Synthesis and Antiproliferative Effects of Novel 5'-Fluorinated Analogues of 5'-Deoxy-5'-(methylthio)adenosine

Article abstract of DOI:10.1021/jm00125a012

5'-Deoxy-5'-<(monofluormethyl)thio>adenosine (9) and 5'-deoxy-5'-fluoro-5'-(methylthio)adenosine (10), two novel analogues of 5'-deoxy-5'-(methylthio)adenosine (MTA), have been synthesized and evaluated for their substrate and inhibitory activities toward MTA phosphorylase and for their biological effects in L1210 (MTA phosphorylase deficient) and L5178Y (MTA phosphorylase containing) murine leukemia cell lines.Compound 9 was a potent competitive inhibitor of MTA phosphorylase with a K_i value of 3.3 μM and was also a substrate, with activity approximately 53percent that of MTA.Compound 10 was significantly less inhibitory toward the phosphorylase with a K_i value of 141 μM; its lack of substrate activity was attributed to rapid nonenzymatic degradation.The 50percent growth inhibitory concentrations (48 h) of 9 were 300 and 200 μM in L1210 and L5178Y cells, respectively; for 10, these respective values were 2 and 0.7 μM.The initial characterization of 9 in these systems reveals that it differs from MTA by not acting as a product regulator of the polyamine biosynthetic pathway.