A novel tetrahydrocurcumin derivative as a potential anti-colorectal cancer agent: studies on its design, synthesis, and in vitro and in vivo biological evaluation.

OBJECTIVE

To design and synthesize a series of tetrahydrocurcumin (THC) derivatives bearing α, β-unsaturated carbonyl moieties, evaluate their anticancer activities, screen potential candidates for colorectal cancer (CRC) therapy, and assess their biological activities.

METHODS

THC derivatives were synthesized in high yield via Knoevenagel condensation reaction, and their anticancer activities were evaluated in HCT116, SW480, SW620, HeLa, A549 and HepG2 cell lines. The in vitro and in vivo anti-CRC activities of the target compound were subsequently investigated.

RESULTS

Most compounds displayed potent antiproliferative activity against multiple tumor cell lines, with notably enhanced sensitivity in CRC cells. The fluorinated derivative 5 (C5) exhibited superior anti-CRC activity (IC50 = 2.66 ± 0.82 μM) relative to the positive control 5-fluorouracil (5-FU). By contrast, its reduced product compound H5 showed a 13-fold decline in potency (IC50 = 35.74 ± 1.40 μM), validating that the α, β-unsaturated carbonyl moiety represents the critical pharmacophore. Furthermore, C5 induced S-phase cell cycle arrest in HCT116 cells, triggered apoptosis via modulation of Bcl-2 family proteins, and suppressed cell migration. Mechanistically, it exerted its anticancer effects by inhibiting the PI3K/AKT/mTOR signaling pathway through downregulating p-AKT and p-mTOR. In vivo, C5 effectively inhibited tumor growth and cancer cell proliferation in HCT116 xenograft models, with higher efficacy and lower toxicity than 5-FU.

CONCLUSIONS

These THC derivatives exhibited selective targeting toward CRC cells and suppressed the PI3K/AKT/mTOR signaling pathway, exerting significant anti-CRC efficacy both in vitro and in vivo, and thus held promise as potential lead compounds for CRC therapy.