Dialdehyde derivative of 5′-deoxyinosine as a more potent analog of the dialdehyde derivative of inosine (NSC 118994)

Abstract

The dialdehyde derivative of 5′-deoxyinosine (5′-deoxyinox) was prepared from 5′-deoxyadenosine by HNO 2 deamination and periodate oxidation. 5′-Deoxyinox was shown to inhibit ribonucleotide reductase activity in cell-free extracts and to inhibit RNA and DNA syntheses in intact cells. Further, 5′-deoxyinox inhibited the conversion of cytidine nucleotides to deoxycytidine nucleotides in intact cells. In comparative studies with the dialdehyde derivative of inosine (Inox), 5′-deoxyinox was shown to be more active on a molar basis in inhibiting RNA or DNA synthesis in intact cells. In addition, 5′-deoxyinox was more inhibitory to the growth of Novikoff hepatoma cells in culture than was Inox. 5′-Deoxyinox, in addition to being more active than Inox, also differed from Inox in its biochemical properties. Inox did not inhibit RNA polymerase activity when added to isolated nuclei. On the other hand, 5′-deoxyinox showed a marked inhibition of the RNA polymerase activity when added to the isolated nuclei. Further, inhibition of the RNA polymerase activity in the nuclei from Inox-treated cells was reversed completely by the addition of exogenous polydeoxyadenylate-deoxythymidylate as template, whereas the inhibition caused by 5′-deoxyi nox was not reversed by this treatment. These studies show that, in addition to the variation in activity caused by altering the purine component, the nature of the dialdehyde moiety also plays a role in the mode of action of this class of compounds.