Lipid Headgroup-Dependent Interactions of an Isovanillin Derivative with DPPC and DPPS Langmuir Monolayers

The interaction of bioactive compounds with lipid membranes strongly influences their biological activity and selectivity. In this study, the interfacial behavior of an isovanillin derivative (1) was investigated using Langmuir monolayers of DPPC and DPPS as models of zwitterionic non-tumorigenic and anionic tumor-associated membranes, respectively. Surface pressure-area isotherms, surface compressional modulus, relaxation assays, PM-IRRAS, and Brewster angle microscopy (BAM) were employed to evaluate the effects of the compound on monolayer organization and mechanics. (1) incorporated into both lipid monolayers at low surface pressures, promoting film expansion and perturbation of lipid packing. However, the interaction became strongly lipid-dependent at membrane-relevant pressures. In DPPC monolayers, the compound remained more persistently associated with the interface, promoting monolayer condensation together with a reduction in compressional modulus, indicating formation of a more compact but mechanically softer film. PM-IRRAS and BAM analyses revealed perturbations in the phosphate, carbonyl, and acyl-chain regions accompanied by significant morphological heterogeneity. In contrast, DPPS monolayers exhibited a more dynamic interaction. Although expansion and softening effects were observed at low pressures, compression induced partial exclusion or redistribution of the compound from the anionic film, resulting in partial recovery of DPPS-like mechanical behavior at higher surface pressures. PM-IRRAS demonstrated strong perturbation of the phosphate and carbonyl regions together with increased acyl-chain disorder. Overall, the results demonstrate that the interaction of (1) with lipid monolayers is strongly governed by lipid headgroup chemistry, hydration, and packing state. The distinct behavior observed for DPPC and DPPS provides mechanistic insight into the lipid-dependent interfacial activity and possible selective biological effects of isovanillin derivatives.