| Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 16, Number 35, 2009
Contents
The Yin and Yang of CD4+
Regulatory T Cells in Autoimmunity and Cancer Pp.
4626-4631
M. Galgani, A. Di Giacomo, G. Matarese, A. La
Cava
[Abstract] [Purchase
Article] [PMID:
19903146 PubMed - indexed for MEDLINE]
Innovations and Opportunities to Improve Conventional
(Deoxy)Nucleo-side and Fluoropyrimidine Analogs in Cancer
Pp. 4632-4643
A.D. Adema, I.V. Bijnsdorp, M.L. Sandvold, H.M.
Verheul and G.J. Peters
[Abstract] [Purchase
Article] [PMID:
19903145 PubMed - indexed for MEDLINE]
The Role of Neopterin in Atherogenesis and Cardiovascular
Risk Assessment Pp. 4644-4653
D. Fuchs, P. Avanzas, R. Arroyo-Espliguero, M. Jenny, L. Consuegra-Sanchez
and J.C. Kaski
[Abstract] [Purchase
Article] [PMID:
19903144 PubMed - indexed for MEDLINE]
Oxidative Stress and Mitochondrial Dysfunction
in Atherosclerosis: Mitochondria-Targeted Antioxidants as
Potential Therapy Pp. 4654-4667
V.M. Victor, N. Apostolova, R. Herance, A. Hernandez-Mijares
and M. Rocha
[Abstract] [Purchase
Article] [PMID:
19903143 PubMed - indexed for MEDLINE]
Pharmacomimetics of Exercise: Novel Approaches for
Hippocampally-Targeted Neuroprotective Agents Pp.
4668-4678
A.M. Stranahan, Y. Zhou, B. Martin and S. Maudsley
[Abstract] [Purchase
Article] [PMID:
19903142 PubMed - indexed for MEDLINE]
Second Messenger Modulation: A Novel Target of Future
Antidepressants? Pp. 4679-4690
D. Marazziti, M. Catena Dell’Osso, G. Consoli and
S. Baroni
[Abstract] [Purchase
Article] [PMID:
19903141 PubMed - indexed for MEDLINE]
Endothelial Calcium Machinery and Angiogenesis: Understanding
Physiology to Interfere with Pathology Pp. 4691-4703
L. Munaron and A. Fiorio Pla
[Abstract] [Purchase
Article] [PMID:
19903140 PubMed - indexed for MEDLINE]
Synthesis of Thieno[2,3-d]oxazines and thieno[2,3-d]thiazines
as Subtype Specific Kainate Receptor Antagonists Pp.
4704-4711
D. Briel, A. Rybak, S. Mann, C. Kronbach and
K. Unverferth
[Abstract] [Purchase
Article] [PMID:
19903139 PubMed - indexed for MEDLINE]
Iron Oxide Based MR Contrast Agents: from Chemistry
to Cell Labeling Pp. 4712-4727
S. Laurent, S. Boutry, I. Mahieu, L. Vander Elst
and R.N. Muller
[Abstract] [Purchase
Article] [PMID:
19903138 PubMed - indexed for MEDLINE]
Multifunctional Lipoic Acid Conjugates Pp.
4728-4742
M. Koufaki, A. Detsi and C. Kiziridi
[Abstract] [Purchase
Article] [PMID:
19903137 PubMed - indexed for MEDLINE]
Gammadelta T Lymphocytes Producing IFNγ
and IL-17 in Response to Candida Albicans
or Mycobacterial Antigens: Possible Implications for Acute
and Chronic Inflammation Pp. 4743-4749
A. Poggi, S. Catellani, A. Musso and M.R. Zocchi
[Abstract] [Purchase
Article] [PMID:
19903136 PubMed - indexed for MEDLINE]
Spectroscopic and Theoretical Approaches for the Determination
of Heparin Saccharide Structure and the Study of Protein-Glycosaminoglycan
Complexes in Solution Pp. 4750-4766
T.R. Rudd, E.A. Yates and M. Hricovíni
[Abstract] [Purchase
Article] [PMID:
19903135 PubMed - indexed for MEDLINE]
Abstracts
[Back to top] [Purchase
Article] [PMID:
19903146 PubMed - indexed for MEDLINE]
The Yin and Yang of CD4+
Regulatory T Cells in Autoimmunity and Cancer
M. Galgani, A. Di Giacomo, G. Matarese, A. La
Cava
The immune system balances effector responses with tolerance,
to protect the host from pathogens while minimizing local
damage to tissue. An altered control of immune homeostasis
can lead to loss of tolerance to self antigens in autoimmunity,
or promote unwanted tolerance to tumor growth. This review
focuses on the dual activity of CD4+
regulatory T cells (Tregs) in autoimmunity and cancer. Tregs
play a key role in the mechanisms of immune tolerance and
actively suppress pro-inflammatory responses, thus providing
a beneficial action in autoimmunity and detrimental effects
in cancer.
[Back to top]
[Purchase
Article] [PMID:
19903145 PubMed - indexed for MEDLINE]
Innovations and Opportunities to Improve Conventional
(Deoxy)Nucleo-side and Fluoropyrimidine Analogs in Cancer
A.D. Adema, I.V. Bijnsdorp, M.L. Sandvold, H.M.
Verheul and G.J. Peters
Many drugs that are currently used for the treatment
of cancer have limitations, such as induction of resistance
and/or poor biological half-life, which reduce their clinical
efficacy. To overcome these limitations several strategies
have been explored.
Chemical modification by the attachment of lipophilic moieties
to (deoxy)nucleoside analogs should enhance the plasma half
live, change the biodistribution and improve cellular uptake
of the drug. Attachment of a lipophilic moiety to a phosphorylated
(deoxy)nucleoside analog will improve the activity of the
drugs by circumventing the rate-limiting activation step of
(deoxy)nucleoside analogs. Duplex and multiplex drugs consist
of distinct active drugs with different mechanisms of action,
which are linked to each other with either a lipid or a phosphodiester.
Enzymatic cleavage of such a prodrug inside the cell releases
the drug or the phosphorylated form of the drug.
Antitumor activity of cytotoxic drugs can also be enhanced
by the use of nanoparticles as carriers. Nanoparticles have
the advantage of high stability, high carrier capacity, incorporation
of hydrophobic and hydrophilic compounds and variable routes
of administration. Encapsulating drugs in liposomes protects
the drug against enzymatic breakdown in the plasma and makes
it possible to get lipophilic compounds to the tumor site.
Nanoparticles and liposomes can be used to target drugs either
actively or passively to the tumor.
In this review we discuss the considerable progress that has
been made in increasing the efficacy of classic (deoxy)nucleoside
and fluoropyrimidine compounds by chemical modifications and
alternative delivery systems. We expect that combining different
strategies could further increase the efficacy of these compounds.
[Back to top]
[Purchase
Article] [PMID:
19903144 PubMed - indexed for MEDLINE]
The Role of Neopterin in Atherogenesis and Cardiovascular
Risk Assessment
D. Fuchs, P. Avanzas, R. Arroyo-Espliguero, M. Jenny, L. Consuegra-Sanchez
and J.C. Kaski
Neopterin is produced by human and primate monocyte/macrophages
upon activation by pro-inflammatory stimuli like Th1-type
cytokine interferon-γ.
Neopterin has pro-oxidative properties, which have been demonstrated
in vitro in physicochemical and cell culture studies
and also in in vivo experiments, e.g. the Langendorff
perfusion model of rat hearts. In the past several years,
the measurement of neopterin concentrations in body fluids
including serum, urine and cerebrospinal fluid has revealed
a potential role of this molecule in the prediction of long-term
prognosis in both patients with cancer and those with systemic
infections such as HIV-1 infection. Moreover, elevated neopterin
concentrations have been reported in patients with coronary
disease compared to controls and in recent years it has become
apparent that increased neopterin concentrations are an independent
marker for cardiovascular disease and a predictor of future
cardiovascular events in patients with coronary artery disease.
Current data suggest that the diagnostic performance of neopterin
testing is comparable to that of well established biomarkers
such as C-reactive protein and cholesterol plasma levels.
The present article reviews the role of neopterin in the pathogenesis
of cardiovascular disease and as a marker of coronary artery
disease progression.
[Back to top]
[Purchase Article] [PMID:
19903143 PubMed - indexed for MEDLINE]
Oxidative Stress and Mitochondrial Dysfunction
in Atherosclerosis: Mitochondria-Targeted Antioxidants as
Potential Therapy
V.M. Victor, N. Apostolova, R. Herance, A. Hernandez-Mijares
and M. Rocha
:Chronic and acute overproduction of reactive oxygen species
(ROS) under pathophysiologic conditions forms an integral
part of the development of cardiovascular diseases (CVD),
and in particular atherosclerosis. These ROS are released
from different sources, such as xanthine oxidase, lipoxygenase,
nicotinamide adenine dinucleotide phosphate oxidase, the uncoupling
of nitric oxide synthase and, in particular, mitochondria.
Endothelial dysfunction, characterized by a loss of nitric
oxide (NO) bioactivity, occurs early on in the development
of atherosclerosis, and determines future vascular complications.
Although the molecular mechanisms responsible for mitochondria-mediated
disease processes are not clear, oxidative stress seems to
play an important role. In general, ROS are essential to cell
function, but adequate levels of antioxidant defenses are
required in order to avoid the harmful effects of excessive
ROS production. Mitochondrial oxidative stress damage and
dysfunction contribute to a number of cell pathologies that
manifest themselves through a range of conditions. This review
considers the process of atherosclerosis from a mitochondrial
perspective, and assesses strategies for the targeted delivery
of antioxidants to mitochondria that are currently under development.
We will provide a summary of the following areas: the cellular
metabolism of reactive oxygen species (ROS) and its role in
pathophysiological processes such as atherosclerosis; currently
available antioxidants and possible reasons for their efficacy
and inefficacy in ameliorating oxidative stress-mediated diseases;
and recent developments in mitochondrially-targeted antioxidants
that concentrate on the matrix-facing surface of the inner
mitochondrial membrane in order to protect against mitochondrial
oxidative damage, and their therapeutic potential as a treatment
for atherosclerosis.
[Back to top]
[Purchase
Article] [PMID:
19903142 PubMed - indexed for MEDLINE]
Pharmacomimetics of Exercise: Novel Approaches for
Hippocampally-Targeted Neuroprotective Agents
A.M. Stranahan, Y. Zhou, B. Martin and S. Maudsley
Coordinated and constructive physical activity is correlated
with the maintenance of cognitive function in humans. Voluntary
running also enhances neuroplasticity in adult and aging rodents,
but the molecular pathways underlying these effects are still
being elucidated. Considering the multifactorial nature of
the biochemical links between physical activity and neurophysiology,
it is likely that there are many pharmacological mechanisms
by which the beneficial actions of exercise can be effectively
reproduced using chemical agents. Most studies to date have
focused on brain-derived neurotrophic factor (BDNF) as a signaling
target for the enhancement of neuronal function by exercise.
The goal of the current review is to move beyond BDNF by exploring
the diversity of molecular pathways regulated by physical
activity in a variety of situations. We will discuss the availability
and mechanism of action for several diverse physical activity
pharmacomimetics. As physical activity enhances both neuroplasticity
and cognition, understanding the molecular targets for these
effects may lead to the development of potent new therapeutic
interventions for age-related neurodegenerative conditions
such as Alzheimer’s disease.
[Back to top]
[Purchase
Article] [PMID:
19903141 PubMed - indexed for MEDLINE]
Second Messenger Modulation: A Novel Target of Future
Antidepressants?
D. Marazziti, M. Catena Dell’Osso, G. Consoli and
S. Baroni
During the transduction of extracellular signals within the
cell, the stimulation of specific G protein-coupled receptors
(GPCRs) can modulate adenylyl or guanylyl cyclase, phospholipase
C activity and ion channels, which regulate second-messengers.
These, in turn, trigger several biochemical cascades, including
Ca2+ release, activation
of protein kinases and gene expression. Significant changes
of monoamine GPCR activity may occur in patients suffering
from mood disorders and the majority of antidepressants exert
part of their effects through GPCR-mediated systems. The main
signal transduction pathways activated by metabotropic receptors
in the brain and their possible involvement in the pathophysiology
of mood disorders will be reviewed herein with a special focus
on the horizons opened by this approach in terms of innovative
therapeutic strategies.
[Back to top]
[Purchase
Article] [PMID:
19903140 PubMed - indexed for MEDLINE]
Endothelial Calcium Machinery and Angiogenesis: Understanding
Physiology to Interfere with Pathology
L. Munaron and A. Fiorio Pla
Endothelial cells (ECs) play a pivotal role in physiological
and altered tissue neovascularization. They face multiple
morphological, biochemical and functional changes during the
different phases of angiogenesis, under the regulation of
a great number of proangiogenic and antiangiogenic signals,
including soluble and insoluble factors, cell-cell and cell-matrix
interactions. ECs mutual contacts (and also interactions with
other cell types, such as pericytes and smooth vascular muscle
cells), motility, proliferation, apoptosis and differentiation
are all calcium-dependent events finely tuned in space and
time.
Most of the angiogenic-related peptidic factors (VEGF, bFGF
and others) promote an increase of cytosolic free calcium
concentration in ECs, giving rise to calcium–activated
intracellular cascades engaged in the different steps of the
angiogenic process. A better knowledge of such signals could
allow to set new diagnostic and therapeutical approaches aimed
to interfere with altered neovascularization, particularly
during cancer progression. This review reports the state of
the art about endothelial angiogenic-related calcium signaling
and discusses the most attractive perspectives for the future.
[Back to top]
[Purchase
Article] [PMID:
19903139 PubMed - indexed for MEDLINE]
Synthesis of Thieno[2,3-d]oxazines and thieno[2,3-d]thiazines
as Subtype Specific Kainate Receptor Antagonists
D. Briel, A. Rybak, S. Mann, C. Kronbach and
K. Unverferth
For the development of new antiepileptics the kainate receptors,
GluR6 and GluR5, are important targets. Based on the anticonvulsant
effects of chinazolines and thieno[2,3-d]pyrimidines that
are known from the literature, thieno[2,3-d][1.3]oxazines
were synthesized and studied for their inhibitory properties
at GluR6 and GluR5 receptors. The strongest inhibitor activity
was observed with 5-methyl-6-phenyl-thieno[2,3-d][1.3]oxazines
with C1 or C3-substituents in position 2 (3b-f).
The 2-trihalide-methyl-substituted compounds 3c
and 3d were the most active inhibitors at
the GluR5-receptor (IC50=23.4
μmol,
16 μl).
The 2-isopropyl-substituted compound 3f displayed
the strongest activity at the GluR6-receptor (IC50=8.7
μmol).
A number of thieno[2,3-d][1.3]thiazines and thieno[2,3-d]pyrimidines
that were synthesized from the thieno[2,3][1.3]oxazines did
not show any activity.
[Back to top]
[Purchase
Article] [PMID:
19903138 PubMed - indexed for MEDLINE]
Iron Oxide Based MR Contrast Agents: from Chemistry
to Cell Labeling
S. Laurent, S. Boutry, I. Mahieu, L. Vander Elst
and R.N. Muller
Superparamagnetic iron oxide nanoparticles can be used for
numerous applications such as MRI contrast enhancement, hyperthermia,
detoxification of biological fluids, drug delivery, or cell
separation. In this work, we will summarize the chemical routes
for synthesis of iron oxide nanoparticles, the fluid stabilization,
and the surface modification of superparamagnetic iron oxide
nanoparticles. Some examples of the numerous applications
of these particles in the biomedical field mainly as MRI negative
contrast agents for tissue-specific imaging, cellular labeling,
and molecular imaging will be given.
Larger particles or particles displaying a non-neutral surface
(thanks to their coating or to a cell transfection agent with
which they are mixed) are very useful tools, although the
cells to be labeled have no professional phagocytic function.
Labeled cells can then be transplanted and monitored by MRI
in a broad spectrum of applications.
Direct in vivo magnetic labeling of cells is mainly
performed by intravenous injection of long-circulating iron
oxide-based MRI contrast agents, which can extravasate and/or
undergo a cellular uptake in an amount sufficient to allow
an MRI visualization of areas of interest such as inflamed
regions or tumors.
Particles with long circulation times, or able to induce a
strong negative effect individually have been also modified
by conjugation to a ligand, so that their cellular uptake,
or at least their binding to the cell surface, could occur
through a specific ligand-receptor interaction, in vivo
as well as in vitro. Thus, experimentally as well
as in a few trials on humans, iron oxide particles currently
find promising applications.
[Back to top]
[Purchase
Article] [PMID:
19903137 PubMed - indexed for MEDLINE]
Multifunctional Lipoic Acid Conjugates
M. Koufaki, A. Detsi and C. Kiziridi
Several hundreds of studies published the last decade have
reported that α-lipoic
acid (LA) possesses the potential to intervene in various
therapeutically interesting pathways. However, it should be
noted that LA reportedly exerts most of its effects at high
micromolar concentrations; that amides of LA exhibit higher
biological activity than the parent compound; and that molecular
combinations (hybrids) obtained by coupling LA with an amino-substituted
bioactive moiety, possess multifunctional activity.
The design and synthesis of hybrid molecules encompassing
two pharmacophores in one molecular scaffold is a well established
approach to the synthesis of more potent drugs with dual activity.
Using this approach, various research groups have recently
designed and synthesized LA containing hybrid compounds with
antioxidant activity hyphenated with a wide variety of other
activities such as neuroprotective, cardioprotective, anti-inflammatory,
antidiabetic and anticancer activity as well as enzyme inhibition.
Moreover, LA represents an ideal chemical entity for the development
of biologically interesting functionalized nanoparticles.
Many recent publications describe the use of LA: i) as component
of nanospheres and nanoprodrugs, ii) as a linker for the attachment
of lipids, carbohydrates, proteins and oligonucleotides on
gold nanoparticles to form Self Assembled Monolayers (SAMs)
and iii) as surface ligand for cap exchange reactions to prepare
water-soluble semiconducting nanocrystal Quantum Dots (QDs).
This review is focused on the growing field of the design
and synthesis of LA conjugates, for the development of novel
molecules with a dual mode of action and the construction
of nanosized antioxidants, Self Assembled Monolayers and Quantum
Dots.
[Back to top]
[Purchase
Article] [PMID:
19903136 PubMed - indexed for MEDLINE]
Gammadelta T Lymphocytes Producing IFNγ
and IL-17 in Response to Candida Albicans
or Mycobacterial Antigens: Possible Implications for Acute
and Chronic Inflammation
A. Poggi, S. Catellani, A. Musso and M.R. Zocchi
T lymphocytes bearing the γδ
T cell receptor are known to play an important role in the
first-line defense against viral, bacterial and fungal pathogens.
Two main subsets of γδ
T cells are known, showing distinct functional behavior: Vδ2
T lymphocytes, circulating in the peripheral blood, are involved
in the response to mycobacterial infections and certain viruses,
including coxsackie virus B3 and herpes simplex virus type
2. Vδ1
T cells are resident in the mucosal-associated lymphoid tissue
and are reported to participate in the immunity against Listeria
monocytogenes and cytomegalovirus. Vδ2
T lymphocytes recognize non-peptidic phosphorylated metabolites
of isoprenoid biosynthesis, expressed by mycobacteria, while
Vδ1
T cells mainly interact with MHC-related antigens (MIC-A and
MIC-B) and with receptors, called UL-16 binding proteins,
for the UL-16 protein produced by cytomegalovirus-infected
cells.
Both Vδ1
and Vδ2
T cells can produce interferon-γ
in response to MIC-A+ cells
or non-peptide antigens, respectively. Moreover, production
of TNF-α
by human Vγ9/Vδ2
T cells has been demonstrated in response to bacterial products
and non-peptidic molecules. Recently, it has been reported
that γδ
T lymphocytes can produce IL-17 during Escherichia coli
or Mycobacterium tuberculosis infections in
mice. This is of interest as IL-17 is emerging as a cytokine
crucial in the control of intracellular pathogens and fungi.
In this review, we will discuss the possible role of IL-17
producing γδ
T cells in the regulation of acute and chronic inflammation,
focusing on the different responses of the two subsets to
mycobacterial, viral or fungal antigens.
[Back to top]
[Purchase
Article] [PMID:
19903135 PubMed - indexed for MEDLINE]
Spectroscopic and Theoretical Approaches for the Determination
of Heparin Saccharide Structure and the Study of Protein-Glycosaminoglycan
Complexes in Solution
T.R. Rudd, E.A. Yates and M. Hricovíni
Glycosaminoglycans (GAGs), such as heparin and heparan sulphate,
are a class of linear, anionic polysaccharides that constitute
the carbohydrate component of proteoglycans. The structure
of GAG complexes with proteins can reveal details of their
mechanisms of action in living systems and help to design
new pharmaceuticals. Molecular modelling together with nuclear
magnetic resonance (NMR) and other spectroscopic techniques
such as circular dichroism (CD) provide indispensable information
on structure and dynamics of GAGs and their complexes. The
present review focuses on applications of high-resolution
NMR, CD and molecular modelling to the analysis of GAGs. The
most advanced theoretical methods used at present in GAG research,
density functional theory methods (DFT), are also discussed.
|
