Abstract
A panel of ferrocenyl-substituted curcumin derivatives has been designed and synthesized as protein tyrosine phosphatase proto-oncogene SHP-2 inhibitors. Antiproliferative activities of the synthesized compounds were tested against colorectal cancer cell lines (including RKO, SW480, and CT26). Compound 3f showed excellent activities against the tested cell lines with IC(50) values of 5.72, 3.71, and 1.42 μM. The cytotoxicity of compound 3f was investigated on human normal colon epithelial cell line NCM460 with IC(50) values of 929 μM compared to curcumin with IC(50) values of 431 μM. The Western blot analysis approved that the expression level of SHP-2 in the CT26 and SW480 cell lines after being treated with 3f was decreased, meanwhile it also affected the SHP-2 in tumor-associated macrophages (THP-1 and RAW264.7), which may support the suggested mechanism of 3f as an SHP-2 inhibitor. Besides, 3f could also inhibit the activation of the PI3K-Akt pathway in SW480 and CT26 cell lines and the tumor microenvironment (TME) by reducing the expression of PI3K and Akt proteins. Some cytokines (Arg-1, TGF-β, and IL-10) and chemokines (chemokine receptors and CC and CXC chemokine subfamilies) in the TME were also inhibited by 3f. Finally, 3f could increase the expression level of cell cycle-related and mitophagy-related proteins p27, PINK1, and Parkin and decrease the expression level of CDK1 and Cyclin-D1 proteins in CT26 and SW480 cells, which proved that 3f could inhibit the proliferation of CRC cells through multiple pathways. Molecular docking studies against ALDH1 (PDB ID: 5ABM) revealed the good binding modes of the newly synthesized compounds.