Study of the Structural Chemistry of the Inclusion Complexation of 4-Phenylbutyrate and Related Compounds with Cyclodextrins in Solution: Differences in Inclusion Mode with Cavity Size Dependency

4-phenylbutyrate (PB) and structurally related compounds hold promise for treating many diseases, including cancers. However, pharmaceutical limitations, such as an unpleasant taste or poor aqueous solubility, impede their evaluation and clinical use. This study explores cyclodextrin (CD) complexation as a strategy to address these limitations. The structural chemistry of the CD complexes of these compounds was analyzed using phase solubility, nuclear magnetic resonance (NMR) spectroscopic techniques, and molecular modeling to inform the choice of CD for such application. The study revealed that PB and its shorter-chain derivative form 1:1 alpha CD complexes, while the longer-chain derivatives form 1:2 (guest:host) complexes. alpha CD includes the alkyl chain of the shorter-chain compounds, depositing the phenyl ring around its secondary rim, whereas two alpha CD molecules sandwich the phenyl ring in a secondary-to-secondary rim orientation for the longer-chain derivatives. beta CD includes each compound to form 1:1 complexes, with their alkyl chains bent to varying degrees within the CD cavity. gamma CD includes two molecules of each compound to form 2:1 complexes, with both parallel and antiparallel orientations plausible. The study found that alpha CD is more suitable for overcoming the pharmaceutical drawbacks of PB and its shorter-chain derivative, while beta CD is better for the longer-chain derivatives.