新型白三烯A4水解酶抑制剂的合成及体外活性评价

Synthesis and Biological Evaluation in Vitro of Novel Leukotriene A4 Hydrolase Inhibitors

白三烯A4水解酶(LTA4H)是抑制炎症和肿瘤的一个潜在靶点.本研究基于LTA4H晶体结构和前期研究基础,以吲哚为母核,在其1,5位分别进行取代,设计合成了两个系列共计30个吲哚衍生物,通过高分辨质谱、核磁氢谱和碳谱确认了结构,上述化合物均为新化合物.通过体外测试评价了其对LTA4H的抑制活性,结果表明上述衍生物对LTA4H均表现出一定的抑制活性,其中部分化合物的抑制活性优于阳性药Bestatin.选取活性较好又有合适连接基团的两个化合物与紫杉醇通过丁二酰连接桥共价偶联为“孪前药”,并对偶联物体外活性进行评价,结果发现与紫杉醇连接的两个偶联物在体外仍保留了一定的LTA4H抑制活性和肿瘤细胞抑制活性,其中对人结直肠癌细胞HCT116的抑制效果尤为明显,这可能与结直肠癌与炎症因子的密切联系有关.本研究设计合成的新型吲哚类衍生物在LTA4H相关的疾病方面有潜在应用,其与紫杉醇的偶联物在与炎症高度相关的肿瘤治疗方面具有重要的研究价值.

Leukotriene A4 hydrolase(LTA4H)is a potential target for inhibiting inflammation and tumor.Based on crystal structure of LTA4H and previous research,indole was chosen as the skeleton in this study and 30 indole derivatives were designed and synthesized by substituting 1,5 positions respectively.Their novel structures were confirmed by highresolution mass spectrometry,^1H-NMR and ^13C-NMR spectroscopy.The inhibitory activity of the derivatives against LTA4H was evaluated in vitro.Most of the above derivatives showed significant inhibitory activity against LTA4H in vitro,some of them even better than that of positive drug Bestatin.Two derivatives with good activity and proper functional group as coupling group were selected to covalently couple with paclitaxel via succinyl bridge,which are called twin drugs or"mutual prodrugs".The in vitro activity of the conjugates was evaluated.The results showed that the conjugates retained certain LTA4H inhibitory activity and tumor cell proliferation inhibitory activity in vitro,especially for HCT116,which may be related to the close relationship between colorectal cancer and inflammatory factors.The new indole derivatives designed and synthesized in this study have potential applications in LTA4H related diseases,and the conjugates with paclitaxel have important research value in tumor therapy highly related to inflammation.