Caffeoyl Pyrrolidine Derivative-LY52 Inhibits Tumor Invasion And Metastasis

Tumor invasion and metastasis consists of a series of sequential steps resulting in the formation of metastatic foci distant from the primary tumor: 1) release from the primary tumor and invasion of the surrounding basement membrane (BM); 2) invasion and penetration of the BM of vascular (or lymphatic) endothelium at the primary site; 3) extravasion, invasion, and penetration of the BM at the metastatic site, and 4) growth at apparently preferred sites. Proteolytic cleavage of BM by MMP-2 and -9 is a key step in the cascading nature of the process, as well as a growing number of key regulatory genes such as cytokines, growth factors, cell surface receptors and adhesion molecules. The enzymes are expressed at various stages of cancer development but are not expressed or, if so, very weakly in normal cells. Therefore, regulation of MMP-2 and -9 is crucial in blocking tumor invasion and metastasis. Three-dimensional structure analysis showed that the S'₁ pocket in human gelatinase is deeper than that of MMP-3. This has provided helpful clues when using structure-based design strategies selectively to block the proteolytic activity of MMP-2 and -9. In the previous studies, Xu Wenfang in the Institute of Chemistry and Pharmacy Study reported some caffonyl pyrrolidine derivatives, which designed based on the analogue reference drug CGS27023A, to fit the deeper S'₁ pocket in gelatinase. He designed the backbone of hydroxyproline linked with the longer and flexible caffonyl group to extend into the deeper S'₁ pocket. Theoretically, the compounds...