Multidisciplinary investigation of atypical inclusion complexes of beta-cyclodextrin and a phospholipase-A2 inhibitor.
BMS-188184, an anthracene derivative, has been found to form at least two complexes with beta-cyclodextrin. The association/dissociation kinetics of the two complexes were extremely slow, with one complex requiring approximately 24 h, and the other complex requiring more than 8 weeks, to reach equilibrium. The stability constants of the two complexes were estimated at approximately 11,000 and 39,000 M(-1) under nonequilibrium conditions. The slow rates of dissociation allowed the complexes and the unbound BMS-188184 to be separated using high-performance liquid chromatography. Exact mass liquid chromatography/mass spectrometry, tandem mass spectrometry, and nuclear magnetic resonance techniques were used to characterize the stoichiometry of both complexes as 1:1. Because of the ability of the complexes to survive high-performance liquid chromatography analysis, their slow reaction rates, and 1:1 stoichiometry, the complexes were tentatively characterized as [2]-rotaxanes. The available data suggest that the two complexes are conformational isomers.
Dahlheim
C E
CE
Pharmaceutical Research Institute, Bristol-Myers Squibb, One Squibb Drive, P.O. Box 191, New Brunswick, New Jersey 08903-0191, USA. charles.dahlheim@bms.com
Dali
M M
MM
Naringrekar
V H
VH
Miller
S A
SA
Shukla
R B
RB
D001798:Blood Proteins / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D012996:Solutions; D047392:beta-Cyclodextrins / Q000737:chemistry*
D001798:Blood Proteins; C400481:PLIalpha; D012996:Solutions; D047392:beta-Cyclodextrins