosides than [18F]FAZA and possible interaction with nucleoside transporters. For a deeper insight, we comparatively studied the interaction of FAZA, β-FAZA, α-FAZDR and β-FAZDR with nucleoside transporters (SLC29A1/2 and SLC28A1/2/3) in vitro, showing variable interactions of the compounds. The highest interactions being for β-FAZDR (IC50 124 ± 33 µM for SLC28A3), but also for FAZA with the non-nucleosidic α-configuration, the interactions were remarkable (290 ± 44 µM {SLC28A1}; 640 ± 10 µM {SLC28A2}). An improved synthesis was developed for β-FAZA. For a PET study in tumor-bearing mice, α-[18F]FAZDR was synthesized (radiochemical yield: 15.9 ± 9.0% (n = 3), max. 10.3 GBq, molar activity > 50 GBq/µmol) and compared to β-[18F]FAZDR and [18F]FMISO, the hypoxia imaging gold standard. We observed highest tumor-to-muscle ratios (TMR) for β-[18F]FAZDR already at 1 h p.i. (2.52 ± 0.94, n = 4) in comparison to [18F]FMISO (1.37 ± 0.11, n = 5) and α-[18F]FAZDR (1.93 ± 0.39, n = 4), with possible mediation by the involvement of nucleoside transporters. After 3 h p.i., TMR were not significantly different for all 3 tracers (2.5⁻3.0). Highest clearance from tumor tissue was observed for β-[18F]FAZDR (56.6 ± 6.8%, 2 h p.i.), followed by α-[18F]FAZDR (34.2 ± 7.5%) and [18F]FMISO (11.8 ± 6.5%). In conclusion, both isomers of [18F]FAZDR showed their potential as PET hypoxia tracers. Differences in uptake behavior may be attributed to a potential variable involvement of transport mechanisms
