Replacement of the 5'-OH group of puromycin aminonucleoside (PAN) with H resulted in the elimination of kidney toxicity associated with administration of PAN. Thus, 5'-deoxy-PAN was not nephrotoxic to rats under the usual criteria. The corresponding 5'-deoxypuromycin derived from 5'-deoxy-PAN was examined in a ribosomal peptidyl transferase assay and was found to be an excellent substrate for the transpeptidation reaction with bacterial ribosomes; the Km was 0.29 mM compared to the Km for puromycin of 0.20 mM. Thus, a puromycin analog has been prepared which retains puromycin-like activity at the ribosomal level, but which is capable of releasing only a non-nephrotoxic aminonucleoside by enzymatic hydrolysis of the p-methoxyphenylalanyl side-chain.
Bibliographical noteFunding Information:
This investigation was supported by Research Career Development Award CA25258 (to R. V .) and Grant CA 13592 from the National Cancer Institute, and Training Grant 5 T01 GM 02064 from the National Institutes of Health, U.S. Public Health Service.