INACTIVATION OF S-ADENOSYL-L-HOMOCYSTEINE HYDROLASE AND ANTIVIRAL ACTIVITY WITH ',6',6'-TETRADEHYDRO-6'-DEOXY-6'-HALOHOMOADENOSINE ANALOGS (4'-HALOACETYLENE ANALOGS DERIVED FROM ADENOSINE)

Treatment of a protected 5,6-dideoxy-beta-D-ribo-hex-5-ynofuranosyl)ad enine derivative with silver nitrate and N-iodosuccinimide (NIS) and d eprotection gave the 6'-iodo acetylenic nucleoside analogue 3c. Haloge nation of ,2-O-isopropylidene-alpha-D-ribo-hex-5-enofuranose gave 6-ha lo acetylenic sugars that were converted to anomeric 1,2-di-O-acetyl d erivatives and coupled with 6-N-benzoyladenine. These intermediates we re deprotected to give the 6'-chloro 3a, 6'-bromo 3b, and 6'-iodo 3c a cetylenic 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 anal ogues resulted in release of Cl- or Br- and Ade, as well as partial re duction of E-NAD(+) to E-NADH. Compounds 3a, 3b, and 3c were inhibitor y to replication of vaccinia virus, vesicular stomatitis virus, parain fluenza-3 virus, and reovirus-1 (3a < 3b < 3c, in order of increasing activity). The antiviral effects appear to correlate with type I mecha nism-based inhibition of S-adenosyl-L-homocysteine hydrolase. Mechanis tic considerations are discussed.