Synthesis of acyclonucleoside hydroxamic acids as inhibitors of ribonucleotide reductase.
N-Hydroxy-alpha-(2-hydroxyethoxy)-1(2H)-pyrimidineacetamides 1-3 were synthesized as potential antitumor agents whose mechanism of action would involve inhibition of ribonucleoside diphosphate reductase (RDPR, EC 1.17.4.1). Acyclonucleoside esters 6-8 were prepared by the stannic chloride catalyzed reaction of methyl chloro[2-(phenylmethoxy)ethoxy]acetate (5) with various silylated pyrimidines, generated in situ from the bases and bis(trimethylsilyl)acetamide. Catalytic didebenzylation of hydroxamate 11 gave 1, while 2 and 3 were synthesized by the reaction of lactones 14 and 22, respectively, with hydroxylamine. In vitro acyclonucleoside hydroxamic acids 1-3 were 3-10-fold less potent than hydroxyurea against calf thymus cytidine diphosphate reductase. 5-Fluorouracil derivative 2 is nearly equipotent with hydroxyurea in inhibiting the growth of HeLa cells, while 1 is a much weaker inhibitor and cytidine derivative 3 is devoid of activity at 200 micrograms/mL.
Farr
R A
RA
Merrell Dow Research Institute, Cincinnati, Ohio 45215.
Bey
P
P
Sunkara
P S
PS
Lippert
B J
BJ
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D006367:HeLa Cells / Q000187:drug effects; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D009705:Nucleosides / Q000138:chemical synthesis* / Q000494:pharmacology; D012262:Ribonucleoside Diphosphate Reductase / Q000037:antagonists & inhibitors*; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D006877:Hydroxamic Acids; D009705:Nucleosides; C019857:CDP reductase; D012264:Ribonucleotide Reductases; D012262:Ribonucleoside Diphosphate Reductase