新型5-脂氧合酶激活蛋白抑制剂的设计、合成及活性评价

Design,Synthesis,and Biological Evaluation of Novel 5-Lipoxygenase-activating Protein Inhibitors

设计、合成5-脂氧合酶激活蛋白(FLAP)抑制剂,并评价其活性。基于靶向FLAP蛋白结构采用计算机辅助药物设计,筛选并合成了一系列FLAP抑制剂,利用^(1)HNMR、^(13)CNMR和TOF-MS表征结构。通过酶联免疫双抗夹心法测定了其对FLAP的抑制活性,并计算半数有效抑制浓度(IC_(50))。设计了558个不同芳基、不同碳链长度的2,2-二甲基-5-烷基-5取代氨基-1,3-二氧六环衍生物,通过氧化反应、格氏反应、Appel反应、胺代反应合成11个化合物,经^(1)HNMR、^(13)CNMR和TOF-MS确认结构。酶抑制实验表明N-(3-甲氧基苄基)-2,2-二甲基-5-十八烷基-1,3-二烷-5-胺对FLAP的抑制活性强于阳性药MK-591(IC_(50)=^(13).78 nmol/L),其IC_(50)达到10.52 nmol/L,具有发展成为FLAP抑制剂的潜力。合成的新型FLAP抑制剂表现出对FLAP较强的抑制作用,在炎症相关疾病的治疗中有潜在应用价值。

5-Lipoxygenase-activating protein(FLAP)inhibitors were designed and synthesized,and their inhibitory activities were evaluated.In this study,a series of FLAP inhibitors were screened and synthesized by computer-aided drug design based on the targeting FLAP.The structures were characterized by ^(1)HNMR,^(13)CNMR and TOF-MS.The enzyme linked immunosorbent assay test was performed to evaluate the inhibitory activity of the compounds.Furthermore,the IC_(50) was calculated.558 Kinds of 2,2-dimethyl-5-alkyl-5-substituted amino-1,3-dioxane derivatives with different aryl groups and carbon chains were designed,11 kinds of compounds were selected by computer virtual screening and synthesized via four steps including oxidation reaction,Grignard reaction,Appel reaction,amination reaction.The structures were confirmed by ^(1)HNMR,^(13)CNMR and TOF-MS.Bioactive evaluation test showed that the inhibitory activity of N-(3-methoxybenzyl)-2,2-dimethyl-5-octadecyl-1,3-dioxan-5-amine(IC_(50)=10.52 nmol/L)is better than positive drug MK-591(IC_(50)=^(13).78 nmol/L).Therefore,it has potential to develop into FLAP inhibitor.In this study,the novel FLAP inhibitors exhibit strong inhibitory effect on FLAP and have potential to treat inflammatory diseases.