Study of inclusion complexes of acridine with β‐ and (2,6‐di‐O‐methyl)‐β‐cyclodextrin by use of solubility diagrams and NMR spectroscopy

Abstract

Previous molecular modeling studies, in our laboratory, have shown that some esters of type RCOO(CH2) nC5H5N+Cl− are potentially active against Alzheimer's disease. We have also demonstrated that acridine, which has strong anticholinesterase activity appears to be a suitable R substituent. The main obstacle to the possible pharmaceutical application of these compounds is their limited solubility in water, which is due to the poor aqueous solubility of acridine itself (0.26 mM). Inclusion complexation with cyclodextrins may overcome this problem. Solubility diagrams and NMR spectroscopy were used to study the inclusion of acridine (Acr) within β‐cyclodextrin (βCD) and heptakis(2,6‐di‐O‐methyl)cyclomaltoheptose (DMβCD). A 1:1 complex was formed for the Acr–βCD system and both 1:1 and 2:1 complexes for the Acr–DMβCD system (apparent Ka 215 ± 20 and 1150 ± 100 M −1, respectively). Data from 1H NMR studies corrected the assignment of the acridine H1, H8 and H4, H5 protons in D2O, which have been erroneously assigned in previous publications. 1H spin–lattice relaxation times T1 measured with selective, non‐selective and null inversion characterize the dynamics of the inclusion complexes. Geometric features of the host–guest inclusion complexes were inferred from intermolecular dipolar interactions obtained by 2D adiabatic off‐resonance ROESY experiments. A more detailed picture of the structure of the inclusion complexes was obtained by combining NMR structural data and molecular modeling (docking, dynamics under NMR constraints and energy calculations). Copyright © 2002 John Wiley & Sons, Ltd.

Enhanced Antiproliferative Activity of the New Anticancer Candidate LPSF/AC04 in Cyclodextrin Inclusion Complexes Encapsulated into Liposomes

“…According to the literature, phase solubility analysis is one of the preliminary requirements for developing a drug/cyclodextrin inclusion complex as it permits an evaluation of the affinity between the drug molecule and cyclodextrin (21). Many researchers have used this approach to determine the molar ratio in which a drug can form a complex with cyclodextrins (11)(12)(13)(14). However, the phase solubility profiles do not demonstrate the formation of inclusion complexes; they only describe how the increasing cyclodextrin concentration influences drug solubility.…”

“…A greater number of reports mentioned the use of cyclodextrins in the formation of inclusion complexes with hydrophobic drugs, including acridine derivatives, for enhancement of their solubility (9)(10)(11)(12)(13)(14).…”

Self-Association of Cyclodextrins and Cyclodextrin Complexes

“…[4][5][6][7] It has also been shown that cyclodextrins are, like noncyclic oligosaccharides, able to form non-inclusion complexes. [8][9][10][11][12][13] For example, Gabelica et al 8,9 have reported that a-cyclodextrin forms both inclusion and noninclusion complexes with a,o-dicarboxylic acids and that the two types of complexes coexist in aqueous solutions. By comparing a-cyclodextrin complexes with those of maltohexaose, a linear analog of a-cyclodextrin, the authors were able to show that the 1:1 a,o-dicarboxylic acid/a-cyclodextrin complexes are mainly inclusion complexes whereas 2:1 complexes, formed by additional complex formation between a given acid and a 1:1 complex, are non-inclusion complexes.…”

Encapsulation of Vitamin C into β‐Cyclodextrin for Advanced and Regulatory Release

“…Any two protons that are located within 0.4 nm in space can produce a nuclear overhauser effect (NOE) cross-correlation in NOE spectroscopy (NOESY) or rotating-frame NOE spectroscopy (ROESY) [23,24]. In the structure of β-CD the H3 and H5 protons are situated inside the conical cavity, particularly, the H3 are placed near the wider rim while H5 are placed near the narrower rim, the other H1, H2 and H4 protons are located at the exterior of the β-CD molecule (Figure 3) [25,26].…”