Structural Studies of Piperine Inclusion Complexes in Native and Derivative β-Cyclodextrins

Abstract

Piperine (PN), the primary pungent alkaloid in black pepper shows several biological activities such as antioxidant, antimicrobial and anti-cancerogenic effects. Similar to other alkaloids, PN is characterized by poor water solubility. One way to improve its solubility and thus its biological activities is by forming inclusion complexes with suitable cyclodextrins. In this work PN inclusion complexes in native β-cyclodextrin (β-CD), its methylated (randomly methylated (RM-β-CD), heptakis-(2,6-di-O-methyl)-β-CD (DM-β-CD) and heptakis-(2,3,6-tri-O-methyl)-β-CD (TM-β-CD)) and 2-hydroxypropylated (HP-β-CD) derivatives are investigated using physicochemical methods, such as phase solubility study and X-ray crystallography complemented by theoretical (molecular dynamics simulations) studies. The determination of the crystal structure of the PN inclusion complexes in β-CD, DM-β-CD and TM-β-CD, reveals the formation of 1:2 guest:host inclusion complexes in the crystalline state. The guest PN molecule threads the hydrophobic cavities of the hosts which are arranged as couples in a tail-to-tail mode in the case of PN/β-CD and in a head-to-tail mode in the cases of PN/DM-β-CD and PN/TM-β-CD. MD studies based on the crystallographically determined structures and docked models show the stability of the examined complexes in an aqueous environment whereas the binding affinity of PN for the host molecules is calculated by the MM/GBSA method. Finally, phase-solubility studies of PN with β-CD, RM-β-CD and HP-β-CD are presented, indicating a Bs-type for the PN/β-CD complex and an AL-type for the PN/RM-β-CD and PN/HP-β-CD complexes with 1:1 guest:host stoichiometry.

Isomerism of Cyclodextrin Tetramer Induced by Alkali Halide Cluster Ions Observed by Ion Mobility Spectrometry–Mass Spectrometry

“…Although the multiple intermolecular hydrogen bonds that form between the portal hydroxyls of CD molecules are primarily responsible for the stability of CD assemblies, the presence of metal cations or proper guest molecules can strongly induce the formation of various CD assemblies. − For representative examples, a sandwich-like assembly of γ-cyclodextrin mediated by Cu 2+ ions has been reported by Bagabas et al Furthermore, the assembly structures and isomerism of Cu 2+ -bound cyclodextrin oligomers have been studied by Chakraborty et al In addition, host–guest interactions may also affect the assembly process of CDs. CD assemblies with various guest molecules such as piperine, , curcumin, − coumaric acids, , amino acids, and many more have been investigated. Guest molecules that fit well in the supramolecular cavity of CD assemblies can stabilize the entire assembly structure.…”