Novel Halolactones Derived from Vanillin: Design, Synthesis, Structural Characterization, and Evaluation of Antiproliferative and Hemolytic Activities

A series of novel γ-halo-δ-lactones and δ-halo-γ-lactones bearing a phenolic ring at the β-position were synthesized from vanillin. The divergent seven-step synthetic route commenced with the benzyl protection of the hydroxy group of the starting material, followed by a four-step transformation that led to the corresponding β-aryl-γ,δ-unsaturated carboxylic acids. Subsequent halolactonization (iodo-, bromo-, and chlorolactonization), followed by selective benzyl deprotection, gave the target halolactones. The structures of all intermediates and final lactones were confirmed by comprehensive spectroscopic analyses, including NMR and HRMS. The resulting halolactones were evaluated for antiproliferative activity against two canine (CLBL-1, CLB70) and two human (T-24, CaCo-2) cancer cell lines, as well as non-cancerous mouse embryonic fibroblasts (NIH/3T3). Hemolytic assays were performed to assess toxicity against human red blood cells (RBCs). Among the tested lactones, the <i>trans</i>δ-iodo-γ-lactone was the most active, particularly against CLBL-1 and T-24 cells. All compounds demonstrated no inhibitory effects on normal fibroblasts and no hemolytic toxicity. This favorable selectivity profile positions this group of lactones, particularly <i>trans</i>-δ-iodo-γ-lactone, as a promising candidate for further development as potential anticancer agents.