Synthesis of hydroxy- and amino-substituted benzohydroxamic acids: inhibition of ribonucleotide reductase and antitumor activity.
Benzohydroxamic acids inhibit mammalian ribonucleotide reductase and exhibit antineoplastic activity in L1210 leukemic mice. Five new hydroxy- and amino-substituted benzohydroxamic acids (3,4- and 3,5-OH, 3,4-NH2, 2,3,4- and, 3,4,5-OH) were prepared and tested along with 12 previously reported benzohydroxamic acids (BHA) for enzyme inhibition and antitumor activity. The most potent enzyme inhibitor in this series was 2,3,4-OH-BHA (ID50 = 3.5 microM), which is 140 times more potent than hydroxyurea, but its toxicity limited the antitumor activity to a 30% increase in life span of L1210 bearing mice at 125 (mg/kg)/day ip for 8 days. The most effective antitumor agent in this series was 3,4-OH-BHA which prolonged the life span of L1210 bearing mice 103% at 600 (mg/kg)/day ip for 8 days.
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D006918:Hydroxyurea / Q000627:therapeutic use; D066298:In Vitro Techniques; D007939:Leukemia L1210 / Q000188:drug therapy; D008114:Liver Neoplasms, Experimental / Q000201:enzymology; D051379:Mice; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D006877:Hydroxamic Acids; D012264:Ribonucleotide Reductases; D006918:Hydroxyurea