Synthesis of 5′-functionalized nucleosides: S-Adenosylhomocysteine analogues with the carbon-5′ and sulfur atoms replaced by a vinyl or halovinyl unit

Adenosine and uridine analogues functionalized with alkenyl or fluoroalkenyl chain at C5′ were prepared employing cross-metathesis, Negishi couplings, and Wittig reactions. Metathesis of the protected 5′-deoxy-5′-methyleneadenosine or uridine analogues with six-carbon amino acids (homoallylglycines)...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2008-05, Vol.16 (10), p.5424-5433
Main Authors: Wnuk, Stanislaw F., Sacasa, Pablo R., Lewandowska, Elzbieta, Andrei, Daniela, Cai, Sumin, Borchardt, Ronald T.
Format: Article
Language:English
Subjects:
Adenosylhomocysteinase - antagonists & inhibitors
Adenosylhomocysteinase - chemistry
Alkylation
Analytical, structural and metabolic biochemistry
Biological and medical sciences
Carbon - chemistry
Catalysis
Cross-coupling
Cross-metathesis
Enzymes and enzyme inhibitors
Fundamental and applied biological sciences. Psychology
Humans
Hydrolases
Medical sciences
Miscellaneous
Molecular Structure
Nucleosides
Nucleosides - chemical synthesis
Nucleosides - chemistry
Nucleosides - pharmacology
Palladium - chemistry
Pharmacology. Drug treatments
S-Adenosylhomocysteine - chemical synthesis
S-Adenosylhomocysteine - chemistry
S-Adenosylhomocysteine hydrolase
Stereoisomerism
Sulfur - chemistry
Vinyl Compounds - chemistry
Wittig reaction
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Summary:Adenosine and uridine analogues functionalized with alkenyl or fluoroalkenyl chain at C5′ were prepared employing cross-metathesis, Negishi couplings, and Wittig reactions. Metathesis of the protected 5′-deoxy-5′-methyleneadenosine or uridine analogues with six-carbon amino acids (homoallylglycines) in the presence of Grubbs catalysts gave nucleoside analogues with the C5′–C6′ double bond. Alternatively, the Pd-catalyzed cross-coupling between the protected 5′-deoxy-5′-(iodomethylene) nucleosides and suitable alkylzinc bromides also provided analogues with alkenyl unit. Stereoselective Pd-catalyzed monoalkylation of 5′-(bromofluoromethylene)-5′-deoxyadenosine with alkylzinc bromides afforded adenosylhomocysteine analogues with a 6′-(fluoro)vinyl motif. The vinylic adenine nucleosides produced time-dependent inactivation of the S-adenosyl- l-homocysteine hydrolases.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2008.04.017