Dipartimento di Farmacia, Università degli Studi "G. D'Annunzio", Via dei Vestini 31, 66100 Chieti (Italy).
ChemMedChem. 2012 Nov;7(11):2021-9. doi: 10.1002/cmdc.201200320. Epub 2012 Sep 13.
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.
（R）-α- 硫辛酸甘氨酰-L-脯氨酰-L-谷氨酸二甲酯前药（LA-GPE，1）被合成作为一种具有抗氧化和神经保护特性的新型多功能药物候选物，用于治疗神经退行性疾病。评估了其物理化学性质、化学和酶稳定性，以及根据体外平行人工膜透过性测定 BBB 评估 LA-GPE 穿透血脑屏障（BBB）的能力。我们还通过 3-（4,5-二甲基噻唑-2-基）-2,5-二苯基四氮唑溴化物（MTT）还原测定法，研究了 LA-GPE 对人神经母细胞瘤细胞系 SH-SY5Y 中 6-羟多巴胺（6-OHDA）和 H2O2 诱导的细胞毒性的潜在有效性。我们的结果表明，前药 1 在 pH 值为 1.3 和 7.4 时均稳定，具有良好的亲脂性（log P=1.51）和 pH 依赖性渗透性特征。此外，LA-GPE 被证明对 SH-SY5Y 细胞中的 H2O2 和 6-OHDA 诱导的神经毒性具有显著的神经保护作用，并具有抗氧化作用。
