Diverse Monoterpene Indole Alkaloids with Unprecedented Chemical Architectures from <i>Rauvolfia vomitoria</i> and Their Potential as Cisplatin Sensitizers

Four novel monoterpene indole alkaloids, designated rauvolvomines A–D ( 1 – 4 ), were isolated from Rauvolfia vomitoria and characterized as potent platinum-based sensitizers possessing unusually diverse carbon skeletons. Their structures were elucidated through comprehensive spectroscopic analysis, single-crystal X-ray diffraction, and ECD calculations. Rauvolvomines A ( 1 ) and B ( 2 ) shared a novel 6/5/5/6/6 pentacyclic scaffold featuring a caged 7-aza-tricyclo[4.3.1.0 3,8 ]decane core fused to an indole moiety. Rauvolvomine C ( 3 ) possessed an unprecedented 6/5/5/5/6/6 hexacyclic skeleton incorporating an extra furan ring, based on the rare class of sarpagine-oxide alkaloids characterized by a 5′ H -spiro[indoline-3,1′-[3,7]methanoindolizin]-2-one core. Rauvolvomine D ( 4 ) represented the first example of a rearranged 18(19→21)- abeo sarpagine-oxide alkaloid. Plausible biosynthetic pathways were proposed. Biologically, skeletons 1 and 3 demonstrated strong synergy with cisplatin across SKOV3 and OVCAR3 cell lines (CI < 0.6), while 2 and 4 enhanced cisplatin sensitivity specifically in SKOV3 cells. Skeletons 1 and 3 were particularly effective in potentiating cisplatin’s cytotoxicity, leading to a significant 1.48- to 5.14-fold reduction in its IC 50 values by potently inducing S-phase arrest and promoting apoptosis. These findings highlighted novel skeletons 1 and 3 as promising molecular scaffolds for development as cisplatin sensitizers in the treatment of ovarian cancer.