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: A Hasan, P C Srivastava
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 35 Issue 8 Pg. 1435-9 (Apr 17 1992) ISSN: 0022-2623 [Print] United States
• PMID: 1573637 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Anti-Bacterial Agents
• Enzyme Inhibitors
• 6-amino-9-(((-3-iodo-2-propenyl)oxy)methyl)purine
• Hydrolases
• Adenosylhomocysteinase
• Adenine
• Adenosine

Topics

• Adenine (analogs & derivatives, chemical synthesis, therapeutic use)
• Adenosine (analogs & derivatives, pharmacokinetics, therapeutic use)
• Adenosylhomocysteinase
• Animals
• Anti-Bacterial Agents (chemical synthesis)
• Enzyme Inhibitors (chemical synthesis)
• Female
• Hydrolases (antagonists & inhibitors)
• Mice
• Mice, Inbred BALB C
• Neoplasms, Experimental (drug therapy)
• Structure-Activity Relationship
• Tissue Distribution