5'Chloropuromycin. Inhibition of protein synthesis and antitrypanosomal activity.
A facile, two-step conversion of puromycin aminonucleoside (PAN) into 5'-deoxy-PAN (5) via 5'-chloro-5'-deoxy-PAN (1) was accomplished. Replacement of the 5'-OH group of PAN with H or Cl resulted in the elimination of kidney toxicity associated with the administration of PAN. The corresponding puromycin derivatives, 5'-chloro-5'-deoxypuromycin (4) and 5'-deoxypuromycin (6), derived from 1 and 5, respectively, were compared in a ribosomal peptidyltransferase assay. Both compounds were excellent substrates for the transpeptidation reaction, confirming our previous observations with 6 that the 5'-OH of puromycin is not essential for activity at the ribosomal level. Thus, 4 represents a new puromycin derivative that retains puromycin-like activity at the ribosomal site but is capable of releasing only a nonnephrotoxic aminonucleoside upon enzymatic release of the p-methoxyphenylalanyl side chain. The chloro derivative 4 exhibited significant antitrypanosomal activity in mice infected with Trypanosoma rhodesiense. The 5'-deoxy derivative 6 was inactive against trypanosomes.
D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D003864:Depression, Chemical; D007674:Kidney Diseases / Q000139:chemically induced; D007700:Kinetics; D051379:Mice; D008813:Mice, Inbred ICR; D010458:Peptidyl Transferases / Q000037:antagonists & inhibitors; D014176:Protein Biosynthesis; D011691:Puromycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D011692:Puromycin Aminonucleoside / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D014344:Trypanocidal Agents / Q000138:chemical synthesis*
D014344:Trypanocidal Agents; D011691:Puromycin; D011692:Puromycin Aminonucleoside; D010458:Peptidyl Transferases