Biological evaluation of carbohydrate-based aprepitant analogs for neuroblastoma treatment

Different studies using Aprepitant, a NK1R antagonist currently used as a clinical drug for treating chemotherapy-related nausea and vomiting, have demonstrated that pharmacological inhibition of NK1R effectively reduces the growth of several tumor types such as neuroblastoma (NB). In a previous work, we demonstrated that a series of carbohydrate-based Aprepitant analogs, derived from either d-galactose or l-arabinose, have shown high affinity and NK1R antagonistic activity with a broad-spectrum Anticancer activity and an important selectivity. In this new study, we explore the selective cytotoxic effects of these derivatives for the treatment of NB. Furthermore, we describe the design and stereoselective synthesis of a new generation of d-glucose derivatives as Aprepitant analogs, supported by docking studies. This approach showed that most of our carbohydrate-based analogs are significantly more selective than Aprepitant. The galactosyl derivative 2α, has demonstrated a marked in vitro selective cytotoxic activity against NB, with IC₅₀ values in the same range as those of Aprepitant and its prodrug Fosaprepitant. Interestingly, the derivative 2α has shown similar apoptotic effect to that of Aprepitant. Moreover, we can select the glucosyl amino derivative 10α as an interesting hit exhibiting higher in vitro cytotoxic activity against NB than Aprepitant, being 1.2 times more selective.

Aprepitant; Carbohydrate-based derivatives; NK1R antagonists; Neuroblastoma.