Melomortsine A - D, unprecedented quinoline alkaloids with anti-breast cancer brain metastasis activity from Melodinus morsei Tsiang.

Four unprecedented alkaloids, melomortsines A-D (1-4), and 13 known alkaloids were isolated from Melodinus morsei Tsiang. Melomortsine A, a monoterpenoid quinolone alkaloid, had an unprecedented 6/6/5/5/5 pentacyclic quinolone alkaloid skeleton. Detailed nuclear magnetic resonance spectra analysis, electronic circular dichroism calculations, and X-ray crystallographic analysis were used to elucidate their structures. These compounds could inhibit the pro-inflammatory cytokine and chemokines secretion, and compound 1 exhibited the strongest inhibitory effect. Scandine N4-oxide (5) significantly inhibited 4T1-BrM by reducing both polymorphonuclear and monocytic myeloid-derived suppressor cells (MDSCs) to remodel immune microenvironment in the brain. Mechanistically, scandine N4-oxide inhibited the secretion of chemokines by regulating JAK2/STAT3 signaling pathway of M2 type microglial cells, thereby suppressing the recruitment of MDSCs. Overall, scandine N4-oxide can effectively inhibit the process of BrM in breast cancer, providing a new potential strategy for the therapeutic of breast cancer BrM.