title: Haloperidol metabolite II prodrug: asymmetric synthesis and biological evaluation on rat C6 glioma cells.
abstract: 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.
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Chieti Gabriele D'Annunzio, Via dei Vestini 31, 66100 Chieti, Italy.
authors.forename: Piera
authors.initials: P
authors.lastname: Sozio
authors.affiliation: Department of Pathology and Cell Biology and Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, 630 W 168th St., New York, NY 10032, USA.
authors.forename: Jole
authors.initials: J
authors.lastname: Fiorito
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Chieti Gabriele D'Annunzio, Via dei Vestini 31, 66100 Chieti, Italy.
authors.forename: Viviana
authors.initials: V
authors.lastname: Di Giacomo
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Chieti Gabriele D'Annunzio, Via dei Vestini 31, 66100 Chieti, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Di Stefano
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Chieti Gabriele D'Annunzio, Via dei Vestini 31, 66100 Chieti, Italy.
authors.forename: Lisa
authors.initials: L
authors.lastname: Marinelli
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Chieti Gabriele D'Annunzio, Via dei Vestini 31, 66100 Chieti, Italy.
authors.forename: Ivana
authors.initials: I
authors.lastname: Cacciatore
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Chieti Gabriele D'Annunzio, Via dei Vestini 31, 66100 Chieti, Italy.
authors.forename: Amelia
authors.initials: A
authors.lastname: Cataldi
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Chieti Gabriele D'Annunzio, Via dei Vestini 31, 66100 Chieti, Italy.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Pacella
authors.affiliation: Department of Molecular Biology and Genetics, Faculty of Science, Erzurum Technical University, 25240 Erzurum, Turkey.
authors.forename: Hasan
authors.initials: H
authors.lastname: Turkez
authors.affiliation: Dipartimento di Scienze del Farmaco, Università degli Studi di Catania, Viale Andrea Doria 6, 95125 Catania, Italy.
authors.forename: Carmela
authors.initials: C
authors.lastname: Parenti
authors.affiliation: Dipartimento di Scienze del Farmaco, Università degli Studi di Catania, Viale Andrea Doria 6, 95125 Catania, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Rescifina
authors.affiliation: Dipartimento di Scienze del Farmaco, Università degli Studi di Catania, Viale Andrea Doria 6, 95125 Catania, Italy. Electronic address: marrazzo@unict.it.
authors.forename: Agostino
authors.initials: A
authors.lastname: Marrazzo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006220:Haloperidol / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D015394:Molecular Structure; D011355:Prodrugs / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D011355:Prodrugs; D006220:Haloperidol
keywords: Glioma; HDAC; Inhibitors; Medicinal chemistry; Sigma receptors