Six new (1, 2, 6, 8, 13, and 20) and twenty previously isolated (3-5, 7, 9-12, 14-19, and 21-26) steroids featuring thirteen different carbocycle motifs were isolated from the organic extract of the soft coral Sinularia polydactyla collected from the Hurghada reef in the Red Sea. The structures and the relative configurations of the isolated natural products have been determined based on extensive analysis of their NMR and MS data. The cytotoxic, anti-inflammatory, anti-angiogenic, and neuroprotective activity of compounds 3-7, 9-12, 14-20, and 22-26, as well as their effect on androgen receptor-regulated transcription was evaluated in vitro in human tumor and non-cancerous cells. Steroids 22 and 23 showed significant cytotoxicity in the low micromolar range against the HeLa and MCF7 cancer cell lines, while migration of endothelial cells was inhibited by compounds 11, 12, 22, and 23 at 20 µM. The results of the androgen receptor (AR) reporter assay showed that compound 11 exhibited the strongest inhibition of AR at 10 µM, while it is noteworthy that steroids 10, 16, and 20 displayed increased inhibition of AR with decreasing concentrations. Additionally, compounds 11 and 23 showed neuroprotective activity on neuron-like SH-SY5Y cells
