Evaluation of novel medicinal compounds for therapeutic efficacy against liver cancer

Hepatocellular carcinoma (HCC), the most common type of liver cancer, makes up over 90% of cases and remains a significant global health issue. Early-stage HCC can be treated with hepatectomy or liver transplant, but advanced disease has a poor outlook due to treatment resistance and widespread drug resistance. Sorafenib, the first-line tyrosine kinase inhibitor for advanced HCC, provides only modest gains in overall survival, highlighting the urgent need for new treatments. This need is especially urgent in the Rio Grande Valley (RGV), where liver cancer rates and mortality are higher than the national average due to high rates of obesity, diabetes, metabolic dysfunction-associated steatotic liver disease (MASLD), hepatitis infections, and limited healthcare access. To address these regional and global disparities, this study evaluates four medicinally privileged molecules: 1. DB5 OTFE, 2. DBMG-5, 3. DBNJ-1, and 4. DB-3-OCAS, for their potential anti-cancer effects. Out of these four compounds, 1 and #4 are natural product mimics with beta-lactam moiety at the core, synthesized by a multi-step procedure. Compound#2 is a macrocycle-fused gamma-lactone and #3 is a pentacyclic triterpene, isolated from plants. Human HCC cell lines SK-HEP1, Hep G2, C3A, and Huh7 will be treated with logarithmic dilutions of each compound (10 mM DMSO stocks) and assessed using the MTT viability assay to determine IC₅₀ values. Phase-contrast microscopy will be used to observe morphological changes and confirm cell viability. We hypothesize that these natural compounds will exhibit dose-dependent cytotoxicity against liver cancer cells and that at least one will have significantly lower IC₅₀ values compared to Sorafenib. Expected outcomes include decreased confluency, alterations in cell morphology, and the identification of a lead compound with strong cell-killing activity. The most effective compound will then undergo structural optimization of its functional groups, followed by re-evaluation against HCC cell lines and comparison with Sorafenib to assess its therapeutic potential. Long-term goals include conducting mechanistic studies and potentially progressing to in vivo models. This research supports developing locally relevant therapies aimed at reducing liver cancer disparities in the RGV and contributes to the broader search for accessible, natural-product-based treatments for HCC.