S'-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.