Synthesis and biological evaluation of mixed aryl-alkyl succinates as modulators of autophagy and apoptosis in gastric carcinoma

Vitamin E succinate and its derivatives have demonstrated encouraging cytotoxic potential in preclinical models of gastric cancer, paving the way for a novel class of therapeutics. Building on a previously described synthetic methodology based on the alkoxy-aryloxycarbonylation of alkenes, this study reports the investigation of the antitumor effects in gastric cancer models of mixed aryl-alkyl succinates esters featuring various substituents on the backbone. Nine compounds were screened for cytotoxicity against AGS and KATO III gastric cancer cell lines. The most active compounds - 2d (R = (CH2)4CH3), 2a (R = Ph), and 2c (R = CH2CH2Ph) - were further evaluated for efficacy, with 2d emerging as the most potent agent (IC50 30.9 μM in AGS; IC50 19 μM in KATO III). Mechanistically, 2d enhanced the expression of activated/cleaved Caspase-3, augmented PARP cleavage, and promoted LC3B lipidation - indicative of programmed cell death. Consistently, ultrastructural analysis of 2d-treated cancer cells revealed morphological hallmarks of both early and late apoptosis, including cytoplasmic vacuolization and autophagic vacuoles. Conversely, treatment with compound 2d did not affect the expression of apoptosis markers in healthy GES-1 gastric epithelial cells, suggesting a favorable safety profile. Overall, our findings provide insights into how specific structural features of succinate derivatives contribute to their antitumor activity, laying the groundwork for the design of more potent succinate-based agents.