Cyclodextrin/imatinib complexation: binding mode and charge dependent stabilities.
Host-guest interactions in various protonation forms of the anticancer drug imatinib with beta-cyclodextrin (CD) and randomly methylated beta-CD (RAMEB) have been investigated using techniques of proton magnetic resonance spectroscopy ((1)H NMR), phase solubility, pH-potentiometry and electrospray ionization mass spectrometry (ESI-MS). Phase-solubility analysis showed A(L)-type diagram with beta-CD, which suggested the formation of 1:1 inclusion complexes. The 1:1 stoichiometry was confirmed by potentiometry in aqueous solution and by ESI-MS in the gas phase. Charge-specific stability constants of the neutral, mono-, di-, and tricationic forms of imatinib were determined for both the beta-CD and RAMEB. Stability of the beta-CD complexes shows an unexpected minimum at the monoprotonated form, while a stepwise decrease with increasing guest charge was observed for RAMEB. The 1:1 complex stoichiometry and stability constants of selected imatinib protonation species were verified by (1)H NMR titrations. Two-dimensional rotating frame nuclear Overhauser effect spectroscopy (ROESY) experiments were carried out to identify the interacting host-guest moieties. The observed ROESY cross-peaks indicated spatial proximities between several aromatic hydrogens of imatinib and beta-CD protons, revealing that the inclusion occurs by accommodation of the benzamide ring of imatinib.
Béni
Szabolcs
S
Semmelweis University, Department of Pharmaceutical Chemistry, Research Group for Drugs of Abuse and Doping Agents, Hungarian Academy of Sciences, H-1092 Budapest, Hogyes E.u.9., Hungary.
Szakács
Zoltán
Z
Csernák
Orsolya
O
Barcza
Lajos
L
Noszál
Béla
B
D000970:Antineoplastic Agents / Q000737:chemistry; D001549:Benzamides / Q000737:chemistry; D001665:Binding Sites; D001667:Binding, Competitive; D004355:Drug Stability; D000068877:Imatinib Mesylate; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D015394:Molecular Structure; D010879:Piperazines / Q000737:chemistry*; D011743:Pyrimidines / Q000737:chemistry*; D012995:Solubility; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods; D013678:Technology, Pharmaceutical / Q000379:methods / Q000639:trends; D047392:beta-Cyclodextrins / Q000737:chemistry*
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D047392:beta-Cyclodextrins; C037689:benzamide; D000068877:Imatinib Mesylate