Quinones/hydroquinones constitute a family of metabolites, widespread in nature, with a wide range of biological activities, including cytotoxicity to cancer cells. Recently, hierridin B, a methylated hydroquinone derivative with a C15 aliphatic chain isolated from the marine picocyanobacterium Cyanobium sp. LEGE06,113, was identified as moderate inhibitor of the growth of colon adenocarcinoma HT-29 cell line, with a GI₅₀ of 100.2 µM. In order to obtain new structurally-related quinone/hydroquinone with improved antiproliferative activity in cancer cell lines, the demethylated hierridin B derivative, norhierridin, as well as structurally-related quinone, were synthesized and evaluated for their growth inhibitory effect in a panel of human tumor cell lines. Norhierridin B showed a great improvement of the antitumor activity when compared to hierridin and its structurally-related quinone with a potent growth inhibitory effect on all cancer cell lines, being the growth inhibitory effect on MDA-MB-231 cells associated with cell cycle arrest and apoptosis. Norhierridin B interfered with several p53 transcriptional targets, increasing p21, Bax, and MDM2, while decreasing Bcl-2 protein levels, which suggested the potential activation of a p53 pathway. Particularly, norhierridin B displayed a prominent growth inhibitory activity against TNBC cells, which are characterized by high therapeutic resistance.