Evodiamine

Hepatocellular carcinoma (HCC) is a highly lethal malignancy with poor prognosis. The clinical benefits of small-molecule therapeutics represented by sorafenib remain limited, underscoring the urgent need to continuously invest in the discovery of novel anti-HCC lead compounds. In this study, structural optimization of the previously identified compound 6f with anti-HCC potential was conducted through diverse substituent modifications on the A- and E-rings, accompanied by systematic structure-activity relationship (SAR) investigations. This effort led to the identification of a new lead compound, Z4, which exhibited potent nanomolar inhibitory activity against four HCC cell lines (IC₅₀ = 0.08 μM for HepG2, 0.16 μM for SK-Hep-1, 0.03 μM for HuH-7, and 0.03 μM for BEL-7404) as well as a doxorubicin-resistant cell line (IC₅₀ = 0.19 μM for SMMC-7721/DOX). Cell-based phenotypic evaluations further demonstrated that Z4 more effectively inhibited proliferation and migration/invasion of BEL-7404 and HuH-7 cells than sorafenib, while inducing cell cycle arrest, mitochondrial dysfunction, reactive oxygen species (ROS) accumulation, and apoptosis. Mechanistically, Z4 exerts its anti-HCC activity primarily through synergistic inhibition of the cAMP-PKA-CREB and PI3K-AKT-mTOR pathways, with only moderate Topo I inhibition observed at high concentrations. In addition, in vivo studies indicated that Z4 possesses acceptable metabolic stability (T₁/₂ = 8.96 h) and exhibits significantly superior antitumor efficacy compared to sorafenib in a HuH-7 xenograft model. Collectively, this study not only further enriches the SAR of the A-ring of the evodiamine scaffold but also provides a promising lead compound Z4 for anti-HCC drug discovery.

Plant-derived alkaloids have attracted growing attention in Colorectal Cancer (CRC) research because of their diverse biological activities and ability to regulate multiple oncogenic pathways. CRC remains a major cause of cancer-related mortality worldwide despite advances in diagnosis and therapy.

This review summarizes experimental and translational studies investigating the anticancer effects of plant-derived alkaloids in CRC, with emphasis on molecular mechanisms, cancer stem cell signaling, pharmacokinetic limitations, and recent patent-related developments.

Experimental studies have demonstrated that several alkaloids, including berberine, matrine, evodiamine, and palmatine, inhibit CRC progression through the induction of apoptosis, suppression of proliferation, inhibition of epithelial-mesenchymal transition, and modulation of inflammatory and oxidative stress-associated pathways. These compounds also influence signaling pathways frequently dysregulated in CRC, including Wnt/β-catenin, PI3K/Akt/mTOR, MAPK, NF-κB, and JAK/STAT signaling. Recent patents have focused on alkaloid-based formulations, nanotechnology-driven delivery systems, and combination strategies designed to improve therapeutic efficacy and bioavailability.

Although preclinical findings remain promising, most alkaloids investigated in CRC research continue to face limitations, including poor bioavailability, insufficient pharmacokinetic characterization, and limited clinical validation.

Plant-derived alkaloids remain promising candidates for CRC therapy and chemoprevention. Further translational studies, pharmacological optimization, and clinically relevant investigations will be necessary to clarify their therapeutic applicability in CRC.