New Ribonucleotide Reductase Inhibitors with Antineoplastic Activity

Abstract

For the purpose of developing an effective anticancer agent with a mode of action directed against ribonucleotide reductase, a number of acyl and aryl hydroxamic acids and their congeners were synthesized and tested for their ability to inhibit ribonucleotide reductase in vitro and to prolong the life span of L1210 leukemia-bearing mice. Benzohydroxamic acid and other six-member aromatic ring hydroxamic acids were found to be as inhibitory as was hydroxyurea in vitro, and they increased the life span of L1210 leukemia-bearing mice. Addition of hydroxy groups to the benzene ring of benzohydroxamic acid increased both inhibition of ribonucleotide reductase and life span of L1210 leukemic mice. Di- and trihydroxybenzohydroxamic acids, particularly when the hydroxyl groups were adjacent, were even more potent both in vitro and in vivo. For example, in comparison to hydroxyurea, 2,3,4-trihydroxybenzohydroxamic acid was 160 times more potent as an inhibitor of ribonucleotide reductase and increased the life span of L1210-leukemic mice at a lower dosage. The hydroxamic acid moiety was not essential for activity, since 2,3,4-trihydroxybenzamide was 100 times more potent than was hydroxyurea in vitro. Of the compounds tested, 3,4-dihydroxybenzohydroxamic acid was most effective in prolonging the life span of L1210-leukemic mice, increasing survival time over 100% and at one-third the dosage of hydroxyurea. © 1979, American Association for Cancer Research. All rights reserved.