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Modified Nucleosides with Antineoplastic Activity as Inhibitors of an Enzyme Containing Adenosine within Its Coenzyme¹

General Clinical Research Center, Roswell Park Memorial Institute, New York State Department of Health, Buffalo, New York 14203

The naturally occurring modified nucleoside N⁶-(²-isopentenyl)adenosine and the synthetic analog N⁶-benzyladenosine are competitive inhibitors for both the coenzyme and substrate of glucose 6-phosphate dehydrogenase from rat liver. Both nucleosides competed more effectively with nicotinamide adenine dinucleotide phosphate than with glucose 6-phosphate. These modified nucleosides are ostensible analogs of adenosine, and it is proposed that they compete for the catalytic site with the adenosine residue within the nicotinamide adenine dinucleotide phosphate coenzyme. It is suggested that the antineoplastic and other biological activities of these modified nucleosides may be manifestations of selective inhibition of the large number of metabolic enzymes that contain adenosine within their coenzymes. Furthermore, this implies a homeostatic role for endogenous modified nucleosides released via transfer RNA turnover in normal and neoplastic cells.

¹ This work was supported in part by Grants 2 MO 1 RR0262-07 and CA-10835 from the USPHS and was presented in abbreviated from (Abstract 1414) at the Fifth International Congress on Pharmacology, San Francisco, Calif., July 1972.

Received 8/21/72. Accepted 10/25/72.