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© 2021 American Chemical Society.1–Deoxynojirimycin, an α–glucosidase inhibitor, possesses various biological activities such as antitumor, antidiabetic, and antiviral effects. However, the application of 1–deoxynojirimycin is restricted by its poor lipophilicity and low bioavailability. In this study, three 1–deoxynojirimycin derivatives (8–10) comprising 1–deoxynojirimycin and kaempferol were designed and synthesized to modify their pharmacokinetics and improve their antitumor efficacy. Among them, compound 10, a conjugate of 1–deoxynojirimycin and kaempferol linked through an undecane chain, exhibited excellent lipophilicity, antiproliferative effects, and α–glucosidase inhibitory activity. Compared with 1–deoxynojirimycin, kaempferol, and their combination, compound 10 downregulated cyclooxygenase–2 (COX–2) expression, arrested the cell cycle at the S phase, induced cellular apoptosis, and inhibited the migration of MCF–7 cells. Moreover, further investigation indicated that compound 10 induced MCF–7 cell apoptosis through a mitochondrial–mediated pathway via the loss of mitochondrial membrane potential. This led to increasing intracellular levels of reactive oxygen species (ROS) and Ca2+, the downregulation of Bcl–2 expression, and the upregulation of Bax levels.
