Current Drug Discovery Technologies

ISSN: 1570-1638

Current Drug Discovery Technologies
Volume 4, Number 4, December 2007

Contents

"Supramolecular Approaches for Improving Drug Delivery Processes"
Guest Editor: Grzegorz Bazylak


Editorial Pp. i


Recognition of Lysine Residues on Protein Surfaces Using Calixarenes and its Application Pp. 220-228
Tatsuya Oshima, Yoshinari Baba, Kojiro Shimojo and Masahiro Goto
[Abstract]


Surface Photochemistry: Organic Molecules within Nanocavities of Calixarenes Pp. 229-245
Luís F. Vieira Ferreira and Isabel L. Ferreira Machado
[Abstract]


Design, Synthesis and Potent Pharmaceutical Applications of Glycodendrimers: A Mini Review Pp. 246-254
Yiwen Li, Yiyun Cheng and Tongwen Xu
[Abstract]


Supramolecular Systems-Based HPLC for Chiral Separation of Beta-Adrenergics and Beta-Adrenolytics in Drug Discovery Schemes Pp. 255-274
Imran Ali, Afzal Hussain, Hassan Y. Aboul-Enein and Grzegorz Bazylak
[Abstract]

Thermal Properties and Microstructures of Methylated Polyrotaxane Solutions Pp. 275-281
Toshiyuki Kataoka, Masatoshi Kidowaki, Changming Zhao, Jun Araki, Takayuki Ikehara and Kohzo Ito
[Abstract]

Cyclodextrin Complexes: Chiral Recognition and Complexation Behaviour Pp. 282-294
Zsolt Bikádi, Róbert Iványi, Lajos Szente, István Ilisz and Eszter Hazai
[Abstract]


¹H NMR Investigations of Inclusion Complexes Between β Cyclodextrin and 1-Hexadecanol Pp. 295-297
Huiming Jiang, Shufen Zhang, Qinglin Guan, Chang Chen, Fan Gao and Yang Zhang
[Abstract]




Abstracts


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Editorial

Celebration by all scientific community 40^th anniversary of supramolecular chemistry (SUP-CHEM) in the year 2007 give rise and also summarize its impact on developments of innovative drug formulation and novel pharmacotherapy schemes. For example, probably the most exploited area of macromolecular nanomedicines in the past four decades is the host-guest complexation of poorly soluble and orally administered drugs by cyclodextrins (CDs), as they are the major class of macrocyclic organic host compounds, and are documented by more than 6000 published papers and approved patents. Incorporation of cyclodextrins into a drug dosage form first affects the activity of basic pharmaceutical ingredients by increasing their dissolution rate, solubility and bioavailability, and, secondly, modify the properties of the whole prepared drug formulation by enhancing its stability, taste masking, binding, filling, channeling, osmogenic action, etc. Nearly 40 marketed commercial drug products have been benefited in the same way from such CD technology in the 2003 year. However, CD-formulated drugs cannot not be considered as the simple generic drugs, but they are considered as the ‘super generic’ drugs there improvement should be accelerated by more adequate bioequivalence testing. This molecular encapsulation approach of therapeutic agents was further exploited in last years by using huge varieties of macrocyclic and macromolecular compounds as calixarenes, dendrimers, rotaxanes, catenanes, polymeric composite materials and monoclonal antibodies. Moreover, this next generation of easy available, nanosized supramolecular materials has enabled not only the development of new targeted and tuneable drug delivery technologies, pathogen inhibition and cell transfection agents, but also has introduced a range of selective and potent antiadhesives, enzyme blocking, anti-thrombotic, and anti-viral agents. Examples of such forefront solutions from nanostructured SUP-CHEM in order to design controlled, smart and personalized drug delivery systems will be illustrated here in a special issue of the journal Current Drug Discovery Technologies.

The introductory review paper by Oshima et al. describes highly specific recognition of protein surfaces by range of anionic calixarene derivatives enabling selective extraction and solubilization of cytochrome c into organic solution without losing catalytic peroxidase activity. These considerations are continued in review paper by Vieira Ferreira and Ferreira Machado, which describes the use of intensified charge couple devices in the surface photochemistry studies on the inclusion of complex formation within tert-butylated calixerene cavity by labile conformers of alkylaryl ketones, diketones and their derivatives. In addition, the minireview paper by Cheng et al. presents recent developments on design, synthesis and precise functional regulation of novel glycodendritic architectures applied as nanostructured immuno-modulating vaccines, nanocontainer glycoproteomics probes, functionalized glycochips, and photoaffinity labeling agents for investigation of receptor binding sites. Similarly, review paper by Bazylak et al. describes the current status of high-throughput chiral HPLC procedures used in the emerging field of enantioselective analysis of beta-adrenergic and beta-adrenolytic drugs, thus enabling fast and reproducible recognition of their diverse pharmacokinetic and pharmacodynamic properties, as well as valuable assessment of their biodistribution, biocompatibility and binding processes by native, modified, derivatized and functionalized cyclodextrins, polysaccharides, macrocyclic glycopeptides and various synthetic receptors. This approach is continued in the research paper by Kataoka et al. describing the thermosensitivity of polyrotaxanes, consisting of methylated alpha-cyclodextrin topologically bound to a linear molecule as poly(ethylene glycol), which enable reversible micellization or gelation of hydrophobic drugs in water. Similar approach is elaborated in the last two research papers by Hazai et al. and Jiang et al., presenting results of comprehensive in silico and proton-NMR studies on chiral recognition and host-guest complexation, respectively, of methyl tryptophane diastereoisomers and 1-hexadecanol by alpha- and beta-cyclodextrin molecules.

The rising healthcare costs in most developed countries can probably be reduced by enlarging the fraction of variety of most sophisticated supramolecular-based drug formulations offered on the global pharmaceutical markets. Further advancements in targeted delivery of macromolecular drugs and nanoparticles could be expected by combining contemporary technologies which identify multiple cell-surface receptor ‘signatures’ and enable to achieve optimal biocompatibility, endocytic internalization, facilitated liberation and lack of clinical resistance for these drugs. Hoping that such promising views will soon be changed into reality also with help of our publishing efforts, I would like to extend my appreciations, as the Guest Editor of the special issue of Current Drug Discovery Technologies, to all authors who kindly 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


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Recognition of Lysine Residues on Protein Surfaces Using Calixarenes and its Application
Tatsuya Oshima, Yoshinari Baba, Kojiro Shimojo and Masahiro Goto

A macrocyclic calix[6]arene carboxylic acid derivative is found to extract lysine-rich protein cytochrome c from aqueous media into organic media through the complexation between the calixarene molecules and lysine residues on the surface of the protein. This article summarizes both the mechanism of protein extraction by the calixarene as well as the potential applications of the extraction process. The extraction process can be used for the purification of proteins through selective extraction and back-extraction under optimized conditions. On the other hand, the extracted protein exhibits enzymatic activity in organic media. The formation of a supramolecular complex by recognizing the residues on a protein surface can be construed as a novel recognition and/or modification method for biomacromolecules.


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Surface Photochemistry: Organic Molecules within Nanocavities of Calixarenes
Luís F. Vieira Ferreira and Isabel L. Ferreira Machado

In order to gain more information regarding photochemical processes in heterogeneous environments (opaque or powdered samples) laser induced time resolved luminescence and diffuse reflectance transient absorption spectroscopies were used for the study of benzophenone (and other neutral organic molecules) as guests and p-tert-butylcalix[n]arenes with n = 4, 6 and 8 (H_nCLX[n]) and partially or totally O-propylated p-tertrt-butylcalix[4]arenes (H_nPr_mCLX[4], n = 2, 1 and 0; m = 2, 3 and 4, respectively) were used as hosts. One of the main conclusions was that the solid support can deeply affect or even control the photochemistry of an adsorbed probe. A simple new methodology for lifetime distribution analysis of the decay of the probes included into calixarenes and other nanocavities was applied with success for decay data obtained with the use of intensified charge couple devices, i.e. intensified charge couple devices, ICCDs. Diffuse reflectance laser flash photolysis and gas chromatography - mass spectrometry techniques also provided complementary information, the former about transient species and the latter regarding the final products formed after light absorption.


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Design, Synthesis and Potent Pharmaceutical Applications of Glycodendrimers: A Mini Review
Yiwen Li, Yiyun Cheng and Tongwen Xu

Dendrimers are a new class of artifical macromolecules with well-defined hyperbranched structures which endue these promising materials with a wide variety of applications. They are useful tools in drug discovery and allow bio-active molecules to be presented in a highly multi-valent fashion on the surface. Recently, the use of dendrimers as scaffolds of carbohydrates to synthesize glycodendrimers with high and specific affinities to various receptors has made it possible for these dendritic materials to participate in extracellular and intracellular biochemical processes. References on synthesis and biological applications of glycodendrimers in the literatures demonstrate that dendrimers are suitable candidates as scaffolds of these bioactive carbohydrates. In this mini-review, different approaches to construct glycodendrimers as well as their promising applications in biological systems are fully discussed.


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Supramolecular Systems-Based HPLC for Chiral Separation of Beta-Adrenergics and Beta-Adrenolytics in Drug Discovery Schemes
Imran Ali, Afzal Hussain, Hassan Y. Aboul-Enein and Grzegorz Bazylak

Increasing amount of data considering polymorphism, splice variants and various affinity states of beta-adrenoceptors has resulted in a new range of opportunities for enantiopure beta-adrenergic and beta-adrenolytic drug discovery and continuous development of reliable high-throughput screening procedures enabling tissue specific pharmacological evaluation of these drugs. Design and fast pharmacological profiling of single enantiomeric molecules combining beta-adrenoceptor affinity with other pharmacophores is also still challenging ability. As the use of chiral stationary phases in HPLC has particularly benefited from results of supramolecular chemistry, this review summarises recent achievements provided by this technique in deciphering of enatiorecognition phenomena affecting pharmacological selectivity of beta-adrenergics and beta-adrenolytics and modifying the efficiency of currently proposed beta-adrenoceptor-targeted therapies. Detailed characteristic of chiral separation performance of these drugs in the range of available supramolecular HPLC systems has also been presented.


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Thermal Properties and Microstructures of Methylated Polyrotaxane Solutions
Toshiyuki Kataoka, Masatoshi Kidowaki, Changming Zhao, Jun Araki, Takayuki Ikehara and Kohzo Ito

Aqueous solutions of polyrotaxanes consisting of poly(ethylene glycol) and methylated alpha-cyclodextrins (alpha-CD) were studied by means of differential scanning calorimetry (DSC), dynamic light scattering, and X-ray diffraction in order to investigate the effect of the degree of methylation on thermoresponsive behavior. Polyrotaxanes with a degree of methylation higher than 50% had a lower critical solution temperature (LCST) and showed reversible associations and dissociations in water. In the transmittance measurements, the cloud point of methylated polyrotaxanes (MePR) shifted to a lower temperature with an increase in the degree of methylation. The heating curve obtained by DSC for the nearly permethylated polyrotaxane showed one broad endothermic peak that was associated with the microcrystallization of methylated CDs by hydrophobic interactions. On the other hand, the DSC profiles for partially methylated polyrotaxanes had several endothermic peaks, indicating multiple phase transitions of the MePR solutions. The results imply that the thermal properties of the MePR-water system are significantly affected by not only the methyl groups on alpha-CDs but also by the remaining hydroxyl groups.


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Cyclodextrin Complexes: Chiral Recognition and Complexation Behaviour
Zsolt Bikádi, Róbert Iványi, Lajos Szente, István Ilisz and Eszter Hazai

Cyclodextrins are well known in supramolecular chemistry as host molecules capable of engulfing molecules in their hydrophobic cavity via noncovalent interactions. Although cyclodextrins are frequently used for chiral separation of racemates, the mechanism of chiral recognition has not yet been fully characterised. The current investigation was aimed at examining chiral recognition mechanism in order to construct an in silico method for prediction of chiral recognition. Amino acids were selected as model guest, whereas αCD was used as model host. The results of molecular docking and molecular dynamic calculations were compared to results of stability constant determination and capillary electrophoresis measurements of enantioseparations. Positive correlation between binding strength and chiral separation ability was found. However, the small energy differences between interaction energy of each enantiomer with αCD fell into the range of standard error of molecular docking calculations limiting its applicability for in silico prediction. Examining the stability of complex geometry during molecular dynamics simulation revealed that stable complex geometry is likely to be a prerequisite for chiral recognition. This hypothesis was tested on methylderivatized tryptophan. Indeed, chiral separation of β-methyl-tryptophans by αCD could be successfully predicted by examining the complex geometries during molecular dynamic simulation.


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¹H NMR Investigations of Inclusion Complexes Betweenβ Cyclodextrin and 1-Hexadecanol
Huiming Jiang, Shufen Zhang, Qinglin Guan, Chang Chen, Fan Gao and Yang Zhang

The inclusion complex between β-CD and 1-hexadecanol is synthesized and identified via ¹H NMR spectrum. The possible conformation of the inclusion complex is figured out. Via MM2 calculations, the possibility of complexation is verified.