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Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 13, Number 15, 2006
Contents
Killing Time for Cancer Stem Cells (CSC): Discovery and Development
of Selective CSC Inhibitors Pp. 1719
María Pérez-Caro and Isidro Sánchez-García
[Abstract]
Emerging Role of Intravascular Ultrasound in the Assessment
of Experimental Anti-Atherosclerotic Therapies Pp.
1727-1734
Stephen J. Nicholls and Ilke Sipahi
[Abstract]
Bringing Kinases Into Focus: Efficient Drug Design Through
the Use of Chemogenomic Toolkits Pp. 1735-1748
Veronique Birault, C. John Harris, Joelle Le, Mike Lipkin,
Ravi Nerella and Adrian Stevens
[Abstract]
Antiviral and Immunomodulatory Properties of New Pro-Glutathione
(GSH) Molecules Pp. 1749-1755
A. Fraternale, M.F. Paoletti, A. Casabianca, J. Oiry, P. Clayette,
J.-U. Vogel, J. Jr. Cinatl, A.T. Palamara, R. Sgarbanti, E.
Garaci, E. Millo, U. Benatti and M. Magnani
[Abstract]
Delivering Drugs to the Central Nervous System: A
Medicinal Chemistry or a Pharmaceutical Technology Issue?
Pp. 1757-1775
Maurizio Ricci, Paolo Blasi, Stefano Giovagnoli and Carlo
Rossi
[Abstract]
Novel Therapeutics for Diabetic Micro- and Macrovascular
Complications Pp. 1777-1788
A. Soro-Paavonen and J.M. Forbes
[Abstract]
Carbon Nanotubes: Materials for Medicinal Chemistry
and Biotechnological Applications Pp. 1789-1798
Georgia Pagona and Nikos Tagmatarchis
[Abstract]
Therapeutic Applications of Glycosaminoglycans
Pp. 1799-1810
Nicola Volpi
[Abstract]
Development of BACE1 Inhibitors for Alzheimer’s
Disease Pp. 1811-1829
Tao Guo and Doug W. Hobbs
[Abstract]
Clinical Proteomics: New Trends for Protein Microarrays
Pp. 1831-1837
K.-F. Becker, V. Metzger, S. Hipp and H. Höfler
[Abstract]
Small Molecule Glucokinase Activators as Glucose Lowering
Agents: A New Paradigm for Diabetes Therapy Pp. 1839-1843
Kevin R. Guertin and Joseph Grimsby
[Abstract]
Abstracts
[Back to top]
Killing Time for Cancer Stem Cells (CSC): Discovery
and Development of Selective CSC Inhibitors
María Pérez-Caro and Isidro Sánchez-García
Can cancer be cured or will it have to be controlled
as a chronic disease? Despite a better understanding of the
biology of tumour cells, the treatment of most cancers has
not significantly changed for the past three decades. Are
current cancer drugs targeted at the wrong kind of cells?
Accumulating evidence has implicated that cancer is a disease
of stem cells. In this context, a small fraction of cancer
cells adopt the properties of stem cells. In some cases, the
cancer stem cells (CSC) could be the close derivative of normal
tissue stem cells. In either situation, the net result will
be the same, in that CSC are the cells to be used as targets
in the development of molecular and pharmaceutical therapies
to treat and prevent human cancer. This could be a paradigm
shift in the treatment of cancer, away from targeting the
blast cells and towards the targeting of the CSC. A challenge
to this approach will be to find a way to specifically target
CSC without toxicity to normal cells. In this article, we
propose how CSC can be used in therapy programs (target identification,
drug discovery, etc.). Therefore, in the future, it might
be possible to rid a patient of all his/her cancer cells,
including the cancer stem cells.
[Back to top]
Emerging Role of Intravascular Ultrasound in the Assessment
of Experimental Anti-Atherosclerotic Therapies
Stephen J. Nicholls and Ilke Sipahi
Intravascular ultrasound (IVUS) imaging within the
coronary arteries has emerged as the gold standard for the
quantitation of the extent of atherosclerosis plaque. Studies
that have utilized IVUS have enhanced our understanding of
the in vivo natural history of atherogenesis. As
IVUS can be performed within the same coronary artery at different
time points it has become an attractive tool for the assessment
of the effect of experimental anti-atherosclerotic strategies
on plaque burden. This review will review the evolution of
IVUS as an imaging modality and highlight its use to assess
a number of interventions that are directed at both modification
of existing risk factors and novel targets that are thought
to play a pivotal role in the pathogenesis of atheroma formation.
[Back to top]
Bringing Kinases Into Focus: Efficient Drug
Design Through the Use of Chemogenomic Toolkits
Veronique Birault, C. John Harris, Joelle Le, Mike Lipkin,
Ravi Nerella and Adrian Stevens
The study of protein target families, as opposed
to single targets, has become a very powerful tool in chemogenomics-led
drug discovery. By integrating comprehensive chemoinformatics
and bioinformatics databases with customised analytical tools,
a ‘Toolkit’ approach for the target family is
possible, thus allowing predictions of the ligand class, affinity,
selectivity and likely off-target issues to be made for the
guidance of the medicinal chemist. In this review, we highlight
the development and application of the Toolkit approach to
the protein kinase superfamily, drawing on examples from lead
optimisation studies and the design of focused libraries for
lead discovery.
[Back to top]
Antiviral and Immunomodulatory Properties of New Pro-Glutathione
(GSH) Molecules
A. Fraternale, M.F. Paoletti, A. Casabianca, J. Oiry, P. Clayette,
J.-U. Vogel, J. Jr. Cinatl, A.T. Palamara, R. Sgarbanti, E.
Garaci, E. Millo, U. Benatti and M. Magnani
Reduced glutathione (GSH) is present in millimolar concentrations
in mammalian cells. It is involved in many cellular functions
such as detoxification, amino acid transport, production of
coenzymes, and the recycling of vitamins E and C. GSH acts
as a redox buffer to preserve the reduced intracellular environment.
Decreased glutathione levels have been found in numerous diseases
such as cancer, viral infections, and immune dysfunctions.
Many antioxidant molecules, such as GSH and N-acetylcysteine
(NAC), have been demonstrated to inhibit in vitro
and in vivo viral replication through different mechanisms
of action. Accumulating evidence suggests that intracellular
GSH levels in antigen-presenting cells such as macrophages,
influence the Th1/Th2 cytokine response pattern, and more
precisely, GSH depletion inhibits Th1-associated cytokine
production and/or favours Th2 associated responses. It is
known that GSH is not transported to most cells and tissues
in a free form. Therefore, a number of different approaches
have been developed in the last years to circumvent this problem.
This review discusses the capacity of some new molecules with
potent pro-GSH effects either to exert significant antiviral
activity or to augment GSH intracellular content in macrophages
to generate and maintain the appropriate Th1/Th2 balance.
The observations reported herein show that pro-GSH molecules
represent new therapeutic agents to treat antiviral infections
and Th2-mediated diseases such as allergic disorders and AIDS.
[Back to top]
Delivering Drugs to the Central Nervous System: A
Medicinal Chemistry or a Pharmaceutical Technology Issue?
Maurizio Ricci, Paolo Blasi, Stefano Giovagnoli and Carlo
Rossi
This review aims to summarize the non-invasive approaches
employed in delivering drugs to the central nervous system
which is severely hindered by the presence of the blood–brain
barrier (BBB) that limits molecular permeation. Particular
attention will be placed on the several available strategies
for delivering drugs into the brain, through circumvention
of the BBB, in order to critically address the medicinal chemistry
and the pharmaceutical technology contributions.
[Back to top]
Novel Therapeutics for Diabetic Micro- and Macrovascular
Complications
A. Soro-Paavonen and J.M. Forbes
Diabetic patients have a two- to four-fold increased risk
for the development of microvascular (renal, neuronal and
retinal) and macrovascular complications. Unfortunately, these
complications may develop in both Type 1 and Type 2 diabetic
patients even with careful glycaemic, blood pressure and lipid
control. With the worldwide increase in the incidence diabetes,
new strategies to prevent the complications are urgently needed.
Mediators of vascular damage of diabetes include poor glycemic
control, lipoprotein abnormalities, hypertension, oxidative
stress, inflammation and advanced glycation end-products (AGEs),
which are modified proteins formed by non-enzymatic glycation.
AGEs are resistant to enzymatic degradation and therefore
very stable, thus their accumulation continues throughout
aging. AGE accumulation causes arterial stiffening in the
vessel wall, glomerulosclerosis in the kidney, and vascular
hyperpermeability in the retina. Through their interaction
with their putative receptor the so-called receptor for AGEs
(RAGE), AGEs activate endothelial cells and macrophages, generate
reactive oxygen species (ROS), induce overexpression of vascular
endothelial growth factor (VEGF) and vascular cell adhesion
molecule-1 (VCAM-1), and quench nitric oxide (NO). The pharmacological
treatment currently available for either Type 1 or Type 2
diabetic patients does not directly address the excess accumulation
of AGEs. Novel compounds that inhibit AGE formation, cleave
AGE cross-links or reverse their interaction with RAGE are
now accessible and could prove useful in meeting this challenge.
Other strategies such as inhibition of the hexosamine pathway,
vitamin therapy to reduce oxidation and AGE accumulation,
reduction of the ROS, or blocking the actions of growth factors
or intracellular messengers of cell differentiation are also
currently under research. This review will recount recent
advances in the development of therapeutic approaches for
inhibiting and treating the development of diabetic end-organ
damage.
[Back to top]
Carbon Nanotubes: Materials for Medicinal Chemistry
and Biotechnological Applications
Georgia Pagona and Nikos Tagmatarchis
Carbon nanotubes are considered as molecular wires exhibiting
novel properties for diverse applications including medicinal
and biotechnological purposes. Surface chemistry on carbon
nanotubes results on their solubilization in organic solvents
and/or aqueous/physiological media. Herein, we will present
how interfacing such novel carbon-based nanomaterials with
biological systems may lead to new applications in diagnostics,
vaccine and drug delivery. Recent developments in this rapidly
growing field will be presented thus suggesting exciting opportunities
for the utilization of carbon nanotubes as useful tools for
biotechnological applications. Emphasis will be placed in
the integration of biomaterials with carbon nanotubes, which
enables the use of such hybrid systems as biosensor devices,
immunosensors and DNA-sensors.
[Back to top]
Therapeutic Applications of Glycosaminoglycans
Nicola Volpi
Complex polysaccharides, hyaluronic acid or hyaluronan
(HA), keratan sulfate (KS), chondroitin sulfates (CSs) and
heparin (Hep)/heparan sulfate (HS), are a class of ubiquitous
molecules exhibiting a wide range of biological functions.
They are widely distributed as glycosaminoglycans (GAGs) sidechains
of proteoglycans (PGs) in the extracellular matrix and at
cellular level. The recent emergence of improved enzymatic
and analytical tools for the study of these complex sugars
has produced a virtual explosion in the field of glycomics.
In particular, the study of the GAG family of polysac¬charides
has shed considerable light on the way in which specific carbohydrate
structures modulate cellular phenotypes. In addition to the
well-known therapeutic applications of some of these macromolecules,
such as HA and derivatives as structure modifying molecules
and possessing gel-like properties able to provide functional
support for tissues, Hep as an anticoagulant and antithrombotic
drug and CS in the treatment of osteoarthritis (OA), this
increased understanding of GAG structure-function relationship
has led to the discovery of novel pharmaceuticals for the
possible treat¬ment of serious diseases, such as cancer.
In this paper, the structure and the therapeutic applications
of several complex natural polysaccharides, including HA,
CS/DS, Hep and their derivatives, are presented and discussed
also in the light of the many questions still left unanswered,
such as improved preparation and GAG-based drugs with improved
properties and new possible therapeutic applications.
[Back to top]
Development of BACE1 Inhibitors for Alzheimer’s
Disease
Tao Guo and Doug W. Hobbs
Alzheimer’s disease (AD) is a progressive neurodegenerative
disease and the most common cause of dementia. The production
and accumulation of β-amyloid
peptides (Aβ)
from the β-amyloid
precursor protein (APP) are believed to play a key role in
the onset and progression of AD. BACE1 (β-site
APP cleaving enzyme 1) is the protease responsible for the
N-terminal cleavage of APP leading to the production of Aβ
peptides and the development of BACE1 inhibitors as potential
therapeutic agents for AD has generated tremendous interests
from both academia and the pharmaceutical industry. A wide
variety of BACE1 inhibitors have been reported, several of
which have demonstrated highly promising efficacy in animal
models of AD. This review focuses on recent disclosures of
BACE1 inhibitors in the patent and scientific literature,
covering the period from approximately May 2004 to November
2005
[Back to top]
Clinical Proteomics: New Trends for Protein Microarrays
K.-F. Becker, V. Metzger, S. Hipp and H. Höfler
Protein microarrays are an emerging class of nanotechnology
for tracking many different proteins simultaneously. Much
progress has been made for applications in basic sciences.
Translation of these methods for the treatment of patients,
however, is slow, because the realities in the clinic are
rarely taken into account, and proteomic changes in cultured
cell lines might not fully reflect human diseases due to the
lack of the tissue microenvironment. In this review, we summarise
current protein microarray approaches that are being developed
for profiling tissues and histopathologically defined cell
populations from cancer patients. We provide an overview of
clinical applications for protein lysate microarrays and discuss
the power of this technology for the discovery of disease
markers for cancer diagnosis and individualised treatment.
[Back to top]
Small Molecule Glucokinase Activators as Glucose Lowering
Agents: A New Paradigm for Diabetes Therapy
Kevin R. Guertin and Joseph Grimsby
Glucokinase (GK) is a molecular sensor that regulates glucose
induced insulin secretion in pancreatic β-cells
and glucose homeostasis in the liver via catalysis
of glucose to glucose-6-phosphate. The recent discovery and
development of small molecule glucokinase activators represents
a potentially important development for the management of
type 2 diabetes. Since the discovery of the first orally active
small molecule GK activator RO0281675, a number of research
groups have reported the identification of potent activators.
In this review, the biological significance of GK in whole
body glucose homeostasis is briefly described coupled with
the recent progress regarding the identification of novel
small molecule GK activators.
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