Synthesis and biological properties of stable phosmidosine analogs.

Abstract

Phosmidosine and a variety of its analogs were synthesized by reaction of N-diisopropyl-N'-(N tritylaminoacyl)phosphorodiamidite derivatives with appropriately protected 8-oxoadenosine derivatives. It was found that replacement of the methyl group of the N-acylphosphoramidate linkage with longer alkyl groups resulted in significant stabilization of the ester linkage. Among the phosmidosine analogs synthesized, the O-ethyl derivative was easily synthesized and was found to be sufficiently stable under acidic and neutral conditions. These stable phosmidosine analogs exhibited similar antitumor activities against several cancer cell lines. The structure-activity relationship is also discussed.