314
that each NMR technique is applied with the view of resolving a
variety of distinct biological issues.
In an attempt to approach and comprehend different issues
related to drug:cyclodextrin (CD) complexation, a wide range of
NMR techniques for liquids and solids have been applied. Of these
two, NMR for liquids is the most often applied, while solid-state
(ss) NMR is the latest technologically evolving.
High-resolution NMR for liquids: One significant feature of
liquid NMR spectroscopy, and specifically
1
H NMR spectroscopy,
is that it can provide quantitative information through the measurement of the intensities of the peaks that compose the NMR
spectrum [4–6]. For this reason, NMR spectroscopy has been used
across a great number of studies in order to obtain quantitative
information for several pharmaceutical systems [6–9].
In addition, liquid NMR spectroscopy provides the appropriate environment to study CDs, since the driving force for drug:CD
complexation is of solvophobic nature [10]. Nuclear Overhauser
effect (NOE) has been used as a key weapon to record quantitative
space correlations [11–13]. Thus, NOE can provide valuable information about conformational details of complexes. Hydrogen
bonding (intramolecular as well as intermolecular) in CD complexes can also be observed by NMR experiments [10, 14, 15].
NMR chemical shift titration is another suitable method to
obtain information on the association constants and stoichiometry
of the CD inclusion complexes as well as conformations of complexes [16–19]. Chiral discrimination of pharmaceutical compounds can be achieved using cyclodextrins and conclusions can be
derived from liquid NMR spectroscopy [20, 21]. The upshot of
this application is that a drug containing a chiral center can be
inserted into a cyclodextrin, to generate diastereoisomers that are
detectable by NMR spectroscopy.
An interesting conclusion (derived also by NMR) about Z or
E configuration was reported in case of indomethacin. This molecule is found to be present in an E/Z mixture (whose stereoisomers are of amide type). The stereoisomers interchange rapidly.
After complexation, NMR NOE experiments as well as molecular
mechanics calculations showed a preference to Z configuration
[16, 22].
Isotope labeling strategy (
15
N,
13
C,
2
H) is applicable mainly for
shedding light on the protein-ligand interactions. An example of
the utility of this strategy was reported in solution NMR studies of
a 42 KDa Escherichia coli maltose-binding protein/β-cyclodextrin
complex [23]. The hard task of reporting weak intermolecular
NOEs among many strong intramolecular ones is thus facilitated
by the isotope labeling.
NMR spectroscopy for solids: ssNMR is applicable in insoluble
molecules and finds wide scope of applications in molecular biology.
Dimitrios Ntountaniotis et al.
that each NMR technique is applied with the view of resolving a
variety of distinct biological issues.
In an attempt to approach and comprehend different issues
related to drug:cyclodextrin (CD) complexation, a wide range of
NMR techniques for liquids and solids have been applied. Of these
two, NMR for liquids is the most often applied, while solid-state
(ss) NMR is the latest technologically evolving.
High-resolution NMR for liquids: One significant feature of
liquid NMR spectroscopy, and specifically
1
H NMR spectroscopy,
is that it can provide quantitative information through the measurement of the intensities of the peaks that compose the NMR
spectrum [4–6]. For this reason, NMR spectroscopy has been used
across a great number of studies in order to obtain quantitative
information for several pharmaceutical systems [6–9].
In addition, liquid NMR spectroscopy provides the appropriate environment to study CDs, since the driving force for drug:CD
complexation is of solvophobic nature [10]. Nuclear Overhauser
effect (NOE) has been used as a key weapon to record quantitative
space correlations [11–13]. Thus, NOE can provide valuable information about conformational details of complexes. Hydrogen
bonding (intramolecular as well as intermolecular) in CD complexes can also be observed by NMR experiments [10, 14, 15].
NMR chemical shift titration is another suitable method to
obtain information on the association constants and stoichiometry
of the CD inclusion complexes as well as conformations of complexes [16–19]. Chiral discrimination of pharmaceutical compounds can be achieved using cyclodextrins and conclusions can be
derived from liquid NMR spectroscopy [20, 21]. The upshot of
this application is that a drug containing a chiral center can be
inserted into a cyclodextrin, to generate diastereoisomers that are
detectable by NMR spectroscopy.
An interesting conclusion (derived also by NMR) about Z or
E configuration was reported in case of indomethacin. This molecule is found to be present in an E/Z mixture (whose stereoisomers are of amide type). The stereoisomers interchange rapidly.
After complexation, NMR NOE experiments as well as molecular
mechanics calculations showed a preference to Z configuration
[16, 22].
Isotope labeling strategy (
15
N,
13
C,
2
H) is applicable mainly for
shedding light on the protein-ligand interactions. An example of
the utility of this strategy was reported in solution NMR studies of
a 42 KDa Escherichia coli maltose-binding protein/β-cyclodextrin
complex [23]. The hard task of reporting weak intermolecular
NOEs among many strong intramolecular ones is thus facilitated
by the isotope labeling.
NMR spectroscopy for solids: ssNMR is applicable in insoluble
molecules and finds wide scope of applications in molecular biology.
Dimitrios Ntountaniotis et al.