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Current
Drug Discovery Technologies
ISSN: 1570-1638
Current Drug Discovery Technologies
Volume 5, Number 2, June 2008
Contents
“Supramolecular Transmembrane Nanocarriers for
Targeted Therapeutics”
Guest Editor: Grzegorz Bazylak
Editorial Pp. 85
Artificial Anion Transporters in Bilayer Membranes
Pp. 86-97
Sabina Licen, Francesco De Riccardis, Irene Izzo and
Paolo Tecilla
[Abstract]
Functionalized Calix[n]arenes as Membrane
Transporters for Biological Compounds. A Minireview
Pp. 98-104
Lucia Mutihac
[Abstract]
Supramolecular Chiro-Biomedical Assays and Enantioselective
HPLC Analyses for Evaluation of Profens as Non-Steroidal Anti-Inflammatory
Drugs, Potential Anticancer Agents and Common Xenobiotics
Pp. 105-120
Imran Ali, Iqbal Hussain, Kishwar Saleem, Hassan Y. Aboul-Enein
and Grzegorz Bazylak
[Abstract]
The Impact of Supramolecular Nanocarriers to
Contemporary Pharmaceutical and Analytical Chemistry: A Minireview
Pp. 121-128
Patryk Bielecki and Wieslaw Wasiak
[Abstract]
Effect of para-Sulfonato-Calix[n]arenes
on the Solubility, Chemical Stability, and Bioavailability
of a Water Insoluble Drug Nifedipine Pp. 129-139
Wenzhan Yang, Daniel P. Otto, Wilna Liebenberg and
Melgardt M. de Villiers
[Abstract]
Solubilization and Stabilization of Sodium Dicloxacillin
by Cyclodextrin Inclusion Pp. 140-145
María Magdalena Echezarreta-López, Iria
Otero-Mazoy, Héctor Luís Ramírez, Reynaldo
Villalonga and Juan José Torres-Labandeira
[Abstract]
Thermodynamic Study of Cyclodextrins Complexation
with Benzimidazolic Antihelmintics in Different Reaction Media
Pp. 146-153
María-Josefa Bernad-Bernad, Jesus Gracia-Mora,
David Díaz and Silvia Elena Castillo-Blum
[Abstract]
First Divalent Metal Complexes of the Polyether Ionophore
Monensin A: X-Ray Structures of [Co(Mon)2(H2O)2]
and [Mn(Mon)2(H2O)2]
and their Bactericidal Properties Pp. 154-161
Ivayla N. Pantcheva, Mariana Io. Mitewa, William S. Sheldrick,
Iris M. Oppel, Rumyana Zhorova and Petar Dorkov
[Abstract]
A Method to Evaluate a Propidium Iodide Association
with Oligonucleotides and Oligonucleotide-Cationic Lipid Interactions
Pp. 162-167
Magda Przybylo, Tomasz Borowik, Andrzej Okruszek and
Marek Langner
[Abstract]
Interactions of β-
and Hydroxypropyl-β-Cyclodextrin
with Some Purine Alkaloids: Thermodynamic Study Pp.
168-172
Irina V. Terekhova
[Abstract]
UV-vis Spectral Analysis of Inclusion Complexes
between β-Cyclodextrin
and Aromatic/Aliphatic Guest Molecules Pp. 173-176
Huiming Jiang, Yingmei Xu, Liyan Na, Rongchao Jin and
Shufen Zhang
[Abstract]
Diversity Oriented High-Throughput Screening
of 1,3,4 Oxadiazole Modified Chlorophenylureas and Halogenobenzamides
by HPLC with Peptidomimetic Calixarene Bonded Stationary Phases
Pp. 177-189
Grzegorz Bazylak, Anna Malak, Imran Ali, Teresa Borowiak
and Grzegorz Dutkiewicz
[Abstract]
Abstracts
[Back to top]
Editorial: “Supramolecular Transmembrane Nanocarriers
for Targeted Therapeutics”
One of the prerequisite processes in living cells
is the ability to maintain the simultaneous, hierarchical
and selective transmembrane transport of ions, molecules and
waste products employing highly evolved proteins, self-organized
in the form of specific and sophisticated ion channels or
biomolecule nanocarriers. The examples of synthetic approach
to the preparation of such supramolecular transporters include
natural protein scaffolds, abiotic structures, peptide-abiotic
hybrids, nanotubular cyclic peptides, hydraphiles and their
variants. In many cases these synthetic ion channels exhibiting
a selective and specific in vitro activity as antibiotics
acting by disruption of cellular ion balance of various microbials.
Similarly, free and macrocycle encapsulated chloride channels
blockers have been found to be useful to promote therapy induced
apoptosis. These both examples show that synthetic biomembrane
nanocarriers would be applied in near perspective as the promising
targeted and/or triggered therapeutics. Thus, in recent years
efforts of supramolecular chemist evolving continuously from
the traditional target-directed to the more complete property-oriented
strategies of synthesis to enable design, preparation and
screening of more substantial, selective, and pharmacoactive
molecules with enhanced transporters mimicking ability. The
significance of these supramolecular nanocarrier approaches
still increasing by the demands of modern gene delivery and
cell transfection technologies. Examples of such novel solutions
offered by a potential supramolecular nanocarrier system will
be illustrated in this special issue of Current Drug Discovery
Technologies.
The introductory review paper by Tecilla et al. focuses
on the currently designed supramolecular synthetic systems,
both artificial channels and nanocarriers, promoting selective
anion transport, thus enabling development of new therapeutics
for variable anion channelopathies, a commonly diagnosed genetic
disease in humans. This approach is continued in the minireview
paper by Mutihac describing the potential applications of
calixarenes and their derivatives in transport of diverse
low-molecular biologically relevant substances through liquid
membranes and for development of new drug formulations with
enhanced drug-target specificity. Basing on a typical supramolecular
function of immobilized chiral stationary phase (CSP) involving
dynamic enantiorecognition of the analyte during the translocation
process in bilayer interphase comprising of each HPLC systems
Bazylak et al. discussed chiral separation of profens,
as the well known non-selective NSAIDs and recently recognized
potential anticancer agents, with use of past-developed polysaccharide-,
cyclodextrin-, glycoantibiotics-CSPs and currently proposed
bimodal, combinatorial, monolithic and polymeric modes. Similar
approach is also elaborated in the last minireview paper by
Bielecki and Wasiak et al. presenting some recent
results on use of various supramolecular nanocarrier molecules
in design of range of analytical devices applicable in drug
screening procedures employing membrane mimicking processes.
In the first research paper by de Villiers et al.
the results of extended study on solubility, stability and
availability of nifedipine encapsulated in various nanocavity
sized para-sulfonato-calixarenes have been described.
Similarly, Bazylak et al. have illustrated separation
abilities of currently available HPLC techniques employing
supramolecular host-guest stationary phases, e.g. octadecylsilica
versus calixarene bonded silica with variable nanosize of
their cavity and upper-rim modification, for screening of
the 1,3,4-oxadiazolureas with potent analgesic activity. The
highly selective separation of positional and E/Z isomers
of these analytes were described in this report as well as
some preliminary data indicating on especially attractive
possibility of use calixarenes as the future nanocarriers
for these compounds. The next four research papers by Torres-Labandeira
et al., Diaz et al., Jiang et al.
and Terekhova deal with detailed thermodynamic, spectral,
kinetic, and computational studies on the solubilization process
of the water insoluble sodium dicloxacillin, benzimidazolic
antihelmintics, purine alkaloids and insecticide intermediates,
respectively, with different cyclodextrins. In addition, the
series of highly innovative divalent metal complexes of moensin
A, a polyether-type antibiotic and anticoccidial agent, have
been described and characterized in research paper by Pantcheva
et al. which enabled to obtain the new kind of antimicrobials
with increased membrane permeabilizing properties and enhanced
activity against Gram-positive bacteria. In last research
paper by Przybylo et al. the results of study by
fluorescence resonance energy transfer (FRET) method on the
oligonucleotide orientation and binding with the lipid bilayer,
used as the carrier of genetic material and mimicking a gene
delivery system, has been reported.
As illustrated by all these reports the progression in the
non-mechanistic understanding of artificial membrane transport
systems at molecular nanoscale is still continuing by use
of supramolecular principles in both of structural and functional
level. In near future this last approach will place the synthetic
channel-forming and nanocarrier entities as the functional
materials in the forefront of the primary candidates for accelerated
development of new therapeutics and drug delivery applications.
In our opinion these highly promising expectations are specially
worthy to be also supported by permanent publishing initiatives,
thus, finally, I would like to express my grateful thanks,
as the Guest Editor of the special issue of Current Drug
Discovery Technologies, to all authors who contributed
in this project.
Dr. Grzegorz Bazylak
Department of Pharmaco-Bromatology & Molecular Nutrition
Faculty of Pharmacy, Collegium Medicum
Nicolaus Copernicus University
Bydgoszcz, Poland
E-mail: gbazylak@cm.umk.pl
[Back to top]
Artificial Anion Transporters in Bilayer Membranes
Sabina Licen, Francesco De Riccardis, Irene Izzo and Paolo
Tecilla
Anion transport across phospholipid membrane is a typical
supramolecular function involving dynamic recognition of the
substrate during the whole translocation process. Supramolecular
chemists, taking inspiration by the natural anion transporters,
have designed artificial systems able to mimic, at the functional
level, several features of the natural ion channels. The scope
of this research is twofold: on one hand to get insight on
the molecular basis of recognition and transport, and on the
other hand to get control of the biomedical relevant processes.
The present review focuses on the synthetic systems promoting
anion transport, covering both artificial channels and carriers
that operate in phospholipid membrane. The design principles
of such systems will be discussed together with the potential
biomedical applications.
[Back to top]
Functionalized Calix[n]arenes as Membrane Transporters
for Biological Compounds. A Minireview
Lucia Mutihac
The present minireview summarizes some potential applications
of calix[n]arenes family in binding and transport
through liquid membranes of various biological compounds.
In this respect, some specific aspects of their applications
as carriers through liquid membrane are discussed in view
of their potential for development of new drug formulation.
The place of calix[n]arenes in the interesting and
challenging field of transmembrane ion transport as synthetic
ionophores is briefly outlined.
[Back to top]
Supramolecular Chiro-Biomedical Assays and Enantioselective
HPLC Analyses for Evaluation of Profens as Non-Steroidal Anti-Inflammatory
Drugs, Potential Anticancer Agents and Common Xenobiotics
Imran Ali, Iqbal Hussain, Kishwar Saleem, Hassan Y. Aboul-Enein
and Grzegorz Bazylak
The permanent world-wide increase in therapeutic administration
of racemic profens as easy available non-prescribed analgesic
drugs and a common first-choice anti-inflammatory agents was
recently linked with renewed interest in their beneficial
use, also as enantiopure formulations, to treat and/or prevent
a variety of human malignancies including its four major types
as colorectal, breast, lung, and prostate cancer. This underlies
the continuous need of selecting perfectly suited chiral separation
methods of profens capable to determine nanolevels of a distomer
in presence of the eutomer in a variety of complex biological
and environmental media. Thus, current improvements for direct
enantiomeric separations of profens by well defined supramolecular-based
chiral HPLC and recently developed monolithic, combinatorial,
bimodal and polymeric chiral stationary phases employing a
modern supramolecular chirality concepts has been outlined
in this review. The use of diverse supramolecular approaches
for chiral HPLC as an easy accessible tool enabling fast development
of nanoscale enantioselective, high-throughput and gradient
screening procedures for in situ monitoring of stereoselective
ADME properties of profens in range of anticancer drug discovery
technologies has been also addressed.
[Back to top]
The Impact of Supramolecular Nanocarriers to Contemporary
Pharmaceutical and Analytical Chemistry: A Minireview
Patryk Bielecki and Wieslaw Wasiak
The paper gives a short review of the most important
research results published recently in the field of the applications
of supramolecular nanocarriers in modern pharmaceutical and
analytical chemistry. The main attention has been paid to
the fast developing technology of chemical sensors, ion-selective
electrodes and separation methods, in particular to newly
designed packing in high-performance liquid chromatography
employing supramolecularly aided and membrane mimicking processes.
[Back to top]
Effect of para-Sulfonato-Calix[n]arenes on the Solubility,
Chemical Stability, and Bioavailability of a Water Insoluble
Drug Nifedipine
Wenzhan Yang, Daniel P. Otto, Wilna Liebenberg and Melgardt
M. de Villiers
This study reports the use of para-sulphonato
calix[8]arene to produce stable complexes with improved bioavailability
for nifedipine, a calcium-channel blocker that is practically
insoluble in water. Thermal analysis and electrospray ionisation
mass spectroscopy confirmed that nifedipine formed complexes
with the calixarenes in a size dependent way. The most stable,
soluble complexes was formed with para-sulphonato
calix[8]arene. Complexation was weakest with the calix[4]arene
while complexation with the calix[6]arene was intermediate.
However, the calix[4 and 6]arenes changed the chemical stability
of the drug in solution because significant amounts of the
nitroso-pyridine derivative was produced, proposing an interaction
between the nifedipine bearing a H substituent at the N-1
position and the calixarenes. This oxidative degradation of
the drug was greatest when combined with the calix[6]arene.
Simultaneous oral ingestion of the calix[6 or 8]arenes significantly
increased the bioavailability of the drug after oral administration
in male Sprague-Dawley rats while not influencing CYP3A activities
in the liver. The pharmacokinetic parameters of the nifedipine:
para-sulfonato calix[8]arene complexes showed it
was bioequivalent to a nifedipine PEG-solution. The absolute
bioavailability for both formulations was ca. 60 %.
[Back to top]
Solubilization and Stabilization of Sodium Dicloxacillin by
Cyclodextrin Inclusion
María Magdalena Echezarreta-López, Iria
Otero-Mazoy, Héctor Luís Ramírez, Reynaldo
Villalonga and Juan José Torres-Labandeira
The aim of this work is to analyze the effect of cyclodextrin
(CD) complexation on the solubilization and stabilization
of sodium dicloxacillin in acid aqueous solutions. The effect
of four cyclodextrins α-,
β-,
γ-
and hydroxypropyl-β-CD
was studied. Phase solubility diagrams obtained are AL
or BS type, depending on
the cyclodextrin used and on the pH of the solution. The highest
stability constants of the inclusion complexes are obtained
with γ-CD
at pH 1 and 2 and HPβ-CD
at pH 3. The structure of the inclusion complex in solution
is characterized by nuclear magnetic resonance (1H-NMR).
This study suggests that the 7-oxo-4-thia-1-azabicyclo group
is located in the CD cavity. Nevertheless, molecular modelling
calculations predict two different orientations of dicloxacillin
in the γ-CD
cavity in vacuum and in aqueous solution. In vacuum, the results
predict the inclusion of the dichlorophenyl ring of dicloxacillin
instead of 7-oxo-4-thia-1-azabicyclo group into the γ-CD
cavity. However, the results are different in aqueous solution
and this conformation is confirmed by the NMR study. The effect
of γ-CD
and HPβ-CD
in the stability of the drug in solution was studied. The
degradation of sodium dicloxacillin in solution follows a
pseudo-first-order kinetics and the cyclodextrin do not change
this fact. Both cyclodextrins increase the stability of the
drug but the efficacy is higher with γ-CD.
[Back to top]
Thermodynamic Study of Cyclodextrins Complexation with Benzimidazolic
Antihelmintics in Different Reaction Media
María-Josefa Bernad-Bernad, Jesus Gracia-Mora,
David Díaz and Silvia Elena Castillo-Blum
The main purpose of this work was to accomplish a comparative
study about cyclodextrins complexation equilibria with three
benzimidazolic antihelmintics: albendazole (Alb), mebendazole
(Meb) and thiabendazole (Thiab).The complexation process with
four different cyclodextrins (α-,
β-,
γ-,
and HP-β-CDs)
was investigated under various temperatures and different
reaction media (aqueous solution buffered at pH 7.5, dimethylsulfoxide
(DMSO) and DMSO/water at 25/75, 50/50, 75/50 (w/w) mixtures).
It was studied by electronic absorption and 1H
NMR (NOESY) spectroscopy. Binding constants were determined
by electronic absorption spectroscopic method, the ΔH
and ΔS
complexation values were evaluated and discussed according
to the diverse factors that affect the chemical interactions
in these systems. Solubility has also been determined by the
Higuchi and Connors method. In general, albendazole and mebendazole
exhibit similar complexation behavior, while thiabendazole
acts differently. Classic and non-classic solvophobic effects
are mainly the driving and stabilizing forces for complex
formation, with the exception in some Thiab-CDs interactions.
In all cases, DMSO, an aprotic solvent, should be considered
as an active component of the reaction systems.
[Back to top]
First Divalent Metal Complexes of the Polyether Ionophore
Monensin A: X-Ray Structures of [Co(Mon)2(H2O)2]
and [Mn(Mon)2(H2O)2]
and their Bactericidal Properties
Ivayla N. Pantcheva, Mariana Io. Mitewa, William S. Sheldrick,
Iris M. Oppel, Rumyana Zhorova and Petar Dorkov
The complexation of carboxylic acid Monensin A (MonH,
1a) with CoCl2.6H2O
and MnCl2.4H2O
leads to the formation of mononuclear complexes [Co(Mon)2(H2O)2],
2a and [Mn(Mon)2(H2O)2],
2b, respectively. The unique crystal structures
of 2a and 2b were determined
by X-ray crystallography. The complexes crystallize in the
monoclinic space group P21
with an octahedrally coordinated transition metal center forming
the crystallographically centrosymmetric chromophore CoO6
or MnO6, respectively. Two
molecules of Monensin A act bidentately through their carboxylate
moiety and a hydroxyl group, and two water molecules are additionally
trans-coordinated. Although the transition metal
ions are not bound into the cavity of the ligand, the unusual
bidentate coordination mode of the ionophore induces its “pseudo-cyclization”
forming 22-membered cycles further stabilized by a number
of H-bonds. The complexes are the first example of divalent
metal complexes of the monovalent polyether ionophore. The
parallel study on the complexation ability of the potassium
complex of Monensin A (MonK, 1b) towards
Co(II) and Mn(II) showed the formation of the isostructural
complexes 2a and 2b accompanied
by loss of the potassium ion due to the new coordination mode
of the ligand. The biological tests performed with the antibiotic
MonH and the corresponding metal(II) complexes show greatly
enhanced antimicrobial activity of complexes 2a-b
against Gram(+)-bacteria.
[Back to top]
A Method to Evaluate a Propidium Iodide Association with Oligonucleotides
and Oligonucleotide-Cationic Lipid Interactions
Magda Przybylo, Tomasz Borowik, Andrzej Okruszek and Marek
Langner
Complex molecular ensembles are frequently considered
an element of new pharmacological formulations. This is especially
evident in the therapies based on genetic information. In
order to obtain an effective drug, it is necessary to associate
a nucleic acid molecule with the components to ensure the
desired aggregate structure and properties. To evaluate the
progress of the supromolecular aggregate formation a range
of methodologies and techniques are needed to test the quality
and uniformity of the formulations. In this paper we propose
a procedure which measures the association of a small molecule
with nucleic acid using propidium iodide and oligonucleotides
as an example. To measure propidium iodide binding constant
the oligonucleotide was covalently labeled with fluorescein
and then the changes in fluorescence resonance energy transfer
(FRET) were determined and handled according to the acceptor-donor
titration methodology. The calculated binding constants were
in a good agreement with the values published previously.
The developed method was then used to evaluate the extent
of an oligonucleotide association with the lipid aggregates.
It was found that two populations of oligonucleotides are
present in all lipid samples studied. The fraction of oligonucleotides
associated with liposomes rises with the increase of a cationic
lipid content, reaching the constant value when the fraction
of cationic lipid exceeded 20 mol%. Energy transfer data combined
with these obtained in quenching experiments show that the
orientation of the oligonucleotide associated with a lipid
bilayer depends on the amount of surface charge.
[Back to top]
Interactions of β-
and Hydroxypropyl-β-Cyclodextrin
with Some Purine Alkaloids: Thermodynamic Study
Irina V. Terekhova
The effect of native and hydroxypropylated β-cyclodextrin
on the solubility and activity of some purine alkaloids was
examined. For this purpose, the solubility of purine alkaloids
in pure water and in aqueous solutions of mentioned β-cyclodextrins
was determined at 298.15 K. Stability constants of inclusion
complexes and their stoichiometry were obtained from solubility
diagrams. Enthalpic characteristics of interactions occurring
between β-cyclodextrins
and purine alkaloids in aqueous solution were calculated from
the direct calorimetric measurements. It was found, that β-cyclodextrin
forms with purine alkaloids weak complexes which are stabilized
only by the entropy term. Due to very low complexing affinity
of both β-cyclodextrins
to studied purine alkaloids their solubilizing effect is insignificant.
The influence of structure of purine alkaloids and β-cyclodextrin
on the thermodynamic parameters of interaction was discussed.
[Back to top]
UV-vis Spectral Analysis of Inclusion Complexes between β-Cyclodextrin
and Aromatic/Aliphatic Guest Molecules
Huiming Jiang, Yingmei Xu, Liyan Na, Rongchao Jin and
Shufen Zhang
β-Cyclodextrin
(β-CD)
forms a series of supramolecular complexes with aromatic or
aliphatic guest molecules such as benzaldehyde, butyl acrylate,
etc. Remarkable blue shifts (λmax)
of the UV-vis absorption peaks of the guest molecules are
observed after the formation of inclusion complexes. The congestion
lines appearing in the guest molecules are reduced in a remarkable
extent accordingly. The mechanisms of the blue shifts are
investigated herein.
[Back to top]
Diversity Oriented High-Throughput Screening of 1,3,4-Oxadiazole
Modified Chlorophenylureas and Halogenobenzamides by HPLC
with Peptidomimetic Calixarene-Bonded Stationary Phases
Grzegorz Bazylak, Anna Malak, Imran Ali, Teresa Borowiak
and Grzegorz Dutkiewicz
Retention profiles in series of the neutral and highly
hydrophobic 1,3,4-oxadiazoles containing chlorophenylurea
and halogenobenzamide moiety and indicating analgesic activity
were determined in the isocratic standard- and narrow-bore
HPLC systems employing, respectively, various octadecylsilica
and different calixarene bonded stationary phases. When acetonitrile
- 2.65 mM phosphoric acid (55 : 45, %, v/v), pH* 3.25, mobile
phase was applied retention of these compounds increased with
decline of their overall hydrophobicity according to the general
preference of more polar compounds by calixarene cavity in
time of its non-specific host-guest supramolecular interactions
with halogenated substances. The size of calixarene nanocavity
and its upper-rim substitution did not change the observed
retention order, resolution and selectivity of separation
for oxadiazoles. Compared to the retention on the non-end-capped
and the highly-end-capped octadecylsilica HPLC column a most
improved separation of some regioisomers of halogenated 1,3,4-oxadiazoles
were observed on both used calixarene-type HPLC supports.
In addition, preliminary data on the self-assembled supramolecular
crystal structure of exemplary 1,3,4-oxadiazolchlorophenylurea
with cis-elongated conformation was reported and
formation of the monovalent inclusion host-guest complexes
between 1,3,4-oxadiazoles and each calixarene-type stationary
phase was studied with molecular modelling MM+
and AM1 methods. The structural, isomeric and energetic factors
leading to the hydrogen bond stabilized inclusion complexes
between these species were considered and used for explanation
of observed retention sequence and selectivity of 1,3,4-oxadiazoles
separation in applied calixarene-based HPLC systems. All these
data would be useful in future development of optimized procedures
enabling encapsulation of 1,3,4-oxadiazolurea-type drugs with
calixarenes.
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