Further Evidence on the Favorable Role of the Anomeric Effect on the Cleavage of HepDirect and Cyclophosphamide Prodrugs

On
the basis of previous conformational and configurational studies
of 4-aryl-substituted cyclophosph­(on)­ates derived from d-xylofuranose
derivatives, wherein it was proposed that the anomeric effect is involved
in the spontaneous isomerization of the P atom and the C4 carbon,
and consequently, this unusual behavior was associated with the cleavage
of the HepDirect prodrugs. We synthesized an analogous series of 2-amino-2-oxo-1,3,2-dioxaphosphorinanes
and performed a conformational and configurational analysis in solution
and the solid state followed by an examination of their mutagenic
activity. The results showed that the 2-amino-2-oxo-1,3,2-dioxaphosphorinanes
with the largest mutagenic activity contain either a 4-methoxyphenyl
or 4-fluorophenyl group at C4 carbon and presented a major chair conformation,
which is prone to weaken the C4O3 bond via the anomeric effect
and facilitates the cleavage for the release of the biologically active
metabolite.