Inactivation of S-adenosyl-L-homocysteine hydrolase and antiviral activity with 5',5',6',6'-tetradehydro-6'-deoxy-6'-halohomoadenosine analogues (4'-haloacetylene analogues derived from adenosine).
Treatment of a protected 9-(5, 6-dideoxy-beta-D-ribo-hex-5-ynofuranosyl)adenine derivative with silver nitrate and N-iodosuccinimide (NIS) and deprotection gave the 6'-iodo acetylenic nucleoside analogue 3c. Halogenation of 3-O-benzoyl-5,6-dideoxy-1, 2-O-isopropylidene-alpha-D-ribo-hex-5-enofuranose gave 6-halo acetylenic sugars that were converted to anomeric 1,2-di-O-acetyl derivatives and coupled with 6-N-benzoyladenine. These intermediates were deprotected to give the 6'-chloro 3a, 6'-bromo 3b, and 6'-iodo 3c acetylenic nucleoside analogues. Iodo compound 3c appears to inactivate S-adenosyl-L-homocysteine hydrolase by a type I ("cofactor depletion") mechanism since complete reduction of enzyme-bound NAD+ to NADH was observed and no release of adenine or iodide ion was detected. In contrast, incubation of the enzyme with the chloro 3a or bromo 3b analogues resulted in release of Cl- or Br- and Ade, as well as partial reduction of E-NAD+ to E-NADH. Compounds 3a, 3b, and 3c were inhibitory to replication of vaccinia virus, vesicular stomatitis virus, parainfluenza-3 virus, and reovirus-1 (3a < 3b < 3c, in order of increasing activity). The antiviral effects appear to correlate with type I mechanism-based inhibition of S-adenosyl-L-homocysteine hydrolase. Mechanistic considerations are discussed.
Robins
M J
MJ
Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah 84602-5700, USA.
Wnuk
S F
SF
Yang
X
X
Yuan
C S
CS
Borchardt
R T
RT
Balzarini
J
J
De Clercq
E
E
D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D043383:Adenosylhomocysteinase; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002522:Chlorocebus aethiops; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D006867:Hydrolases / Q000037:antagonists & inhibitors*; D007700:Kinetics; D008826:Microbial Sensitivity Tests; D010920:Placenta / Q000201:enzymology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D014709:Vero Cells; D014779:Virus Replication / Q000187:drug effects
C114812:9-(5,6-dideoxy-6-iodo-ribo-hex-5-ynofuranosyl)adenine; C114811:9-(6-bromo-5,6-dideoxy-ribo-hex-5-ynofuranosyl)adenine; C114810:9-(6-chloro-5,6-dideoxy-ribo-hex-5-ynofuranosyl)adenine; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D006867:Hydrolases; D043383:Adenosylhomocysteinase; D000241:Adenosine