Design, synthesis, and biological evaluation of C1–phosphonamidate analogues of 2-deoxy-d-ribose-1-phosphate

Abstract

A novel series of phenoxy C1–phosphonamidate derivatives of 2-deoxy-d-ribose have been synthesised as stable analogues of 2-deoxy-α-d-ribose-1-phosphate. A number of synthetic routes were explored for the preparation of these targets. The successful approach involved the synthesis of a protected C1–phosphonate ester 17 via Michaelis–Arbuzov reaction, which was then hydrolysed and coupled with different amino acid esters using aldrithiol. Subsequent hydrogenolysis afforded the targets 2a–g, which were isolated as a mixture of diastereoisomers. The compounds were assayed for inhibition of thymidine phosphorylase (TP) and uridine phosphorylase (UP) and for antiviral and cytostatic activity.