The synthesis, conformation and hydrolytic stability of an N,S-bridging thiophosphoramidate analogue of thymidylyl-3′,5′-thymidine

Abstract

A 3′-N,5′-S-bridging thiophosphoramidate analogue of thymidylyl-3′,5′-thymidine was synthesised under aqueous conditions. ¹H NMR conformational measurements show that the 3′-N-substituted deoxyribose ring is biased towards the ‘north’, RNA-like conformation. Rate constants for hydrolysis of the analogue were measured at 90 °C in the pH range 1.3–10.9. The pH-log k_obs profile displays a pH-independent region between approximately pH 7 and 10 (t_1/2 ∼13 days). Under acidic conditions, k_obs displays a first order dependence on [H₃O⁺].