NUCLEIC-ACID RELATED-COMPOUNDS - 101 - S-ADENOSYL-L-HOMOCYSTEINE HYDROLASE DOES NOT HYDRATE (5'-FLUORO)VINYL OR (6'-HALO)HOMOVINYL ANALOGS DERIVED FROM 3'-DEOXYADENOSINE OR 3'-(CHLORO OR FLUORO)-3'-DEOXYADENOSINE

S-Adenosyl-L-homocysteine (AdoHcy) hydrolase is crucial for the mainte nance of biomethylation. The usual mechanistic sequence involves oxida tion of AdoHcy at C3' followed by elimination of L-homocysteine, Micha el addition of water, and reduction to give adenosine. A 6'-fluorohomo vinyladenosine analogue (EDDFHA) undergoes hydration of the 5',6' doub le bond (hydrolytic activity) at a more rapid rate than oxidation at C 3'. Three 4',5'-didehydro-5'-deoxy-5'-fluoro nucleoside analogues were prepared from 3'-deoxy- and 3'-(chloro and fluoro)-3'-deoxyadenosine via generation of the vinyl fluorides by thermolysis of 5'-fluoro-5'-t hioether sulfoxides. The 3'-deoxy analogues of 6'-halohomovinyladenosi nes were prepared by Wittig extension with a 3'-deoxy-5'-carboxaldehyd e and halodestannylation of vinyl stannanes. The 3'-hydroxyl group app ears to be essential for binding to AdoHcy hydrolase. No hydrolytic ac tivity at C5' or C6' was observed with the nonoxidizable 3'-deoxy or 3 '-(chloro or fluoro) analogues in contrast with their 3'-hydroxy count erparts (ZDDFA and EDDFHA). These 3'-modified analogues cannot reduce enzyme-bound NAD(+) to NADH and do not produce time-dependent inhibiti on of AdoHcy hydrolase, but are weak competitive inhibitors (K-i = 150 -200 mu M).