Importance of the hydrophobic sulfoxide substituent on nontoxic analogs of sparsomycin.

Nontoxic analogs of sparsomycin were competitive inhibitors of puromycin in the peptidyl transferase assay with Escherichia coli polysomes. The sensitivity of HeLa cells in vitro to the analogs was used as a preliminary index of cellular toxicity. In vitro killing of HeLa cells by this class of compounds correlated well with in vivo 50% lethal doses. The data indicate that modification of the hydrophobic sulfoxide substituent on sparsomycin decreases the toxicity of the molecule for mammalian cells by several hundredfold. Such modifications have less of an effect on the inhibitory activity of the compounds for peptidyl transferase. The differential effects of an analog active against bacterial but not mammalian cells was due to a decreased uptake of the compound by HeLa cells.