Effect of Temperature on the Kinetics of the Activation of Treosulfan and Hydrolytic Decomposition of Its Active Epoxy Derivatives

Treosulfan (TREO) is a prodrug applied in the treatment of ovarian cancer and a myeloablative conditioning prior to stem cell transplantation. A sequential activation of TREO to intermediate monoepoxide (S,S-EBDM) and then to (2S,3S)-1,2:3,4-diepoxybutane (S,S-DEB) involves a nonenzymatic intramolecular nucleophilic substitution. The aim of this study is to determine the effect of temperature on the rate constants (k) for the activation of TREO and the hydrolysis of its epoxy derivatives in a phosphate buffer of pH 7.4 at an ionic strength of 0.16-0.17 M. Over the tested temperature range, the ln of k changed linearly with a reciprocal of absolute temperature. The mean activation energy (Ea) values for the TREO → S,S-EBDM and S,S-EBDM → S,S-DEB reactions were close to each other (122 and 118 kJ/mol, respectively). In opposition, the Ea for the hydrolysis of S,S-EBDM and S,S-DEB differed significantly (140 and 80 kJ/mol, respectively), which indicates that the structure of S,S-EBDM hampers a nucleophilic attack of water on the epoxide ring. The obtained results show that a temperature change by 1°C, from 36.5°C to 37.5°C, entails a 17% increase in the k of TREO decay, which might lead to an increased TREO clearance in vivo.