Synthesis and biological evaluation of 5'-sulfamoylated purinyl carbocyclic nucleosides.
The first series of 5'-sulfamoylated carbocyclic purinyl nucleosides was synthesized and tested for antitumor and antibacterial activities. The target compounds were formed by reacting the 2',3'-acetonide-protected carbocyclic nucleosides with sulfamoyl chloride, followed by deprotection. The agents were tested for cytotoxic activity against P388 mouse leukemia cells. Two compounds, 5'-sulfamoyl carbocyclic adenosine (2) and 5-sulfamoyl-8-aza carbocyclic adenosine (6) exhibited IC50 values as low as 62 and 15 nM, respectively. These analogs inhibited protein biosynthesis and slowed down DNA and RNA biosyntheses in the P388 cells. None of the target molecules were as potent against Escherichia coli as they were against the tumor cells. Also, in cell-free systems, agents 2 and 6 were more effective inhibitors of protein synthesis in rabbit reticulocyte lysate than in E. coli. These new carbocyclic derivatives appear to be somewhat selective for eukaryotic over prokaryotic cells in affecting translation.
Peterson
E M
EM
Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis 55455-0343.
Brownell
J
J
Vince
R
R
D000659:AMP Deaminase / Q000378:metabolism; D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D000243:Adenosine Deaminase / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology; D000964:Antimetabolites, Antineoplastic / Q000138:chemical synthesis / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D004926:Escherichia coli / Q000187:drug effects; D066298:In Vitro Techniques; D007941:Leukemia P388; D051379:Mice; D008826:Microbial Sensitivity Tests; D011500:Protein Synthesis Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D011817:Rabbits; D014407:Tumor Cells, Cultured
D000900:Anti-Bacterial Agents; D000964:Antimetabolites, Antineoplastic; D011500:Protein Synthesis Inhibitors; D000243:Adenosine Deaminase; D000659:AMP Deaminase; D000241:Adenosine