title: Synthesis and biological studies of unsaturated acyclonucleoside analogues of S-adenosyl-L-homocysteine hydrolase inhibitors.
abstract: The design, synthesis, and biological evaluation of several unsaturated acyclonucleosides related to augustmycin A are described. The (propargyloxy)methyl acyclonucleoside analogues of 6-chloropurine, adenine, 6-methoxypurine, hypoxanthine, 6-mercaptopurine, and azathioprine have been prepared. The 9-[(propargyloxy)methyl]adenine (5) and 9-[(propargyloxy)methyl]hypoxanthine (12) analogues were converted to the corresponding 5'-tributylstannyl intermediates (9 and 13), respectively, which gave 9-[[[(Z)-5-iodo-5-propenyl]oxy]methyl]adenine (10) and 9-[[[(Z)-5-iodo-5-propenyl]oxy]methyl]hypoxanthine (14), respectively, after iododestannylation. The [125I]-radiolabeled congeners of 10 and 14 were prepared as potential metabolic markers. Among the unsaturated acyclonucleosides tested, 9-[(propargyloxy)methyl]-6-chloropurine (3), 9-[(propargyloxy)methyl]-6-mercaptopurine (15), 9-[(propargyloxy)methyl]azathioprine (17), and angustmycin A analogue 10 showed inhibition of cancer cell growth, but only at a minimal level, and 17 also showed 14% cancer cell death in vitro. Compound 10 provided approximately 50% protection against HIV at 10(-4) M concentrations. Biodistribution results of [125I]-10 in mice indicate that compound 10 is readily metabolized via deiodination in vivo, possibly by serving as a substrate for the enzyme S-adenosyl-L-homocysteine hydrolase.
authors.affiliation: Health and Safety Research Division, Oak Ridge National Laboratory, Tennessee 37831-6022.
authors.forename: A
authors.initials: A
authors.lastname: Hasan
authors.forename: P C
authors.initials: PC
authors.lastname: Srivastava
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000627:therapeutic use; D000241:Adenosine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D043383:Adenosylhomocysteinase; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis; D005260:Female; D006867:Hydrolases / Q000037:antagonists & inhibitors*; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000188:drug therapy; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; C074205:6-amino-9-(((-3-iodo-2-propenyl)oxy)methyl)purine; D006867:Hydrolases; D043383:Adenosylhomocysteinase; D000225:Adenine; D000241:Adenosine