Novel biselyngbyaside analogs, biselyngbyolide C (1) and biselyngbyasides E (2) and F (3), were isolated from the marine cyanobacterium Lyngbya sp., collected on Ishigaki Island, Japan. The gross structures of 1–3 were determined by NMR spectral analyses, and their stereochemistries were established based on NOESY spectra and CD data. These compounds inhibited the growth of HeLa and HL60 cells. From the results of an MTT assay, the geometry of the trisubstituted olefin in the side chain and the lack of the sugar moiety were found to be important for the biological activity. In addition, 1 was found to exhibit ER stress- and apoptosis-inducing activities in HeLa cells.

trans-2-Phenylcycloproylamine (trans-PCPA) has been used as the scaffold to develop covalent-binding inhibitors against lysine-specific demethylase 1 (LSD1/KDM1A), a therapeutic target for several cancers. However, the effects of different structural moieties on the inhibitory activity, selectivity, and reactivity of these derivatives, including the cis isomers, against LSD1 and its paralogue LSD2/KDM1B are not fully understood. Here we synthesized 65 cis- and trans-PCPA derivatives and evaluated their inhibitory activity against LSD1 and LSD2. One of the derivatives, 7c (cis-4-Br-2,5-F₂-PCPA; S1024), inhibited LSD1 and LSD2 with K _i values of 0.094 μM and 8.4 μM, respectively, and increased the level of dimethylated histone H3 at K4 in CCRF-CEM cells. A machine learning-based regression model (Q ² = 0.61) to predict LSD1-inhibitory activity was also constructed and showed a good prediction accuracy (R ² = 0.81) for 12 test-set compounds, including 7c. The present methodology would be useful when designing covalent-binding inhibitors for other enzymes.