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6-Substituted 5,8-O-dimethyl-1,4-naphthoquinones (6-DMNQ), the promising anticancer scaffolds, were selectively generated by oxidative demethylation of 2-substituted 1,4,5,8-tetramethoxynaphthalenes with CAN in EtOAc/H₂O in comparatively high yields. An interesting finding was that apart from the reported electron-withdrawing effects of substituents on position 2 of naphthalene ring, regioselective synthesis of 6-DMNQ was largely dependent on the steric effects in CAN-mediated oxidation. The selective cytotoxicities of 6-DMNQ from the in vitro cell-based assays were exhibited between the cancer cells and normal cells. Moreover, most of sulfur-containing 6-DMNQ derivatives displayed better anticancer activities than the corresponding oxygen-containing ones, which could provide an available strategy for the design of 6-DMNQ derivatives as potential anticancer agents.