NUCLEIC-ACID RELATED-COMPOUNDS .84. SYNTHESIS OF 6'-(E AND Z)-HALOHOMOVINYL DERIVATIVES OF ADENOSINE, INACTIVATION OF S-ADENOSYL-L-HOMOCYSTEINE HYDROLASE, AND CORRELATION OF ANTICANCER AND ANTIVIRAL POTENCIES WITH ENZYME-INHIBITION

Treatment of 9-[6-(E)-(tributylstannyl)-5,6-dideoxy-2 furanosyl]adenin e [2b(E)] or the 6-N-benzoyl derivative 2a(E) with iodine (or N-iodosu ccinimide) or bromine (or N-bromosuccinimide) gave virtually quantitat ive and stereospecific conversions to the 6'-(E)-(halohomovinyl)nucleo side analogues. Analogous treatment of the 6'-(Z)-vinyl-stannanes gave the 6'-(Z)-halo compounds. Treatment of 2a or 2b with chlorine or xen on difluoride/silver triflate gave E and Z mixtures of the respective 6'-chloro- or 6'-fluorohomovinyl products. Deprotection gave the 9-[6- (E and ,6-dideoxy-beta-D-ribo-hex-5-enofuranosyl]adenines [(E and Z)-5 ',6'-didehydro-6'-deoxy-6'-halohomoadenosines, EDDHHAs and ZDDHHAs, 4c - 7c(E and Z)]. The acetylenic 5',5',6',6'-tetradehydro-6'-deoxyhomoa denosine (3c) and the 5'-bromo-5'-deoxy-5'-methylene adenosine (10c) r egioisomer of EDDBHA [5c(E)] also were obtained from 2. Concentration- and time-dependent inactivations of S-adenosyl-L-homocysteine (AdoHcy ) hydrolase were observed with 3c and the 6'-(halohomovinyl)adenosine analogues. The order of inhibitory potency was I > Br > Cl > F and E > Z for the geometric isomers. AdoHcy hydrolase effected ''hydrolysis'' of the 6'-halogen from the (halohomovinyl)Ado compounds (to give the putative 6'-carboxaldehyde which underwent spontaneous decomposition) independently of its oxidative activity. Partition ratios for these hy drolytic turnovers/lethal inhibitory events were in the order F > Cl > Br > I. Biological activities were evaluated with several viruses and cancer cell lines, and potencies were generally in the order I > Br > Cl > F and E > Z isomers. This represents the first observation of a direct correlation of cytostatic activity with inhibition of AdoHcy hy drolase and highlights the potential of this enzyme as a viable target for chemotherapeutic intervention in anticancer as well as antiviral drug design.