In a continuing study, we explored how the individual rings in neo-tanshinlactone (1) influence its potent and selective in vitro anti-breast cancer activity. Accordingly, we discovered a novel class of anti-breast cancer agents, 2-(furan-2-yl) naphthalen-1-ol derivatives, based on an active C-ring opened model compound 5. Further optimization led to 18 and 21, which showed decreased cytotoxic potency, but better selectivity than neo-tanshinlactone analog 2. Interestingly, compound 20 showed broad cytotoxicity against human cancer cell lines.