The γ-butyrolactone and δ-valerolactone structural units are present in different natural products with significant pharmacological properties. Fumaric acid ester-based drugs are used for the treatment of psoriasis and, more recently, multiple sclerosis. We synthesized different γ-butyrolactone and δ-valerolactone derivatives where the fumarate moiety is forced into a lactone ring in search of strategies to maintain the anti-inflammatory activity of fumaric acid esters limiting the side effects and enhancing the bioavailability. The structures of all synthesized compounds obtained were identified on the basis of their spectral data. The toxicity profile as well as the neuroprotective properties of the synthesized derivatives were evaluated in human neuroblastoma SH-SY5Y cell line. All tested fumaric esters presented lower cytotoxicity and higher neuroprotective properties, in comparison to dimethyl fumarate. Pre-treatment of cells with at least seven compounds for 24 h lead to a significantly neuroprotection against H₂O₂-induced cell damage. Our results demonstrate that SH-SY5Y cells are suitable cellular model to evaluate the neuroprotective role of fumaric acid esters, and support further evaluation of BG-12 derivatives aimed at decreasing cytotoxicity and limiting the side effects for improvement of treatments for multiple sclerosis and psoriasis.

γ-丁内酯和δ-戊内酯结构单元存在于具有明显药理特性的不同天然产物中。基于富马酸酯的药物用于治疗牛皮癣，并且最近用于治疗多发性硬化症。我们合成了不同的γ-丁内酯和δ-戊内酯衍生物，其中富马酸酯部分被迫进入内酯环，以寻求策略来维持富马酸酯的抗炎活性，从而限制了副作用并提高了生物利用度。根据其光谱数据鉴定得到的所有合成化合物的结构。在人神经母细胞瘤SH-SY5Y细胞系中评估了合成衍生物的毒性特征以及神经保护特性。与富马酸二甲酯相比，所有测试的富马酸酯均具有较低的细胞毒性和较高的神经保护特性。用至少七种化合物预处理细胞24小时会导致针对H的明显神经保护₂ O ₂诱导的细胞损伤。我们的结果表明，SH-SY5Y细胞是评估富马酸酯的神经保护作用的合适细胞模型，并支持进一步评估BG-12衍生物，以降低细胞毒性并限制副作用，以改善多发性硬化症和牛皮癣的治疗方法。