Synthesis of homologated halovinyl derivatives from aristeromycin and their inhibition of human placental S-adenosyl-L-homocysteine hydrolase.
Moffatt oxidation of 2',3'-O-isopropylidenearisteromycin (1a) and treatment of the 5'-carboxaldehyde with [(p-tolylsulfonyl)methylene]triphenylphosphorane gave the homologated vinylsulfone 2. Treatment of 2 with tributylstannane/AIBN gave the (E/Z)-vinylstannanes which were converted into the E and Z fluoro- and iodovinyl analogs. Chain extension via the 5'-cyano-5'-deoxy derivative 10a gave the 6'-carboxaldehyde of homoaristeromycin. S-Adenosyl-L-homocysteine hydrolase was strongly inhibited by the fluorovinyl, 5b, and iodovinyl, 4b and 7b, compounds, and time-dependent kinetics were observed [1-2 microM (Ki) and 0.1-0.2 min-1 (kinact)]. The mechanism of inactivation was shown to involve addition of water at the vinyl 5' or 6' carbons with elimination of halide.
Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah 84602-5700, USA.
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Yuan
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Borchardt
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Robins
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D043383:Adenosylhomocysteinase; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D006801:Humans; D006867:Hydrolases / Q000037:antagonists & inhibitors*; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D015394:Molecular Structure; D009705:Nucleosides / Q000138:chemical synthesis*; D010920:Placenta / Q000201:enzymology
D004791:Enzyme Inhibitors; D009705:Nucleosides; C030034:aristeromycin; D006867:Hydrolases; D043383:Adenosylhomocysteinase; D000241:Adenosine