Meloaxilines A-E, five unprecedented monoterpenoid indole alkaloids from Melodinus axillaris, suppress colorectal cancer by targeting the iron metabolism pathway.

Monoterpenoid indole alkaloids represent a large class of structurally diverse natural products with potent anticancer activity, holding great promise for the discovery of novel antitumor agents with unprecedented mechanisms of action. In this study, five unprecedented monoterpenoid indole alkaloids with fifteen known analogues, were isolated from Melodinus axillaris using HSQC-DeepSAT technology. Particularly, compounds 1-5, which possess a unique 6/5/5/5/5 ring system, represent the first reported examples of N4-C3 bond cleavage in monoterpenoid indole alkaloids. Their structures were elucidated by 1D and 2D NMR, computer-assisted structure elucidation (CASE), DP4/DP4+/DP5 analyses, and ECD calculations. The anti-colorectal cancer activity of compounds 1-20 was evaluated, among which compound 1 demonstrated significant inhibitory effects in both cell models and 3D spherical organoids. Mechanistic investigations demonstrated that compound 1 disrupts cellular iron homeostasis by suppressing the key iron metabolism proteins TFR1 and FPN, thereby inducing ferroptosis.