Structure and supramolecular organization of N-acylserinols: agonists of the G-protein coupled receptor, GPR-119

Abstract

N-acyl serinols, the amphiphilic molecules produced by gastrointestinal bacteria regulate metabolic hormone production and glucose homeostasis in the host species, and also exhibit anti-cancer activity. In this study, molecular structure, supramolecular organization and intermolecular interactions of two N-acylserinols (NASOHs), viz., N-nonanoylserinol (N9SOH) and N-pentadecanoylserinol (N15SOH), are determined by single-crystal X-ray diffraction. The molecular structure and packing are compared and discussed with the structurally related molecules, N-acylethanolamine (NAE) and N-acyl tris (NAT) as NASOHs and NATs are derived by substituting one/two α-hydrogen(s) (with respect to amide N-H) of NAE with hydroxymethyl group(s). Structures of N9SOH and N15SOH were solved in the triclinic system in the P-1 space group and both molecules are organized in a tilted head-to-head (and tail-to-tail) manner, resembling a bilayer membrane. The acyl chains in N9SOH and N15SOH are tilted by 20.43° and 18.12°, respectively, with respect to the bilayer normal. Several N—H⋯O, O—H⋯O, and C—H⋯O hydrogen bonds between the hydroxyl and amide moieties of the head groups of NASOH molecules belonging to adjacent and opposite layers stabilize the overall supramolecular organization. These results suggest that the α-hydroxymethyl groups exhibit considerable influence on the crystal structure, molecular packing, and phase structure of these amphiphiles.

Graphical abstract

Removing one of the CH₂OH moieties of N-acylserinol gives N-acylethanolamine, whereas introducing one more CH₂OH moiety on the α-carbon gives N-acyltris. While both N-acylethanolamine and N-acylserinol adopt tilted bilayer structure, the larger head group of N-acyltris induces it to adopt an interdigitated bilayer structure.