Inhibition of ribonucleotide reductase and L1210 cell growth by N-hydroxy- N′-aminoguanidine derivatives

Abstract

A series of N-hydroxy- N′-aminoguanidine derivatives was studied for their effects on L1210 cell growth and ribonucleotide reductase activity. With the twelve compounds studied, there was a good correlation between the inhibition of L1210 cell growth and the inhibition of ribonucleotide reductase activity. The most potent compound required concentrations of only 1.4 and 2 μM for 50% inhibition of L1210 cell growth and ribonucleotide reductase activity respectively. These guanidine analogs specifically inhibited the conversion of [ 14C]cytidine and deoxycytidine nucleotides in the nucleotide pool and the incorporation of [ 14C]cytidine into DNA without altering the incorporation of [ 14C]cytidine into RNA. Ribonucleotide reductase activity in drug-treated cells was reduced markedly. Iron-chelating agents did not either increase or decrease the inhibition caused by the N-hydroxy- N′-aminoguanidine derivatives. No evidence was obtained that these derivatives selectively inactivated one of the subunits of ribonucleotide reductase. These compounds appear to inhibit ribonucleotide reductase by a mechanism different from hydroxyurea or the thiosemicarbazone derivatives.