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.
Wnuk
S F
SF
Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah 84602-5700, USA.
Yuan
C S
CS
Borchardt
R T
RT
Robins
M J
MJ
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