5'-Chloropuromycin. Inhibition of protein synthesis and antitrypanosomal activity

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Abstract
A facile, 2-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 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.