Kinetic and Thermodynamic Study of the Epimerization of Dihydroartemisinin and of a Monoketoaldehyde (MKA)Decomposition Product by Dynamic HPLC and UPLC

As a result of our ongoing studies on semi-synthetic derivatives of artemisinin1,2 as antimalarial drugs, we focused our attention on dihydroartemisinin 1, obtained by NaBH4 reduction of the lactone group at C-10 of artemisinin, which was shown to interconvert between two lactol hemiacetal epimers (namely, 1 and 1) during its passage through a chromatographic column.3 In the present work, we studied the epimerization process of 1 at C-10 (Scheme 1) by dynamic HPLC. In particular, the influence of temperature, mobile phase pH, nature of organic modifier and type of stationary phase was evaluated. The activation parameters (G#, H# and S#) were determined by simulation of the dynamic chromatograms, using the classical stochastic approach as theoretical model.4 Moreover, we found that 1 rearranges and decomposes to the known peroxyhemiacetal 2 (hereafter named monoketo-aldehyde, MKA) upon heating to 120°C for 1h. Compound 2, previously reported to have significant antimalarial activity in an in vitro assay (IC50 in the 12 ng/mL range),5 was also expected to occur in solution as a mixture of C-10 epimers, namely, 2 and 2 (Scheme 2). The kinetic and thermodynamic study on 1 was then extended to MKA, by means of dynamic UPLC and HPLC, and the activation parameters obtained properly compared.