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Ceramides have emerged as potential therapeutic option with novel mechanism to affect the proliferation, differentiation, senescence, and apoptosis of cancer cells through regulation of multiple signal transduction. Aiming at the improvement of the apoptosis activity and pharmacokinetic profiles of ceramides, a novel series of ceramide analogs were developed through structure simplification and conformation restriction. Among them, compound 12 bearing an alkoxyl naphthyl motif, with favorable rat pharmacokinetic properties, showed better anti-proliferative activity against various colon cancer cells (IC 50 ∼20 μM) than other ceramide analogues, as well as the synergistic effect combined with AKT inhibitor MK2206. Additionally, we demonstrated that this combination therapy promoted caspase 3-dependent apoptotic pathway and intensified cell cycle arrest in the G0/G1 phase. Furthermore, the combination of compound 12 and MK2206 displayed synergistic anti-tumor effect in vivo. [Display omitted] • Novel ceramide analogs bearing naphthyl-substituted amino diol were designed, synthesized and evaluated. • The structure-activity relationship (SAR) of this novel series of ceramide analogs was demonstrated. • Compound 12 and MK2206 exhibit synergistic anti-tumor effect in colon cancer cells, which is associated with cell apoptosis, ROS generation and cell cycle arrest.. • Compound 12 exhibited superior pharmacokinetic properties. • Combination therapy of compound 12 and MK2206 has synergistic effect on tumor growth in vivo. [ABSTRACT FROM AUTHOR]