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( R )‐α‐Lipoyl‐Glycyl‐ L ‐Prolyl‐ L ‐Glutamyl Dimethyl Ester Codrug as a Multifunctional Agent with Potential Neuroprotective Activities
Author(s) -
Cacciatore Ivana,
Baldassarre Leonardo,
Fornasari Erika,
Cornacchia Catia,
Di Stefano Antonio,
Sozio Piera,
Cerasa Laura Serafina,
Fontana Antonella,
Fulle Stefania,
Di Filippo Ester Sara,
La Rovere Rita Maria Laura,
Pinnen Francesco
Publication year - 2012
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201200320
Subject(s) - lipophilicity , neuroprotection , chemistry , cytotoxicity , neurotoxicity , bromide , in vitro , stereochemistry , viability assay , mtt assay , antioxidant , biochemistry , pharmacology , toxicity , organic chemistry , biology
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 H 2 O 2 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 H 2 O 2 ‐ and 6‐OHDA‐induced neurotoxicity in SH‐SY5Y cells.