硫化氢供体型美金刚衍生物的合成及其活性

Synthesis and biological evaluation of H_2S donor memantine derivatives

H_2S具有保护缺血再灌注损伤的神经元、显著降低脑梗死面积的作用,但高浓度H_2S产生神经毒性。N-甲基-D-天冬氨酸(NMDA)受体拮抗剂美金刚可以降低高浓度H_2S引起的神经毒性。将硫化氢缓释供体5-对羟基苯基-1,2-二硫杂环戊烯-3-硫酮(ADT-OH)与美金刚通过烷烃连接臂拼合,设计了9个结构全新的化合物I_1~I_9,以ADT-OH为原料,经过4步反应得到目标化合物,其化学结构经~1H NMR、^(13)C NMR和HRMS确证。利用MTT法评价不同浓度目标化合物对谷氨酸损伤的HT-22细胞的影响,结果发现,该类化合物在1μmol/L时能明显提高受损HT-22细胞的生存率(P<0.01),对于谷氨酸诱导损伤的神经元细胞具有较好的保护作用。

H2S has a role of protecting neurons from ischemia-reperfusion injury and significantly reducing the cerebral infarction area, but high concentration of H2S can induce neurotoxicity. Memantine, a N-methyl-D-aspar- tic acid （NMDA） receptor antagonist, could reduce the neurotoxicity of H2S at high concentration. Nine novel structures（compounds I1-I9） were designed by coupling（4-hydroxy phenyl）-3H-1, 2-dithiole-3-thione（ADT-OH） with memantine through alkanes as linkers and synthesized by four-step reactions from ADT-OH. Their neuropro- tection against damage induced by glutamate on HT-22 cells was evaluated by MTT method. The results indicated that these compounds markedly increased the survival rates of damaged HT-22 ceils at the concentration of 1μmol/L （ P 〈 0. 01）, which suggested that these compounds could preferably protect neurons against induced by glutamate.