Synthesis and preliminary enzymatic evaluation of polyol-based 4-phenylbutyrate derivatives

4-Phenylbutyric acid (4-PBA) is clinically used for the treatment of urea cycle disorders and has attracted increasing attention due to its ability to modulate endoplasmic reticulum stress through its dual function as a chemical chaperone and histone deacetylase (HDAC) inhibitor. In addition to its effects on HDACs, 4-PBA also inhibits pyruvate dehydrogenase kinases (PDKs) and enhances mitochondrial respiration in cancer cells. In this work, a series of novel polyol-based 4-PBA derivatives were designed as potential prodrugs, inspired by the clinically used glycerol phenylbutyrate. Sorbitol, xylitol, and erythritol were fully esterified at all hydroxyl groups with 4-PBA under optimized conditions, affording the corresponding derivatives in high yields (≈85-91%). Structural characterization was confirmed by NMR spectroscopy and high-resolution mass spectrometry (HRMS). Preliminary enzymatic hydrolysis studies using porcine pancreatic lipase were conducted on sorbitol phenylbutyrate as a representative liquid, oily polyol derivative. This compound exhibited significantly slower hydrolysis than glycerol phenylbutyrate, suggesting a sustained-release profile. In contrast, the erythritol derivative, due to its highly crystalline nature, failed to form an enzyme-accessible phase in simulated intestinal fluid, precluding enzymatic evaluation and indicating a potential dissolution-limited release mechanism.