title: (R)-α-lipoyl-glycyl-L-prolyl-L-glutamyl dimethyl ester codrug as a multifunctional agent with potential neuroprotective activities.
abstract: The (R)-α-lipoyl-glycyl-L-prolyl-L-glutamyl dimethyl ester codrug (LA-GPE, 1) was synthesized as a new multifunctional drug candidate with antioxidant and neuroprotective properties for the treatment of neurodegenerative diseases. Physicochemical properties, chemical and enzymatic stabilities were evaluated, along with the capacity of LA-GPE to penetrate the blood-brain barrier (BBB) according to an in vitro parallel artificial membrane permeability assay for the BBB. We also investigated the potential effectiveness of LA-GPE against the cytotoxicity induced by 6-hydroxydopamine (6-OHDA) and H2O2 on the human neuroblastoma cell line SH-SY5Y by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction assay. Our results show that codrug 1 is stable at both pH 1.3 and 7.4, exhibits good lipophilicity (log P=1.51) and a pH-dependent permeability profile. Furthermore, LA-GPE was demonstrated to be significantly neuroprotective and to act as an antioxidant against H2O2- and 6-OHDA-induced neurotoxicity in SH-SY5Y cells.
authors.affiliation: Dipartimento di Farmacia, Università degli Studi "G. D'Annunzio", Via dei Vestini 31, 66100 Chieti (Italy). cacciatore@unich.it.
authors.forename: Ivana
authors.initials: I
authors.lastname: Cacciatore
authors.forename: Leonardo
authors.initials: L
authors.lastname: Baldassarre
authors.forename: Erika
authors.initials: E
authors.lastname: Fornasari
authors.forename: Catia
authors.initials: C
authors.lastname: Cornacchia
authors.forename: Antonio
authors.initials: A
authors.lastname: Di Stefano
authors.forename: Piera
authors.initials: P
authors.lastname: Sozio
authors.forename: Laura Serafina
authors.initials: LS
authors.lastname: Cerasa
authors.forename: Antonella
authors.initials: A
authors.lastname: Fontana
authors.forename: Stefania
authors.initials: S
authors.lastname: Fulle
authors.forename: Ester Sara
authors.initials: ES
authors.lastname: Di Filippo
authors.forename: Rita Maria Laura
authors.initials: RM
authors.lastname: La Rovere
authors.forename: Francesco
authors.initials: F
authors.lastname: Pinnen
mesh_terms: D000975:Antioxidants / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D009842:Oligopeptides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D008063:Thioctic Acid / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D018696:Neuroprotective Agents; D009842:Oligopeptides; D008063:Thioctic Acid; D006861:Hydrogen Peroxide; C062053:glycyl-prolyl-glutamic acid