The chemical instability of the survivin inhibitor – sepantronium bromide (YM155) studied by stimulated Raman, NMR and UV–Vis spectroscopies

Abstract

Sepantronium bromide, which shows a broad spectrum of anticancer action, is allegedly chemically unstable. This instability might significantly limit the final antineoplastic efficacy of the drug. Here, we report our studies on these chemical stability issues under different chemical environments using advanced spectroscopies. With UV–Vis spectroscopy, we observed a degradation product which absorbs around 450 nm. The degradation accelerated strongly at alkaline pH (>8.5) and in the presence of a buffer, particularly PBS. We performed NMR and stimulated Raman studies to identify the degradation product and analysed the degradation kinetics. With both methods, we observed H → D isotope exchange at the methyl group linked to the imidazole group of YM155, after dissolving YM155 in D₂O. The exchange was similarly both alkaline- and buffer-catalysed. We were unable to identify the 450 nm-absorbing product of the degradation neither by NMR nor stimulated Raman, yet our studies pointed at imidazole-linked methyl as being associated with the YM155 degradation. The alkaline degradation of YM155 could be related to its mechanism of action – binding to DNA in mitochondria with pH values above 8.