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Combinatorial Chemistry &
High Throughput Screening
ISSN: 1386-2073
Combinatorial Chemistry &
High Throughput Screening
Volume 9, Number 6, July 2006
Contents
Combinatorial Antioxidants
Guest Editor: Sibel Suzen
Editorial Pp. 407
Recent Developments of Melatonin Related Antioxidant
Compounds Pp. 409-419
Sibel Suzen
[Abstract] [Purchase
Article]
Combinatorial Library Synthesis of Antioxidant Compounds
Pp. 421-423
Stifun Mittoo
[Abstract]
[Purchase
Article]
Antioxidants and Inflammatory Disease: Synthetic
and Natural Antioxidants with Anti-Inflammatory Activity
Pp. 425-442
Athina A. Geronikaki and Antonios M. Gavalas
[Abstract]
[Purchase
Article]
Antioxidant Activity of Two Wild Edible
Mushrooms (Morchella vulgaris and Morchella esculanta)
from North Turkey Pp. 443-448
Mahfuz Elmastas, Ibrahim Turkekul, Lokman Öztürk,
Ilhami Gülçin, Omer Isildak and Hassan Y. Aboul-Enein
[Abstract]
[Purchase
Article]
Screening the Oxidative Potential of Several Mono-
and Di-Halogenated Biphenyls and Biphenyl Ethers in Rat Hepatocytes
Pp. 449-454
Hande Gurer-Orhan, Hilmi Orhan, Nico P. Vermeulen and
John H. Meerman
[Abstract]
[Purchase
Article]
General Articles
The Use of Artificial Neural Networks for
the Selection of the Most Appropriate Thermal Parameters and
for the Classification of a Set of Phenylcarbamic Acid Derivates
Pp. 455-464
Michal H. Umbreit, Piotr Nowicki, Jolanta Klos and Josef
Cizmarik
[Abstract]
[Purchase
Article]
Analysis and Prediction of Combinatorial Chemistry
Synthesis and Screening Data Pp. 465-472
Nanxiang Ge, Paul Fogel, Sidney S. Young, Richard E. Austin,
Eric Wegrzyniak and James A. Connelly
[Abstract]
[Purchase
Article]
Application of Self-Organizing Maps in Compounds
Pattern Recognition and Combinatorial Library Design
Pp. 473-480
Aixia Yan
[Abstract]
[Purchase
Article]
A Method for Rapid Protease Substrate Evaluation
and Optimization Pp. 481-487
Igor A. Kozlov, Peter C. Melnyk, Chanfeng Zhao, John P.
Hachmann, Veronika Shevchenko, Anu Srinivasan, David L. Barker
and Michal Lebl
[Abstract]
[Purchase
Article]
Meet the Guest Editor
Pp. 489
Abstracts
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Editorial
Free radicals are atoms or groups of atoms with an odd (unpaired)
number of electrons and can be formed when oxygen interacts
with certain molecules. Once formed these highly reactive
radicals can start a chain reaction. Their danger comes from
the damage they can do when they react with important cellular
components such as DNA, or the cell membrane. Increasingly,
their role in a number of human disease processes is being
accepted, although conclusive evidence is lacking in many
cases, due to the difficulties in detecting free radicals
that have very short lifetimes.
To prevent free radical damage the body has a defense system
of antioxidants. Antioxidants interact with and stabilize
free radicals and can prevent some of the damage free radicals
otherwise might cause. Antioxidants are intimately involved
in the prevention of cellular damage, cancer, aging, and a
variety of diseases. However, these benefits have not been
confirmed by recent large clinical trials.
Research suggests that consumption of antioxidant-rich foods
reduces damage to cells and biochemicals from free radicals.
This can slow down, prevent, and even reverse certain diseases
that result from cellular damage, and perhaps even slow down
the natural aging process. An antioxidant may act by catalysis,
or, in cells, it may act as a cofactor that transfers reducing
equivalents from NADPH.
Finding of novel drugs is a very difficult process. Combinatorial
chemistry is one of the important methodologies that can help
to reduce the time and costs associated with producing new
drugs. In the process of finding new drug candidates medicinal
chemists nowadays have a variety of options from which to
choose, and one is to apply combinatorial chemistry techniques.
It is now possible to produce compound libraries to screen
for novel bioactivities. In the preparation of drug candidates,
the automated, and combinatorial use of chemical building
blocks facilitates the generation and screening of large numbers
of compounds. Combinatorial chemistry has been proven to be
an efficient way of generating libraries of compounds and
can be used to identify lead compounds in a short period of
time. It is relatively unexplored when considering the discovery
of novel anti-oxidative agents.
The purpose of this special issue is to serve as a guide to
what antioxidants are and to briefly review their role in
general health. Recent developments of melatonin related antioxidant
compounds, antioxidant containing foods especially in the
Black Sea region of Turkey, evaluation and comparison of the
ROS generating and LP inducing effect of several halogenated
aromatic compounds, the relationship between antioxidants
and inflammatory diseases, and finally, combinatorial library
synthesis of antioxidant compounds are addressed in this special
issue.
I would like to thank the authors for their contributions
and the editor of Combinatorial Chemistry & High Throughput
Screening for the invitation to act as guest editor for
this special issue.
Sibel Süzen
Ankara University
Faculty of Pharmacy
Department of Pharmaceutical Chemistry
06100 Tandogan
Ankara
Turkey
E-mail: sibel@pharmacy.ankara.edu.tr
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Article]
Recent Developments of Melatonin Related Antioxidant
Compounds
Sibel Suzen
Melatonin is known for its radical scavenger activity, which
is related to its ability to protect cells from different
kinds of oxidative stress. Oxidative stress has been implicated
in the development of neurodegenerative diseases like Parkinson,
Alzheimer’s disease, Huntington’s disease, epileptic
seizures, stroke, and as a contributor to aging and some cancer
types. The antioxidant properties of melatonin include scavenging
free radicals and the regulation of the activity and expression
of antioxidant and pro-oxidant enzymes. Due to its free radical
scavenger and antioxidant properties, multiple melatonin-related
compounds such as melatonin metabolites and synthetic analogues
are under investigation to determine which exhibit the highest
activity with the lowest side effects. This review addresses
recent studies with melatonin and related compounds.
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Combinatorial Library Synthesis of Antioxidant
Compounds
Stifun Mittoo
Since oxidative cellular damage contributes to the development
of cancers, heart disease and ageing, the synthesis of antioxidative
agents which are able to either prevent or mitigate oxidative
stress to cells is an important area of investigation. Combinatorial
chemistry has had a profound impact on the discovery and optimisation
of potential lead compounds, especially in the medicinal field.
This review details recent examples of combinatorial chemistry
dealing with the synthesis of novel antioxidants with an emphasis
on solid phase compound synthesis and parallel library synthesis.
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Antioxidants and Inflammatory Disease: Synthetic
and Natural Antioxidants with Anti-Inflammatory Activity
Athina A. Geronikaki and Antonios M. Gavalas
Oxidants play a significant role in the pathogenesis of a
number of disorders such as inflammation, rheumatoid arthritis,
asthma, psoriasis and contact dermatitis leading to oxidative
stress. Oxidative stress may be defined as an imbalance between
cellular production of reactive oxygen species (ROS) and antioxidant
defense mechanisms. ROS (e.g., superoxide radical, peroxynitryl,
hydroxyl radical and hydrogen peroxide) are constantly produced
as a result of metabolic reactions in living systems. The
aim of this review is to describe recent developments in the
study of antioxidants and their role in preventing the formation
of ROS. The processes associated with inflammatory responses
are complex and often involve ROS. There are many mediators,
which initiate and amplify the inflammatory response such
as histamine, serotonin, pro-inflammatory cytokines (interleukin-1B
(IL-1b) and tumor necrosis factor (TNF-α)),
inflammatory cells (leukotrienes, macrophages), metabolic
products of arachidonic acid (thomboxane A2,
prostaglandins and leukotrienes). The first part of this review
focuses on the role of ROS in inflammation. The second part
concerns synthetic antioxidants with antiinflammatory activity,
and the third part addresses naturally occurring antioxidants
with antiinflammatory activity.
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Article]
Antioxidant Activity of Two Wild Edible Mushrooms
(Morchella vulgaris and Morchella esculanta)
from North Turkey
Mahfuz Elmastas, Ibrahim Turkekul, Lokman Öztürk,
Ilhami Gülçin, Omer Isildak and Hassan Y. Aboul-Enein
The ethanol extracts of Morchella vulgaris (EEMV)
and Morchella esculanta (EEME) were analysed for
their antioxidant activities in different systems including
reducing power, free radical scavenging, superoxide anion
radical scavenging, total antioxidant activity, and metal
chelating activity. EEMV and EEME had similar reducing power,
free radical scavenging, superoxide anion radical scavenging,
hydrogen peroxide scavenging, and metal chelating activity
at concentrations of 50, 100, and 150 µg/mL. These various
antioxidant activities were compared to standard antioxidants
such as butylated hydroxyanisole (BHA), butylated hydroxytoluene
(BHT), and α-tocopherol.
The percent inhibition of different concentrations of EEMV
on peroxidation in the linoleic acid system was 85 and 87
% respectively, which was greater than that of 100 and 250
μg/mL
of α-tocopherol
(50 and 77%, respectively) and similar to 250 µg/mL
of BHA (85, 87%, respectively). The percent inhibition of
different concentrations of EEME on peroxidation in the linoleic
acid system was 80 and 87 % respectively, which was greater
than that of 100 and 250 μg/mL
of α-tocopherol
(50, 77%) and similar to 250 μg/mL
BHA (87%). On the other hand, the percent inhibition of 100
and 250 μg/mL
of BHT was 97 and 99%, respectively. In addition, the total
phenolic compounds in EEMV and EEME were determined as gallic
acid equivalents.
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Article]
Screening the Oxidative Potential of Several Mono- and Di-Halogenated
Biphenyls and Biphenyl Ethers in Rat Hepatocytes
Hande Gurer-Orhan, Hilmi Orhan, Nico P. Vermeulen and
John H. Meerman
The present study was designed to investigate the potential
of reactive oxygen species (ROS) generating and subsequent
ROS-mediated lipid peroxidation (LPO) inducing effect of several
mono- and di-halogenated biphenyls and biphenyl ethers in
rat hepatocytes in vitro. For this aim, 4-chloro-
and 4-bromo biphenyl (4-CB and 4-BB), 4-OH, 4´-BB,
4-bromo diphenylether (4-BDE), 4,4´-dichlorobiphenyl
(4,4´-DCB),
4,4´-dibromobiphenyl
(4,4´-DBB),
and 3,4-dichlorobiphenyl (3,4-DCB) were incubated with freshly
isolated rat hepatocytes. Their oxidative potential was evaluated
by detecting the intracellular ROS formation by oxidant-sensing
fluorescent probes (2´,7´-dichlorofluorescein
diacetate and C11-BODIPY581/591
) using a multiplate reader and determining the levels of
eight LPO products (formaldehyde, malondialdehyde, propanal,
butanal, pentanal, hexanal, octanal, and nonanal) by a gas
chromatography-electron capture detection. 4-BDE was found
to be active both in cytoplasm and in the cell membrane in
terms of inducing the formation of ROS. Another important
finding was the increase in ROS-inducing potential of 4-BB
when the same concentration of the hydroxylated derivative,
4-OH,4´-BB,
was incubated with hepatocytes. 4-BDE was also found to be
the most effective among all tested compounds in inducing
LPO where 4-OH, 4´-BB
was again more potent than its unmetabolized form, 4-BB. Lactate
dehydrogenase leakage analyses indicated that all tested compounds
are cytotoxic; 4-BDE caused the highest LDH leakage compared
to other mono-halogenated biphenyls tested. Our results suggest
that ROS formation by chlorinated biphenyls and mono-hydroxylated
bromobiphenyls, and concomitant induction of LPO might be
involved in the cytotoxic effects of these industrial pollutants.
Similar effects of mono-BDE are also reported, which is a
novel observation.
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The Use of Artificial Neural Networks for the Selection
of the Most Appropriate Thermal Parameters and for the Classification
of a Set of Phenylcarbamic Acid Derivates
Michal H. Umbreit, Piotr Nowicki, Jolanta Klos and Josef
Cizmarik
The objective of this work was to apply artificial neural
networks (ANNs) to the classification group of 43 derivatives
of phenylcarbamic acid. To find the appropriate clusters Kohonen
topological maps were employed. As input data, thermal parameters
obtained during DSC and TG analysis were used. Input feature
selection (IFS) algorithms were used in order to give an estimate
of the relative importance of various input variables. Additionally,
sensitivity analysis was carried out to eliminate less important
thermal variables. As a result, one classification model was
obtained, which can assign our compounds to an appropriate
class. Because the classes contain groups of molecules structurally
related, it is possible to predict the structure of the compounds
(for example the position of the substitution alkoxy group
in the phenyl ring) on the basis of obtained parameters.
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Analysis and Prediction of Combinatorial Chemistry
Synthesis and Screening Data
Nanxiang Ge, Paul Fogel, Sidney S. Young, Richard E. Austin,
Eric Wegrzyniak and James A. Connelly
The goal of combinatorial chemistry is to simultaneously synthesize
sets of compounds possessing properties that are then distinguished
through screening. As the size of a compound set increases,
data analysis becomes more challenging. Analysis of Variance
(ANOVA) is an accepted statistical method that offers a straightforward
solution to this problem. Two steps encountered by combinatorial
scientists appear well suited to ANOVA: the prediction of
synthetic outcomes (purity and yield) of set members and the
analysis of screening data to identify combinations of reagent
inputs that result in molecules with a desired property. To
illustrate, a subset of a combinatorial array, referred to
as a reaction rehearsal set, is evaluated to create a model
predictive of the individual synthetic outcomes of the full
matrix. In a second exercise, the biochemical screening data
obtained from a combinatorial library is analyzed to identify
reagent interactions that result in molecules possessing the
sought activity.
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Application of Self-Organizing Maps in Compounds
Pattern Recognition and Combinatorial Library Design
Aixia Yan
In the computer-aided drug design, in order to find some
new leads from a large library of compounds, the pattern recognition
study of the diversity and similarity assessment of the chemical
compounds is required; meanwhile in the combinatorial library
design, more attention is given to design target focusing
library along with diversity and drug-like¬ness criteria.
This review presents the current state-of-art applications
of Kohonen self-organizing maps (SOM) for studying the compounds
pattern recognition, comparing the property of molecular surfaces,
distinguishing drug-like and nondrug-like molecules, splitting
a dataset into the proper training and test sets before constructing
a QSAR (Quantitative Structural-Activity Relationship) model,
and also for the combinatorial libraries comparison and the
combinatorial library design. The Kohonen self-organizing
map will continue to play an important role in drug discovery
and library design.
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A Method for Rapid Protease Substrate Evaluation and
Optimization
Igor A. Kozlov, Peter C. Melnyk, Chanfeng Zhao, John P.
Hachmann, Veronika Shevchenko, Anu Srinivasan, David L. Barker
and Michal Lebl
We have developed a high throughput assay for the measurement
of protease activity in solution. This technology will accelerate
research in functional proteomics and enable biologists to
streamline protease substrate evaluation and optimization.
The peptide sequences that serve as protease substrates in
this assay are labeled on the carboxy terminus with a biotin
moiety and a fluorescent tag is attached to the amino terminus.
Protease cleavage causes the biotin containing fragment to
be detached from the labeled peptide fragment. Following the
protease treatment, all biotin containing species (uncleaved
substrates and the cleaved carboxy terminal fragment of the
substrate) are removed by incubation with streptavidin beads.
The cleaved fluorescently labeled amino terminal part of the
substrate remains in solution. The measured fluorescence intensity
of the solution is directly proportional to the activity of
the protease. This assay was validated using trypsin, chymotrypsin,
caspase-3, subtilisin-A, enterokinase and tobacco etch virus
protease.
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