Synthesis, properties, and biological activity of some nucleoside cyclic phosphoramidates

Abstract

Reaction of the appropriate nucleoside with phosphoryl trichloride and then with N-methylethanolamine gave 2′,3′-O-isopropylidene-5′-O-(3″-methyl-1″-oxa-3″-aza-2″-phosphacyclopentan-2″-yl)uridine 2″-oxide (4), 5′-O-(3″-methyl-1″-oxa-3″-aza-2″-phosphacyclopentan-2″-yl)thymidine 2″-oxide (5), and 2′-deoxy-5-fluoro-5′-O-(3″-methyl-1″-oxa-3″-aza-2″-phosphacyclopentan-2″-yl)uridine 2″-oxide (6). A similar sequence of reactions, but using N,N′-dimethylethylenediamine, gave 5′-O-(1″,3″-dimethyl-1″,3″-diaza-2″-phosphacyclopentan-2″-yl)thymidine 2″-oxide (7) and 2′-deoxy-5′-O-(1″,3″-dimethyl-1″,3″-diaza-2″-phosphacyclopentan-2″-yl)-5-fluorouridine 2″-oxide (8).

Compounds (4)–(8) were hydrolysed readily in the pH range 6.0–7.0 at 25 °C, the kinetics being first order in hydrogen ions and in substrate. The 1-oxa-3-aza-2-phospha derivatives were hydrolysed more readily than the 1,3-diaza-2-phospha derivatives and the 2′-deoxy-5-fluorouridine derivatives more rapidly than the thymidine derivatives. In each case hydrolysis resulted in the fission of one P–N bond.

Compound (8) inhibited the growth of leukemia L1210 cells. It acted as a thymidylate synthetase inhibitor in the cell culture, but itself was not a substrate for the isolated, purified enzyme.