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Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 13, Number 13, 2006
Contents
Dietary Small Molecules and Large-Scale Gene Expression Studies:
An Experimental Approach for Understanding their Beneficial
Effects on the Development of Malignant and Non Malignant
Proliferative Diseases Pp. 1481-1489
Devi Mariappan, Johannes Winkler, Vijaya Parthiban, Michael
Xavier Doss, Jürgen Hescheler and Agapios Sachinidis
[Abstract]
Strategies for Efficient Lead Structure Discovery from Natural
Products Pp. 1491-1507
J.M. Rollinger, T. Langer and H. Stuppner
[Abstract]
Controlling Biofilms of Gram-Positive Pathogenic Bacteria
Pp. 1509-1524
Wolf-Rainer Abraham
[Abstract]
The Application of Freidinger Lactams and their Analogs in
the Design of Conformationally Constrained Peptidomimetics
Pp. 1525-1556
Andrej Perdih and Danijel Kikelj
[Abstract]
Natural and Adaptive Immune Cell-Based Therapies in
Autoimmunity Pp. 1557-1566
Antonio La Cava and Fu-Dong Shi
[Abstract]
Selective α7
Nicotinic Acetylcholine Receptor Ligands Pp. 1567-1584
Anatoly Mazurov, Terry Hauser and Craig H. Miller
[Abstract]
Comprehensive Therapy in Osteoporosis Using a Single
Drug:From ADFR to Strontium Ranelate Pp. 1585-1590
C. Manette, J. Collette, N. Sarlet, A. Tancredi,
B. Zegels and J.-Y. Reginster
[Abstract]
Abstracts
[Back to top]
Dietary Small Molecules and Large-Scale Gene Expression
Studies: An Experimental Approach for Understanding their
Beneficial Effects on the Development of Malignant and Non
Malignant Proliferative Diseases
Devi Mariappan, Johannes Winkler, Vijaya Parthiban, Michael
Xavier Doss, Jürgen Hescheler and Agapios Sachinidis
Epidemiological studies have repeatedly demonstrated
a correlation between nutrition, development and the severity
of malignant and non-malignant proliferative diseases such
as cancer and atherosclerosis. Therefore, the prevention of
chronic proliferative diseases through dietary intervention
is currently receiving considerable attention. Until now,
much of the research is being focused on the cellular and
molecular action mechanisms of dietary small molecules explaining
their beneficial effects. Dietary chemicals may affect gene
expression in several human diseases. However, significant
progress has been made and several molecular action mechanisms
have been proposed. Alteration of genetical pathways by nutrition,
also called "Nutrigenomics", may offer a new approach
for understanding the beneficial effects of dietary compounds
on the development of severe polygenic diseases, such as cardiovascular
disease, diabetes and hypertension. This review focuses on
the nutritional genomics of dietary chemicals with a special
emphasis on catechins. Catechins belong to the flavonoid family,
which are polyphenolic compounds available in foods of plant
origin. Several epidemiological studies have reported that
consumption of flavonoids, and especially catechins might
function as chemopreventive agents against cancer and cardiovascular
diseases.
[Back to top]
Strategies for Efficient Lead Structure Discovery
from Natural Products
J.M. Rollinger, T. Langer and H. Stuppner
This investigation aims to evaluate strategies for
an efficient selection of bioactive compounds from the multitude
and biodiversity of the plant kingdom. Statistics prove natural
products (NPs) as a source leading most consistently to successful
development of new drugs. However, there are several reasons
why the interest in finding bioactive NPs has generally declined
at several major pharmaceutical companies. Their substantial
argument is that the research in this field is time-consuming,
highly complex and ineffective.
A more rational and economic search for new lead structures
from nature must therefore be a priority in order to overcome
these problems. In this paper, different strategies are described
to exploit the molecular diversity of bioactive secondary
metabolites, namely classical pharmacognostic approaches and
computational methods. The latter include various data mining
tools, like virtual screening filtering experiments using
pharmacophore models, docking studies, and neural networks,
which help to establish a relationship between chemical structure
and biological activity. The strengths and weaknesses of these
methods will be shown in this review.
Focusing on selected targets within the arachidonic acid cascade
(phospholipase A2,
5-lipoxygenase, cyclooxygenase-1 and -2), several studies
of successful discoveries in the field of anti-inflammatory
NPs were scrutinized for the applied strategies. Both the
compilation of relevant published data and recent studies
supported by our own research clearly demonstrate the benefits
of the synergistic effect of a hybridization of these strategies
for an effective drug discovery from natural ingredients.
[Back to top]
Controlling Biofilms of Gram-Positive Pathogenic
Bacteria
Wolf-Rainer Abraham
Many bacteria can form aggregates on interfaces,
called biofilms, where they are much more protected against
toxic agents such as antibiotics or antibodies. Bacteria organized
in biofilms are therefore very difficult to control and often
even high dosages of antibiotics cannot clear infectious biofilms.
To form biofilms bacteria have to start a complex genetic
program to switch from planktonic to sessile lifestyle. This
starts with the determination of their cell density, a process
called quorum sensing, triggered by small, water soluble molecules,
so called autoinducers. From Gram-positive bacteria several
small peptides are known, many of them thiolactones. More
recently another group of compounds was discovered probably
formed from ribose-homocysteine and the first autoinducer-II
identified is a furanosyl borate diester. While small peptides
are found to trigger the intraspecies communication autoinducer-II
is assumed to be used for communication at the interspecies
level. Taking the lead structure from these peptides several
derivatives have been developed which prevent biofilm formation
in many Gram-positive bacteria, including Staphylococcus
aureus. Some of these compounds are already in clinical
studies. In this review the different approaches to control
bacterial biofilms are discussed together with the difficulties
arising from the species-specificity of the autoinducers.
[Back to top]
The Application of Freidinger Lactams and their Analogs
in the Design of Conformationally Constrained Peptidomimetics
Andrej Perdih and Danijel Kikelj
Peptides exist in solution as an equilibrium mixture of conformers.
The backbone conformational constraints are of interest as
a means of limiting degrees of freedom and thereby constraining
a synthetic peptide into the bioactive conformation. This
concept plays an important role in the design of peptidomimetics
in the drug development process. In the early eighties, Freidinger
proposed the concept of protected lactam-bridged dipeptides,
which was a milestone in the design of conformationally constrained
peptides. These types of compounds, now widely known as Freidinger
lactams, have been of interest to many medicinal and peptide
chemists. This review seeks to present the various applications
that Freidinger lactams and their hetero-, fused- and unsaturated
analogs have found in the design of conformationally constrained
peptidomimetics in different therapeutic areas.
[Back to top]
Natural and Adaptive Immune Cell-Based Therapies in
Autoimmunity
Antonio La Cava and Fu-Dong Shi
Recent studies have raised great interest in the modulation
of autoimmune responses by manipulation of immunoregulatory
cells. Several lymphocyte subpopulations responsible for the
induction and maintenance of immune tolerance have been extensively
studied, and much has been learned about their properties.
Lately, a series of attempts to harness the immunoregulatory
activities of these cells for therapeutic purposes has proven
successful in preclinical studies. The development of new
strategies for the expansion of glycolipid-induced activation
of NKT cells and antigen-specific regulatory T cells represent
examples that have generated considerable interest and that
are leading to the development of immunoregulatory cell-based
approaches translating the findings from the bench to the
bedside. This review highlights the advances, obstacles and
limitations of these studies and critically discusses the
most recent findings in this rapidly expanding field.
[Back to top]
Selective α7
Nicotinic Acetylcholine Receptor Ligands
Anatoly Mazurov, Terry Hauser and Craig H. Miller
Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand
gated ion channels of broad distribution and structural heterogeneity.
Their functional diversity demonstrated involvement in a variety
of neuronal processes (e.g., sensory gating and cognitive
function) and generated great interest in them as targets
for therapeutic intervention in a number of neuropathological
conditions and diseases. In order to control distinct nicotinic
functions pharmacologically, it is important to design ligands
that selectively interact with distinct receptor subtypes
in such a way as to maximize the therapeutic effect and minimize
the adverse effects. The α7
nAChR, a CNS subtype, has been the most intensively studied
nAChR in recent years. Selective α7
nAChR agonists have been developed as potential candidates
for the treatment of schizophrenia, cognitive disorders (including
Alzheimer’s disease), and inflammation. Despite early
concerns that the rapid desensitization property of the α7
nAChR would limit their therapeutic potential, several have
already been advanced to clinical trials (e.g., PH-399733,
Pfizer; MEM 3454, Memory Pharmaceuticals/Roche). Further development
of allosteric modulators and pharmaceutically relevant antagonists
might expand the therapeutic potential of compounds that target
α7
nAChRs. In this review we briefly describe the structure and
function of the α7
nAChR and its in vitro and in vivo pharmacology,
discuss the clinical relevance of these efforts, and review
the current progress in α7
ligand development.
[Back to top]
Comprehensive Therapy in Osteoporosis Using a Single
Drug:From ADFR to Strontium Ranelate
C. Manette, J. Collette, N. Sarlet, A. Tancredi,
B. Zegels and J.-Y. Reginster
In vitro, strontium ranelate increases collagen
and non-collagenic proteins synthesis by mature osteoblast
enriched cells. The effects of strontium ranelate on bone
formation were confirmed as the drug enhanced preosteoblastic
cell replication. In the isolated rat osteoclast, a preincubation
of bone slices with strontium ranelate induced a dose-dependent
inhibition of the bone resorbing activity of treated rat osteoclast.
Strontium ranelate dose-dependently inhibited preosteoclast
differentiation. In a phase II dose ranging trial Strontium
ranelate (500 mg, 1000 mg, 2000 mg/day) or placebo were given
to 353 postmenopausal women with prevalent vertebral osteoporosis.
At the conclusion of this 2-year study, the annual increase
in lumbar BMD of the group receiving 2000 mg of strontium
ranelate was + 7.3%, a significant increase in bone alkaline
phosphatase, over a 6-month period and a significant decrease
in N-telopeptide crosslinks throughout the 2-year period were
seen. During the second year of treatment, the dose of 2000
mg was associated with a 44% reduction in the number of patients
experiencing a new vertebral deformity. The primary analysis
of the SOTI study, evaluating the effect of strontium ranelate
2000 mg on vertebral fracture rates, revealed a 41% reduction
in the relative risk of patient experiencing a first new vertebral
fracture with strontium ranelate throughout the 3-year study.
The TROPOS study showed a significant reduction in the risk
of experiencing a first non-vertebral fracture by 16% in the
group treated with strontium ranelate throughout the 3-year
study. A reduction in the risk of experiencing a hip fracture
by 36% was also demonstrated in the patients at high risk
of hip fracture (age ≥74 years and Femoral Neck T score
≤-2.4 according to NHANES normative value).
All these results suggest that strontium ranelate is a new,
effective and safe treatment of vertebral and non-vertebral
osteoporosis, with a unique mode of action.
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