Synthesis and biological studies of unsaturated acyclonucleoside analogues of S-adenosyl-L-homocysteine hydrolase inhibitors

Article abstract of DOI:10.1021/jm00086a012

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 ~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.