Cisplatin-synergistic monoterpene indole alkaloids with diverse scaffolds from Rauvolfia vomitoria

Twelve previously unreported monoterpene indole alkaloids (MIAs), rauvotines A - L (1-12), and thirteen known analogs (13-25), were obtained from Rauvolfia vomitoria. These MIAs were categorized as ajmaline (1,2,13), suaveoline (3, 4, 14, 15), peraksine (5, 6, 16, 17), yohimbine oxindole (7-9, 18), and yohimbine (10-12, 19-25) frameworks, respectively. Structurally, 3 and 4 constituted the first suaveoline-type MIAs characterized by a trans-fused 1H-pyrano[3,4-c]pyridine ring system. 7 represented the first natural yohimbine oxindole MIA with a 7R configuration. Compounds 10-12 were identified as rare N-oxide derivatives of the yohimbine-type framework. Bioactivity evaluation of the sensitizing potential of these isolates revealed that thirteen compounds significantly enhanced the responsiveness of SKOV3 cells to cisplatin, whereas five compounds exhibited comparable potentiation in OVCAR3 cells. Notably, the novel alkaloids 3, 5, and 12 demonstrated dual-cell line sensitization, with 3 notably reducing the IC₅₀ values of cisplatin by 2.15-fold and 3.14-fold in SKOV3 cells and OVCAR cells, respectively. Mechanistic investigations further indicated that 3, 5, and 12 established their effects by inducing S-phase cell-cycle arrest and triggering apoptosis, thereby underscoring R. vomitoria-derived MIAs as promising cisplatin-sensitizing agents for ovarian cancer treatment.