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Mode of Inhibition of Tumor Cell Ribonucleotide Reductase by 2,3-Dihydro-1H-pyrazolo[2,3-A]imidazole (NSC 51143)¹

Department of Biochemistry, College of Medicine, University of South Florida, Tampa, Florida 33612

2,3-Dihydro-1H-pyrazolo[2,3-a]imidazole (NSC 51143; IMPY) inhibits partially purified ribonucleotide reductase from Ehrlich tumor cells. Both cytidine 5'-diphosphate and adenosine 5'-diphosphate reductase activities were inhibited by IMPY, although adenosine 5'-diphosphate reductase activity was inhibited to a greater extent than was cytidine 5'-diphosphate reductase activity at all concentraions of IMPY studied. The inhibition of the intact enzyme by IMPY could be reversed by the addition of the exogenous non-heme iron-containing subunit (tris(hydroxymethyl)aminomethane fraction) but not by the addition of the effector-binding subunit. Further, the inhibition of the intact enzyme or the tris(hydroxymethyl)aminomethane fraction by IMPY could be reversed by the addition of 6 µM Fe(NH₄)₂(SO₄)₂, and the inhibition of IMPY could be potentiated by 0.167 mM ethylenediaminetetraacetic acid. These results demonstrate that IMPY inhibits tumor cell nucleotide reductase by interaction with the iron of the non-heme iron-containing subunit.

¹ This study was supported by Grant CA 27398 from the National Cancer Institute, USPHS, and funds from the C. T. Meyer Estate.

² To whom requests for reprints should be addressed, at Department of Biochemistry, College of Medicine, University of South Florida, Box 7, 12901 N. 30th Street, Tampa, Fla. 33612.

Received 3/24/80. Accepted 7/17/80.