Structure, supramolecular organization and thermotropic phase behavior of N-acyl tris homologs (n = 9–18): Structural analogs of apoptosis inducing ceramides

Abstract

N-Acyl tris(hydroxymethyl)aminomethanes (N-acyl tris, NATs) are structural analogs of ceramides, which were reported to induce apoptosis either by elevation of ceramide levels or by activation of pro-apoptotic effectors that are physiological targets of ceramide. In this study, we synthesized and characterized a homologous series of NATs bearing saturated acyl chains (n = 9–18) and investigated their supramolecular organization and thermotropic phase behavior. Transition enthalpies and entropies obtained from differential scanning calorimetric studies showed linear dependence on the chain length in both dry and hydrated states. The crystal structure of N-lauroyl tris (NLT), solved in monoclinic system in the P21/c space group, showed that owing to the bulky head group, NLT molecules pack in an interdigitated bilayer fashion. A number of OH⋯O and CH⋯O hydrogen bonds between the hydroxymethyl groups of the head groups of NLT molecules belonging to opposite layers as well as NH⋯O and CH⋯O hydrogen bonds between adjacent molecules belonging to the same layer, besides dispersion interactions between the all-trans hydrocarbon chains, stabilize the overall supramolecular organization of the self-assembled, interdigitated bilayer system. d-Spacings obtained from powder X-ray diffraction studies on all the NATs exhibited a linear dependence on the acyl chain length, suggesting that all of them adopt an interdigitated bilayer structure. These observations are relevant to developing structure-activity relationships for these amphiphiles and their analogs such as ceramides, N-acylserinols, N-acylalaninols and N-bis(2-hydroxyethyl)acylamides.