2,2-二甲基-1,3-二氧戊环-4,5-二羧酸衍生物的设计、合成及其神经营养活性

Design,synthesis and evaluation of 2,2-dimethyl-[1,3]-dioxolane-4,5-dicarboxylic acid derivatives as neuroimmunophilin ligands

目的设计并合成具有神经营养活性的小分子化合物。方法根据FKBPs家族蛋白活性位点在序列和构象上高度保守的特点以及FKBP12配体的关键结构特征,设计并合成新结构的FKBPs配体。应用鸡胚背根神经节体外无血清培养模型和H2O2损伤NG108-15细胞模型对新结构的FKBPs配体的神经营养活性进行评价。结果与结论合成了27个2,2-二甲基-1,3-二氧戊环-4,5-二羧酸衍生物。初步药理实验结果显示化合物7d对H2O2损伤NG108细胞有明显的保护效果;化合物7o具有一定的促神经生长作用。

Aim To design and synthesize novel 2, 2-dimethyl- [ 1, 3 ]-dioxolane-4, 5-dicarboxylic acid derivatives as neuroimmunophilin ligands. Methods Both the sequences and conformation of FK506-binding site in FKBPs （FK506 binding proteins） family are highly conserved. According to this characteristic of FKBPs and the structural feature of ligands binding to FKBP12, CADD （computer-aided drug design） was employed to design and virtually screen the novel 2, 2-dimethyl-[ 1, 3]-dioxolane-4, 5-dicarboxylic acid derivatives. These compounds were synthesized by a liquid-phase synthetic method. A model of chick embryos dorsal root ganglion （DRG） cultures free of serum and a model of NG108-15 cell injured by H2O2 were applied to evaluate neurotrophic activity of these target compounds. Results and conclusion 27 target compounds were synthesized. In cultured chick DRGs, compound 70 produced a little neurotrophic effect and promoted neurite outgrowth in vitro. In the model of H2O2-induced NG108 cell damage, compound 7d showed a significantly protective effect on NG 108 cell.