Add time:08/10/2019         Source:sciencedirect.com

The 2′-deoxy-2′-methylene derivatives of adenosine (MdAdo), guanosine (MdGuo), tubercidin (MdTu), cytidine (MdCyd) and undine (MdUrd) were synthesized as mechanism-based inhibitors directed at ribonucleotide reductase. It was shown that MdCyd 5′-diphosphate irreversibly inactivated ribonucleotide reductase from Escherichia coli (Baker et al., J Med Chem34: 1879–1884, 1991). In studies reported here, MdAdo/EHNA, MdGuo and MdCyd inhibited L1210 cell growth with IC50 values of 3.4,10.6 and 1.4 μM, respectively. Since MdAdo is a substrate for adenosine deaminase, the presence of EHNA was required to give maximal growth inhibition. 8-Aminoguanosine was not required to maximize the cytotoxic effects of MdGuo. The 2′-deoxy-2′-methylene derivatives of tubercidin and uridine did not inhibit L1210 cell growth at concentrations as high as 50 μM (MdTu) or 100 μM (MdUrd). L1210 cell lines resistant to hydroxyurea (directed at the non-heme iron subunit of ribonucleotide reductase) or deoxyadenosine (directed at the effector binding subunit of ribonucleotide reductase) were not resistant to MdCyd. An L1210 cell line that. was highly resistant to dGuo due to the loss of a relatively specific deoxyribonucleoside kinase (Cory et al., J Biol Chem268: 405–409, 1993) had a 6.6 fold increase in the IC50 value toward MdCyd, but showed only a 2-fold increase in resistance to MdGuo. Another L1210 cell line that was markedly deficient in adenosine kinase activity was highly resistant to MdAdo. Analysis by now cytometry showed that MdCyd slowed the transit of the cells through the G2/M phase of the cell cycle resulting in the buildup of the G2/M population. MdAdo, MdGuo and MdCyd inhibited the incorporation of [14C]cytidine into DNA without an effect on RNA synthesis or total cellular uptake of [14C]cytidine. The conversion of [14C]cytidine to deoxycytidine nucleotides was partially inhibited by MdGuo, but not by MdAdo or MdCyd. These data show that the 2′-deoxy-2′-methylene derivatives of adenosine, guanosine and cytidine are activated via specific nucleoside kinases and that the modes of action of these compounds are not identical.

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