肿瘤微环境（tumor microenvironment，TME）在癌症的生长和侵袭过程中发挥关键作用。TME的生物标志物之一是成纤维细胞激活蛋白（fibroblast activation protein, FAP）。FAP在超过90%的人类上皮肿瘤中存在过表达，而在正常组织中几乎没有表达。因此，FAP是一个良好的癌症诊疗靶点。设计和合成新型、高效的FAP抑制剂对开发癌症诊疗药物具有重要意义。
      本课题基于对FAP具有良好抑制活性的（4-喹啉）-甘氨酸-（2-氰基吡咯烷）（N-(4-quinolinoyl)-Gly-(2-cyanopyrrolidine)）骨架，进行取代基的精细调控，共合成9种衍生物，并测定其对FAP的抑制活性。
      对氰基吡咯烷片段采取开环策略后，抑制剂的生物活性明显下降；向甘氨酸片段和氰基吡咯烷片段引入生物电子等排体，也会导致抑制剂活性的降低。这表明这两个片段在抑制剂与FAP的结合过程中起重要作用。在后续的FAP抑制剂开发中，应慎重对甘氨酸片段和氰基吡咯烷片段进行改造。随着氰基吡咯烷片段的脂肪链的延长，抑制剂对FAP的结合能力有上升趋势，后续可以尝试将五元吡咯烷改造为六元或七元环，以期获得具有更高抑制活性的FAP抑制剂。

    Tumor microenvironment (TME) plays a key role in the growth and invasion of cancer. One of the biomarkers of TME is fibroblast activation protein (FAP). FAP is overexpressed in more than 90% human epithelial tumors while barely expressed in normal tissues. Therefore, FAP is an excellent biological target for cancer diagnosis and treatment. The design and synthesis of novel and efficient FAP inhibitors is important for the development of cancer therapeutic agents.
    Based on the N-(4-quinolinoyl)-Gly-(2-cyanopyrrolidine) backbone, which has high inhibitory activity against FAP, a total of nine derivatives were synthesized by fine regulation of substituents and their inhibitory activity against FAP was determined.
    Ring-opening strategy on the cyanopyrrolidine fragment resulted in a significant decrease in the biological activity of the inhibitor. Introduction of bioisosteres to the glycine fragment and the cyanopyrrolidine fragment also resulted in a decrease in inhibitory activity. This suggests that these two fragments play an important role in the binding process of inhibitors to FAP. In the subsequent development of FAP inhibitors, the modification of the glycine fragment and cyanopyrrolidine fragment should be carried out with caution. With the extension of the aliphatic chain of the cyanopyrrolidine fragment, the binding ability of the inhibitor to FAP tends to rise. In the future, the five-membered pyrrolidine ring can be changed into a six- or seven-membered ring to develop FAP inhibitors with higher inhibitory activity.