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Combinatorial Chemistry &
High Throughput Screening
ISSN: 1386-2073
Combinatorial Chemistry &
High Throughput Screening
Volume 10, Number 5, June 2007
Contents
Supramolecular Devices for the High-Throughput Screening
of Drugs, Nutrients and Metabolites in Postgenomic Era (Part
1)
Guest Editor: Grzegorz Bazylak
Editorial Pp.
299-300
Review Articles
Solution Phase Enantioselective Recognition and Discrimination
by Electrospray Ionization –Mass Spectrometry: State-of-the-Art,
Methods, and an Eye Towards Increased Throughput Measurements
Pp. 301-316
Kevin A. Schug
[Abstract]
High-Throughput Screening and Optimization Approaches
for Chiral Compounds by Means of Microfluidic Devices
Pp. 317-325
Debby Mangelings and Yvan V. Heyden
[Abstract]
Homochiral Drug Design and Development by Racemization
Pp. 326-335
Imran Ali
[Abstract]
Dendrimer-Based Prodrugs: Design, Synthesis, Screening
and Biological Evaluation Pp. 336-349
Yiyun Cheng, Yang Gao, Tingling Rao, Yiwen Li and Tongwen
Xu
[Abstract]
Research Articles
Thermodynamics of Molecular Recognition of Bile Salts
by 3,6’-(Oligoethylenediamino- Bridged) β-Cyclodextrin
Dimers Pp. 350-357
Yu Liu, Shu Kang, Yong Chen, Rui Cao and Jun Shi
[Abstract]
Screening of Mucoadhesive Microparticles Containing
Hydroxypropyl-Beta-Cyclodextrin for the Nasal Delivery of
Risperidone Pp. 358-367
Mario Jug and Mira Becirevic-Lacan
[Abstract]
Biomimetic PAMAM-Poly(Benzyl L-Glutamate) Amphiphiles
with Multi-Armed Architecture: Synthesis, Physical Properties
and Self-Assembled Nanoparticles Pp. 368-376
Hui Huang, Chang-Ming Dong and Yen Wei
[Abstract]
Screening of Antioxidant Compounds During Sprouting
of Brassica oleracea L. var. costata DC
Pp. 377-386
Carla Sousa, Graciliana Lopes, David M. Pereira, Marcos
Taveira, Patrícia Valentão, Rosa M. Seabra,
José A. Pereira, Paula Baptista, Federico Ferreres
and Paula B. Andrade
[Abstract]
Comparison of the Chromatographic Behavior of Tricyclic
Neuroleptics on Calixarene- Bonded, Monolithic and Conventional
RP-HPLC Columns Pp. 387-396
Hisham Hashem and Thomas Jira
[Abstract]
Abstracts
[Back to top]
Editorial
One of the high impact events to celebrate during
2007 is the 40th anniversary
of the publication of the first supramolecular chemistry paper
(Pedersen, C.J. J. Am. Chem. Soc., 1967,
89, 2495-2496) and its coincidence with the 20th
anniversary of the Nobel Prize recognizing the pioneers in
this field, namely, Charles J. Pedersen (1904-1989), Donald
J. Cram (1919-2001) and Jean-Marie Lehn (1939). The vigorous
and impressive development of various supramolecular concepts
since then has enabled the fashionable ‘nano’
boom of today and the current global investment in nanotechnology-based
industry. Indeed, the basic supramolecular chemistry concept
combined with the possibility to recognize, control and manipulate
molecular information is still seminal and by dynamic exploration
of the structure-energy hypersurface would lead to construction,
testing and, quite soon, large-scale production of light driven
autonomous artificial molecular machines and/or their natural-artificial
hybrids for clinical analysis, drug delivery and more sophisticated
therapeutic treatment related to tissue modification and engineering.
Before this optimistic view will be realized, the supramolecular
dynamics approach should enable construction of a range of
high throughput screening (HTS) devices, arrays and robotics
for systematic assay of vast amounts of synthetic and natural
compounds to find candidates with desirable bioactive properties.
Some of these HTS concepts will soon evolve to more complicated
HTS machines enabling a fast, reproducible and high content
screening of variable dynamic self-recognition, self-organization
and self-optimization nanoscale phenomena leading to molecular
and supramolecular diversity, activity and reproduction of
interacting entities, e.g., receptors and drugs. Examples
of such solutions from HTS progress will be illustrated in
a three part special issue of Combinatorial Chemistry
& High Throughput Screening entitled, Supramolecular
devices for the high-throughput screening of drugs, nutrients
and metabolites in postgenomic era, which commemorates
the excellence of the scientific work, sophisticated achievements
and vision of the noble supramolecular chemistry founders.
Part 1, presented in the current issue, includes papers related
to HTS that concern chiral and molecular recognition properties
of synthetic and natural small molecules, as drug-like candidates
or real metabolites and their macrocyclic nano-carriers. These
considerations are discussed in the review paper by Schug
which describes the current status and future prospects of
electrospray ionization mass spectrometry that is enabling
solution phase multiplexed HTS of nanosized samples of chiral
analytes and quantitative characteristics of non-covalent
enantiomeric discrimination and recognition processes observed
in thousands of self-assembling and binding drug-carrier or
drug-target systems. In addition, the minireview paper by
Mangelings and Vander Heyden describes the recent advances
in construction and use of microfluidic and microchip supramolecular
devices employed in various chromatographic modes for the
high resolution and accelerated HTS of minute amounts of drug
enantiomers and labeled small molecule building blocks in
time of miliseconds. Similarly, the review paper by Ali presents
some in vitro and in vivo urgent needs and
challenges related to homochiral drug design, selection, development,
therapeutic application, and side effects monitoring, thus
implying the importance of implementating dedicated, miniaturized,
and high content HTS procedures for such these emerging studies.
One approach to solving these problems is modification of
the pharmacological properties of homochiral drugs by the
use of macrocyclic compounds as drug nano-carriers and prodrug
nano-scaffolds. This approach is elaborated in the mini-review
paper by Cheng et al., describing the covalent and
cleavable conjugation of various drugs to the surface of dendrimers
followed by their modification, molecular tuning and nanopatterning
to fit highly specific therapeutic demands. Subsequently,
a mini-series of three research papers is presented by Liu
et al., Jug et al., and Dong et al.,
describing in-depth studies on the formation, stability and
pharmacological property screening of preorganized nano-structures
and nano-particles using, respectively, oligoalkylamine bridged
β-cyclodextrin
dimers, hydroxypropyl-β-cyclodextrin
monomers and multi-armed helical polypeptide amphiphiles.
The last two research papers in this issue by Andrade and
Jira, with their collaborators illustrate the range of currently
available HPLC techniques employing supramolecular host-guest
stationary phases, e.g., octadecylsilica versus calixarene
bonded silica, for HTS of natural phenolic antioxidant compounds
and tricyclic neuroleptics, respectively. The highly selective
separation of positional and E/Z isomers of these
compounds is described in these reports as well as some preliminary
data indicating the attractive possibility of the use of calixarenes
as nano-carriers for these compounds and drugs.
All the papers in Part 1 of this special issue of Combinatorial
Chemistry & High Throughput Screening share one vital
opinion representing a fundamental supramolecular principle,
that molecular recognition and self-assembly at biological
interfaces hold great promise for the development of decision
making biomolecules and topspin drugs. Exploiting the adaptive
and evolutionary aspects of this approach will undoubtedly
constitute the next stage of supramolecular chemistry and
impact, in the near future, the development of triggered and/or
targeted drug release systems, including compatible HTS.
Grzegorz Bazylak
Department of Pharmaco-Bromatology & Molecular Nutrition
Faculty of Pharmacy, Collegium Medicum
Nicolaus Copernicus University
PL-85067 Bydgoszcz
Poland
E-mail: gbazylak@cm.umk.pl
[Back to top]
Solution Phase Enantioselective Recognition and Discrimination
by Electrospray Ionization –Mass Spectrometry: State-of-the-Art,
Methods, and an Eye Towards Increased Throughput Measurements
Kevin A. Schug
A review is given from the stand-point of applying methods
utilizing electrospray ionization – mass spectrometry
(ESI-MS) for quantitative binding (affinity and selectivity)
determinations in small molecule host-guest (receptor-ligand,
selector-selectand, etc.) systems. Advantages over more commonly
utilized and traditional solution phase approaches, both in
the context of developing new chiral selector molecules for
separation and purification of enantiomers and in drug discovery
applications, are presented. Although the majority of studies
employing methods such as host-guest screening, competitive
binding, and titrations have focused on large protein-ligand,
DNA-ligand, and RNA-ligand systems, the use of ESI-MS for
studying small molecule and chiral recognition systems is
growing. For the latter case, greater care must be given to
considering the effects of the ESI process on the ionization
of the species involved in equilibria of interest. Some basic
mechanistic and practical concerns for performing solution-phase-targeting
quantitative measurements by ESI-MS are given in this light.
Finally, an account of the application of these methods in
a high throughput format is given, highlighting the potential
of traditional and novel screening and titration approaches
which allow scientists to screen the performance of hundreds,
if not thousands, of compounds in a single day.
[Back to top]
High-Throughput Screening and Optimization Approaches
for Chiral Compounds by Means of Microfluidic Devices
Debby Mangelings and Yvan V. Heyden
Chiral separations facilitated using microchip devices are
reviewed in this paper. The first research paper on this topic
was published in 1999. It was seen that analysis times are
greatly reduced compared with more conventional techniques
such as liquid chromatography and capillary electrophoresis,
and that these devices enable the separation of chiral molecules.
Method optimization can be conducted in a rather easy manner,
reducing the total method development time. Finally, minute
amounts of sample and buffer are used during analysis, which
makes the systems ultra-economical. Although the number of
applications in the chiral separation field on these miniaturized
systems is still rather limited, they exhibit much potential
towards high-throughput screening. Some efforts are, however,
still needed regarding detection modes, because derivatisation
of the samples is often needed to enable their detection.
[Back to top]
Homochiral Drug Design and Development by Racemization
Imran Ali
One of the enantiomers of a racemic drug may be pharmacologically
inactive or toxic or ballast and, hence, U.S. FDA and European
agencies have issued certain guidelines for marketing of optically
active (homochiral) drugs. However, some homochiral drug enantiomers
racemize in to human body leading to the generation of other
antipodes, which may be toxic or ballast to the human beings.
In addition, racemization reduces the administrated dosage
concentration when the optically active enantiomer is converted
into its inactive form. Therefore, racemization studies of
homochiral drugs are the important and urgent need of today.
This article reviews in vitro and in vivo
racemization of homochiral drugs. The racemization of some
homochiral drugs is described considering the affect of different
variables such as temperature, concentration of the drug,
ionic concentration, pH, addition of cyclodextrins, formation
of inclusion complexes, etc. Efforts have also been made to
discuss the mechanisms of the racemization process. Attempts
have been made to suggest safe dosages of such drugs.
[Back to top]
Dendrimer-Based Prodrugs: Design, Synthesis, Screening
and Biological Evaluation
Yiyun Cheng, Yang Gao, Tingling Rao, Yiwen Li and Tongwen
Xu
Dendrimers are a new class of artificial macromolecules with
well-defined hyperbranched structures which enable bio-active
molecules such as drugs to be presented in a highly multi-valent
fashion. Covalent conjugation of drugs to the surface of dendrimers
can be easily achieved either by direct chemical reactions
between dendrimers and drug molecules including esterification
and amidation or through cleavable linkers, depending on the
functional groups on the surface of dendrimers. The pharmacological
properties of these dendrimer-based prodrugs such as biocompatibility,
biodistribution, biostability, bioadhesion and biopermeability
can be modulated by further modifying dendrimers with specific
functional molecules to fit a specific medicinal purpose.
In this mini-review, recent advances on the use of dendrimers
as prodrug nano-scaffolds were briefly demonstrated. The design
and synthesis of dendrimer-based prodrugs as well as screening
their intrinsic properties in biological systems were fully
discussed.
[Back to top]
Thermodynamics of Molecular Recognition of Bile Salts
by 3,6’-(Oligoethylenediamino- Bridged) β-Cyclodextrin
Dimers
Yu Liu, Shu Kang, Yong Chen, Rui Cao and Jun Shi
The molecular recognition behaviors of some representative
bile salts by three 3,6’-bridged β-cyclodextrin
dimers with oligo(ethylenediamino) linkers in different lengths,
i.e. 3,6’-(ethylenediamino-bridged) β-cyclodextrin
dimer (1), 3,6’-(diethylenetriamino-bridged) β-cyclodextrin
dimer (2), and 3,6’-(triethylenetetraamino-bridged)
β-cyclodextrin
dimer (3), were investigated in aqueous phosphate buffer solution
(pH 7.20) at 25°C by means of 2D NMR spectroscopy and
isothermal titration microcalorimetry. Owing to the cooperative
host-linker-guest binding mode between host and guest, these
3,6’-bridged β-cyclodextrin
dimers showed significantly enhanced binding abilities and
molecular selectivities as compared with native β-cyclodextrin
through the simultaneous contributions of hydrophobic, hydrogen
bond, and electrostatic interactions. Thermodynamically, the
inclusion complexations of these β-cyclodextrin
dimers with bile salts were mainly driven by large enthalpic
gain, accompanied by slight to moderate entropic loss. An
enthalpy-entropy compensation analysis demonstrated that these
β-cyclodextrin
dimers experienced large conformational changes and extensive
desolvation effect upon inclusion complexation with guest
molecules.
[Back to top]
Screening of Mucoadhesive Microparticles Containing
Hydroxypropyl-Beta-Cyclodextrin for the Nasal Delivery of
Risperidone
Mario Jug and Mira Becirevic-Lacan
Interaction of the antipsychotic drug risperidone with hydroxypropyl-beta-cyclodextrin
(HPBCD) in solution and in the solid state was studied with
the aim of overcoming the limitations associated with nasal
administration of low solubility drugs. Risperidone solubility
studies revealed inclusion complex formation with a 1:1 stoichiometry.
Low concentrations (0.1 w/v %) of hydroxypropylmethyl cellulose
(HPMC) and carbomer affected risperidone solubility in water.
No formation of a ternary complex was detected. The solid
inclusion complex was prepared by spray drying and was characterised
by thermal (DSC) and spectral (FTIR) analyses. Risperidone
and the inclusion complex were loaded into microparticles
by spray drying using HPMC, carbomer and HPMC/carbomer interpolymer
complex (IPC) as mucoadhesive components. The microparticles
were characterised with respect to drug loading, particle
size distribution, thermal analysis, and zeta potential measurements.
Mucoadhesive properties of the microparticles were studied
by measuring the work of adhesion. Carbomer and IPC based
microparticles revealed superior mucoadhesive microparticles
compared to HPMC based microparticles. Drug incorporation
into microparticles reduced their mucoadhesive properties,
while incorporation of the cyclodextrin complex caused no
additional reduction in mucoadhesion. The in vitro
dissolution studies showed that formation of the inclusion
complex significantly increased the risperidone dissolution
rate from the microparticles, thus providing sustained drug
release.
[Back to top]
Biomimetic PAMAM-Poly(Benzyl L-Glutamate) Amphiphiles
with Multi-Armed Architecture: Synthesis, Physical Properties
and Self-Assembled Nanoparticles
Hui Huang, Chang-Ming Dong and Yen Wei
Biomimetic poly(amidoamine)-poly(benzyl L-glutamate) (PAMAM-PBLG)
amphiphiles with multi-armed architecture were synthesized
by the ring-opening polymerization (ROP) of β-benzyl-L-glutamate
N-carboxyanhydride (BLG-NCA) using primary amine-terminated
PAMAM dendrimer as the macroinitiator. Both 1H
NMR and 13C NMR demonstrated
that all the primary amines of PAMAM participated in initiating
the ROP of BLG-NCA monomer, and the chain length of PBLG can
be adjusted linearly by the molar ratio of BLG-NCA monomer
to PAMAM. These multi-armed PAMAM-PBLG amphiphiles exhibited
both α-helix
and β-sheet
conformations similar to linear analogues, while their multi-armed
architecture could enhance the secondary conformation content
of PBLG segments. Meanwhile, the PAMAM-PBLG amphiphiles showed
weaker liquid crystalline textures than the linear analogues.
Moreover, spherical nanoparticles could be generated by direct
injection of these PAMAM-PBLG solutions into distilled water,
and their average size (38 - 275 nm) could be adjusted through
the multi-armed architecture, the PBLG composition, and the
concentration of the amphiphiles. These nanoparticles were
stable in aqueous solution for up to 64 days at room temperature
and 16 days at 37oC. Consequently, this will provide a convenient
method not only to synthesize multi-armed polypeptides amphiphiles,
but also to generate biodegradable and biocompatible nanoparticles
with adjustable size for drug/gene release.
[Back to top]
Screening of Antioxidant Compounds During Sprouting
of Brassica oleracea L. var. costata DC
Carla Sousa, Graciliana Lopes, David M. Pereira, Marcos
Taveira, Patrícia Valentão, Rosa M. Seabra,
José A. Pereira, Paula Baptista, Federico Ferreres
and Paula B. Andrade
The changes in antioxidant compounds of Brassica oleracea
L. var. costata DC seeds were monitored during the
first twelve days of seedling development. Sprouts were screened
at time intervals of two days for phenolic compounds and organic
acids. The identified phenolic compounds included esters of
sinapic acid with glucose, gentiobiose and kaempferol, as
well as sinapoylcholine. The organic acids were oxalic, aconitic,
citric, pyruvic, malic, shikimic, and fumaric acids. During
germination, a depletion of phenolic compounds was observed,
although no qualitative changes were seen. Among individual
compounds, kaempferol, choline and glucose esters of sinapic
acid showed a marked decrease between days two and six, whereas
the changes in gentiobiose esters of sinapic acid were smaller.
The total organic acids content increased rapidly during the
first four days, with less significant variations thereafter.
Malic acid, the major organic acid found in sprouts, greatly
contributed to this result though oxalic, pyruvic, and fumaric
acids also increased in the same manner. In contrast, aconitic,
citric and shikimic acids showed decreases between days two
and twelve of germination.
[Back to top]
Comparison of the Chromatographic Behavior of Tricyclic
Neuroleptics on Calixarene- Bonded, Monolithic and Conventional
RP-HPLC Columns
Hisham Hashem and Thomas Jira
The effect of different chromatographic conditions, such as
buffer concentration and type of organic modifier, on the
retention behavior of nine tricyclic neuroleptics on three
different RP-HPLC columns was investigated. Two recently developed
columns, calixarene-bonded (CALTREX®
AIII) and monolithic (Chromolith®
Performance RP-18e) columns, were compared with a conventional
RP-C18 HPLC column (LiChrospher®).
The results showed how the mobile phase conditions had different
effects on the analyte retention on these three columns. For
example, the elution order of some analytes and the initiation
of separation of the geometric isomers of the three analytes
- which have E/Z-isomers (cis/trans-isomers) –
could be altered by changing the conditions and the column
type. Under identical conditions, a calixarene-bonded phase
was the best for this separation, a monolithic phase gave
comparable results and the conventional RP-column was the
least effective. Concerning the geometric isomers separation,
the Chromolith®
Performance RP-18e was superior.
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