Ferrocenyl-Substituted\nCurcumin Derivatives as Potential\nSHP‑2 Inhibitors for Anticolorectal Cancer: Design, Synthesis\nand <i>In Vitro</i> Evaluation

A panel of ferrocenyl-substituted curcumin derivatives\nhas been\ndesigned and synthesized as protein tyrosine phosphatase proto-oncogene\nSHP-2 inhibitors. Antiproliferative activities of the synthesized\ncompounds were tested against colorectal cancer cell lines (including\nRKO, SW480, and CT26). Compound <b>3f</b> showed excellent\nactivities against the tested cell lines with IC<sub>50</sub> values\nof 5.72, 3.71, and 1.42 μM. The cytotoxicity of compound <b>3f</b> was investigated on human normal colon epithelial cell\nline NCM460 with IC<sub>50</sub> values of 929 μM compared to\ncurcumin with IC<sub>50</sub> values of 431 μM. The Western\nblot analysis approved that the expression level of SHP-2 in the CT26\nand SW480 cell lines after being treated with <b>3f</b> was\ndecreased, meanwhile it also affected the SHP-2 in tumor-associated\nmacrophages (THP-1 and RAW264.7), which may support the suggested\nmechanism of <b>3f</b> as an SHP-2 inhibitor. Besides, <b>3f</b> could also inhibit the activation of the PI3K-Akt pathway\nin SW480 and CT26 cell lines and the tumor microenvironment (TME)\nby reducing the expression of PI3K and Akt proteins. Some cytokines\n(Arg-1, TGF-β, and IL-10) and chemokines (chemokine receptors\nand CC and CXC chemokine subfamilies) in the TME were also inhibited\nby <b>3f</b>. Finally, <b>3f</b> could increase the expression\nlevel of cell cycle-related and mitophagy-related proteins p27, PINK1,\nand Parkin and decrease the expression level of CDK1 and Cyclin-D1\nproteins in CT26 and SW480 cells, which proved that <b>3f</b> could inhibit the proliferation of CRC cells through multiple pathways.\nMolecular docking studies against ALDH1 (PDB ID: 5ABM) revealed the good\nbinding modes of the newly synthesized compounds.