Haloperidol metabolite II prodrug: Asymmetric synthesis and biological evaluation on rat C6 glioma cells

In a previous work we reported the antiproliferative effects of (±)-MRJF4, a novel haloperidol metabolite II (HP-mII) (a sigma-1 antagonist and sigma-2 agonist) prodrug, obtained through conjugation to 4-phenylbutyric acid (PhBA) [a histone deacetylase inhibitor (HDACi)] via an ester bond. As a continuation of this work, here we report the asymmetric synthesis of compounds (R)-(+)-MRJF4 and (S)-(-)-MRJF4 and the evaluation of their biological activity on rat C6 glioma cells, derived from glioblastoma multiforme (GBM), which is the most common and deadliest central nervous system (CNS) invasive malignancy. Favourable physicochemical properties, high permeability in the parallel artificial membrane permeability assay (PAMPA), good enzymatic and chemical stability, in vivo anticancer activity, associated with the capacity to reduce cell viability and to increase cell death by apoptosis, render compound (R)-(+)-MRJF4 a promising candidate for the development of a useful therapeutic for gliomas therapy.

In a previous work we reported the antiproliferative effects of (±)-MRJF4, a novel haloperidol metaboliteII (HP-mII) (a sigma-1 antagonist and sigma-2 agonist) prodrug, obtained through conjugation to 4-phenylbutyric acid (PhBA) [a histone deacetylase inhibitor (HDACi)] via an ester bond. As a continuationof this work, here we report the asymmetric synthesis of compounds (R)-(þ)-MRJF4 and (S)-()-MRJF4 and the evaluation of their biological activity on rat C6 glioma cells, derived from glioblastomamultiforme (GBM), which is the most common and deadliest central nervous system (CNS) invasivemalignancy. Favourable physicochemical properties, high permeability in the parallel artificial membranepermeability assay (PAMPA), good enzymatic and chemical stability, in vivo anticancer activity, associatedwith the capacity to reduce cell viability and to increase cell death by apoptosis, render compound(R)-(þ)-MRJF4 a promising candidate for the development of a useful therapeutic for gliomas therapy.