Curcumin is recognized for its diverse biological activities, including the ability to induce apoptosis and ferroptosis. Therefore, it represents a promising candidate for the development of new compounds with neuroprotective and anticancer properties. In order to synthesize mimics with improved pharmacokinetic properties (better solubility and stability than curcumin) here, we present the design and synthesis of novel curcumin analogues named Ethylphosphonate-based curcumin mimics (EPs), which preserve the pharmacophoric features of curcumin. New EP mimics were synthesized by tyrosol- and melatonin-based building blocks using an orthogonal protection approach of the different precursors’ OH functions with good yields and in a few steps. Comparative screenings of the cytotoxic and cytoprotective properties (curcumin was used as a reference compound) were carried out on all new mimics in different cell lines (HeLa, A375, WM266, MDA-MB-231, LX2, and HDF). Assays with inhibitors of ferroptosis (Ferrostatin-1, Fer-1) and apoptosis (Quinoline-Val-Asp-difluorophenoxymethyl ketone, Q-VD), in combination with curcumin, suggested the specific cell death pathway (apoptotic or ferroptotic) of EPs, depending on the aromatic moieties contained in them. Interestingly, EP4 exhibited substantial cytotoxic effects against various human cancer cell lines (HeLa, A375, WM266) while sparing normal cells (HDFs). EP4 displayed a five-times-higher toxicity in triple-negative MDA-MB-231 and LX2 stellate cells than curcumin. The cytotoxicity exerted by EP4 involves only an apoptotic mechanism, contrary to curcumin, which exerts both apoptotic and ferroptotic effects. Additionally, EP4 was also found to be a very potent inhibitor of the ubiquitin-activating enzyme E1, reinforcing the anticancer potential of this compound. Furthermore, EP2 possesses high antioxidant properties, efficiently protects against cell death by ferroptosis, and inhibits the amyloid aggregation involved in AD.

Recent phytochemical investigations have demonstrated that Luvunga scandens is a rich source of structurally diverse secondary metabolites; however, its potential antioxidant-active constituents and their underlying mechanisms remain largely unexplored. In this study, an NMR-guided fractionation strategy applied to the rhizomes and leaves of L. scandens led to the isolation of ten limonoids, including three new compounds, Luvungas B–D (3, 4, and 8). Their structures and absolute configurations were determined through extensive spectroscopic analysis, X-ray diffraction, and ECD calculations. Based on the isolated analogues, a biosynthetic pathway is proposed, featuring the metabolic bifurcation of a key acyclic intermediate into the isoobacunoic acid and propellane-type lineages. Biological evaluation revealed that 8 inhibits RSL3-induced ferroptosis in HepaRG liver cells with an EC₅₀ of 16.1 µM. Mechanistic studies demonstrated that, unlike classical antioxidants, compound 8 mitigates lipid peroxidation without exhibiting direct radical-scavenging or iron-chelating activities. These findings suggest that 8 suppresses ferroptosis via non-canonical mechanisms.