(R)-α-Lipoyl-Glycyl-L-Prolyl-L-Glutamyl Dimethyl Ester Codrug as a Multifunctional Agent with Potential Neuroprotective Activities

被引：39

作者：

Cacciatore, Ivana ^{[1
]}

Baldassarre, Leonardo ^{[1
]}

Fornasari, Erika ^{[1
]}

Cornacchia, Catia ^{[1
]}

Di Stefano, Antonio ^{[1
]}

Sozio, Piera ^{[1
]}

Cerasa, Laura Serafina ^{[1
]}

Fontana, Antonella ^{[1
]}

Fulle, Stefania ^{[2
]}

Di Filippo, Ester Sara ^{[2
]}

La Rovere, Rita Maria Laura ^{[2
]}

Pinnen, Francesco ^{[1
]}

机构：

[1] Univ G DAnnunzio, Dipartimento Farm, I-66100 Chieti, Italy

[2] Univ G DAnnunzio, Dipartimento Neurosci & Imaging, I-66100 Chieti, Italy

来源：

CHEMMEDCHEM | 2012年 / 7卷 / 11期

关键词：

(R)-alpha-lipoic acid; antioxidants; glycyl-L-prolyl-L-glutamate; neurodegenerative diseases; neurological agents; peptides; MEMBRANE-PERMEABILITY ASSAY; N-TERMINAL TRIPEPTIDE; OXIDATIVE STRESS; PARKINSONS-DISEASE; SUBSTANTIA-NIGRA; SELECTIVE INCREASE; ALZHEIMERS-DISEASE; L-DOPA; BRAIN; ANTIOXIDANTS;

D O I：

10.1002/cmdc.201200320

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The (R)-alpha-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 bloodbrain 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.

引用

页码：2021 / 2029

页数：9

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