From Chemoenzymatic Synthesis to Biological Effects: Enantiomerically Enriched Vanillin-Derived δ-Iodo-γ-Lactones as Modulators of Cancer Cell Viability and Inducers of Cell Death

Abstract

Enantiomerically enriched vanillin-derived cis- and trans-β-aryl-δ-iodo-γ-lactones were synthesized using a chemoenzymatic pathway based on Candida antarctica lipase B (CALB)-catalyzed transesterification of racemic (E)-4-(4′-benzyloxy-3′-methoxyphenyl)but-3-en-2-ol, followed by Claisen rearrangement, hydrolysis, iodolactonization, and deprotection. The trans orientation of substituents on the γ-lactone ring of the target compounds was identified as the key structural feature enhancing cell-viability-reducing activity against selected human cancer cell lines. No statistically significant differences were observed between the enantiomerically enriched pairs of the studied lactones: the most active trans-δ-iodo-γ-lactones, 7b, exhibited similarly high potency (IC50 = 3.98 ± 2.60 μM and 5.08 ± 1.30 μM) against the multidrug-resistant (MDR) gastric adenocarcinoma cell line EPG85-257RDB. Their IC50 values were not significantly different from that determined for doxorubicin under the same experimental conditions (IC50 = 5.48 ± 0.75 μM). Notably, both enantiomers exhibited high selectivity indices (SI = 9.22 and 10.19, respectively). TUNEL analysis demonstrated that enantiomer (4R,5S,6R)-7b induced concentration-dependent DNA fragmentation, increasing the percentage of TUNEL-positive cells from 8.30 ± 0.95% to 74.10 ± 4.26%. Flow cytometric analysis further revealed the pronounced accumulation of cells in the G2/M phase, with up to 55.25 ± 2.74% of cells detected at the highest tested concentration. The observed activity of enantiomerically enriched vanillin-derived trans-β-aryl-δ-iodo-γ-lactone 7b in the multidrug-resistant EPG85-257RDB cell line warrants its further investigation in additional drug-resistant cancer models.