Abstract: Colorectal cancer is considered to be a highly immune-related disease, and the severe chronic inflammatory stress in the tumor microenvironment (TME) greatly impedes the effective prognosis and treatment of colorectal cancer. Based on a dual strategy, anti-proliferation and inhibition of inflammatory factor HMGB1, a series of GN-derivatives were synthesized and screened for their anticancer efficacy, and compound 22 showed the strongest anti-proliferative activity against HCT116 cells, with IC₅₀ value 13.1 μmol·L⁻¹. To improve the solubility, compounds 23−40 were synthesized and then evaluated for activities against colon cancer cells. Finally, compounds 23 and 24 with good water solubility were screened as target molecules. In anti-proliferation tests, both displayed the strongest activity on CT26 cells, with IC₅₀ value 1.1 and 1.4 μmol·L⁻¹, respectively; in the cloning tests, they also showed a strong anti-proliferative activity against CT26 cells; moreover, they promoted apoptosis, and blocked cells in G₂/M phase in a concentration-dependent manner; in Western Blot tests, they decreased the levels of cyclin A2, cyclin B1 and CDK1 in a concentration-dependent manner. In anti-inflammation aspect, both them displayed strong anti-inflammation activity; compound 23 reduced the levels of NO in both RAW264.7 cells and CT26 cells in the anti-inflammatory tests, and the IC₅₀ values were 10.3 and 1.1 µmol·L⁻¹, respectively; Western Blot showed 23 decreased the levels of HMGB1, RAGE, TNF-α, IL-6, IL-1 and COX-2 in a dose-dependent manner. In animal tests, compound 23 reduced the volume and weight of tumor more obviously than compound 24 and 5-FU, and its effect was a dose-dependent. In summary, compound 23 has therapeutic effect for the treatment of colorectal cancer in some degree, and it has potential to be a candidate for treatment of colorectal cancer.