| Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 16, Number 29, 2009
Contents
Targeting Epidermal Growth Factor Receptor
in Solid Tumors: Critical Evaluation of the
Biological Importance of Therapeutic Monoclonal
Antibodies Pp. 3797-3804
Ch. Gialeli, D. Kletsas, D. Mavroudis, H.P. Kalofonos,
G.N. Tzanakakis and N.K. Karamanos
[Abstract] [Purchase
Article]
Selective Matrix Metalloproteinase Inhibitors
for Cancer Pp. 3805-3827
Nian-Guang , Zhi-Hao Shi, Yu-Ping Tang and
Jin-Ao Duan
[Abstract] [Purchase
Article]
Circulating Biomarkers for the Diagnosis and Prognosis
of Heart Failure Pp. 3828-3840
D. Tousoulis, A.M. Kampoli, G. Siasos, E. Stefanadi, C.
Antoniades, A.G. Papavassiliou and C. Stefanadis
[Abstract] [Purchase
Article]
Cardiovascular Effects of Losartan and Its Relevant
Clinical Application Pp. 3841-3857
Feichao Xu, Caiping Mao, Yali Hu, Can Rui, Zhice Xu and
Lubo Zhang
[Abstract] [Purchase
Article]
Medicinal Chemistry Approaches for Glucokinase
Activation to Treat Type 2 Diabetes Pp. 3858-3874
Manojit Pal
[Abstract] [Purchase
Article]
Adenosine and Adenosine Receptors: Their Contribution
to Airway Inflammation and Therapeutic Potential in Asthma
Pp. 3875-3885
M. Caruso, K. Varani, G. Tringali and R. Polosa
[Abstract] [Purchase
Article]
Role of Nuclear Steroid Receptors in Apoptosis Pp.
3886-3902
Joana D. Amaral, Susana Solá, Clifford J. Steer and Cecília M.P. Rodrigues
[Abstract] [Purchase
Article]
Design Strategies of Novel NNRTIs to Overcome
Drug Resistance Pp. 3903-3917
Peng Zhan, Xinyong Liu, Zhenyu Li, Christophe Pannecouque and Erik De Clercq
[Abstract] [Purchase
Article]
Abstracts
[Back to top]
[Purchase
Article]
Targeting Epidermal Growth Factor Receptor in Solid Tumors:Critical
Evaluation of the Biological Importance of Therapeutic
Monoclonal Antibodies
Ch. Gialeli, D. Kletsas, D. Mavroudis, H.P. Kalofonos,
G.N. Tzanakakis and N.K. Karamanos
Numerous cellular pathways have a significant impact in
the growth and metastatic potential of tumors. Essential element
of such pathways is the epidermal growth factor receptor (EGFR),
a member of the HER family of receptor tyrosine kinases. One
of the most important issues in cancer, which attracted the
attention of clinical oncologists, is the potential use of
targeted therapies. EGFR signaling pathway is implicated in
the control of cell survival, proliferation, metastasis and
angiogenesis. EGFR is, therefore, an appealing target for
molecular-targeted cancer therapy as it is expressed in a
variety of solid tumors (colorectal, breast, head and neck,
etc.). Receptor antagonists that target EGFR have already
been of high interest for a number of years. Multiple therapeutic
strategies have been developed to target EGFR, including monoclonal
antibodies (mAbs), tyrosine kinase inhibitors (TKIs), ligand-toxin
conjugates, and antisense oligonucleotides. In particular,
mAbs block ligand from binding to the extracellular domain
of the receptor. Two mAbs that block EGFR (erbB1), cetuximab
and panitumumab, have been approved by FDA. Cetuximab is a
chimeric IgG1 anti-EGFR monoclonal antibody, whereas panitumumab
is a fully human IgG2 anti-EGFR monoclonal antibody. This
review highlights the cellular effects of EGFR blockade by
mAbs and their relationship to therapeutic efficacy and biological
significance.
[Back to top]
[Purchase
Article]
Selective Matrix Metalloproteinase Inhibitors
for Cancer
Nian-Guang , Zhi-Hao Shi, Yu-Ping Tang and
Jin-Ao Duan
The matrix metalloproteinases are a family of nearly 30
enzymes that are intimately involved in tissue remodeling.
Disease processes associated with the matrix metalloproteinases
are generally related to imbalance between the inhibition
and activation of matrix metalloproteinases resulting in excessive
degradation of the extracellullar matrix. These include osteoarthritis,
rheumatoid arthritis, tumor metastasis and congestive heart
failure. Despite massive research and development efforts,
there are only two drugs launched on the market: periostat
(doxycycline), a tetracycline used for periodontal disease
and glucosemine sulfate, for osteoarthritis. Possible reasons
for the low success rate of matrix metalloproteinase inhibitors
in the clinic are mainly from unwanted side effects caused
by their lack of selectivity, since inhibition of collagenase-1
may be responsible for the musculoskeletal side effects observed
clinically with broad-spectrum inhibitors. Considering these
data, many efforts were directed to developing a more selective
second generation of inhibitors against the specific matrix
metalloproteinases believed to be involved in the different
pathologies. This review mainly focuses on selective matrix
metalloproteinase inhibitors development on matrix metalloproteinases
in terms of antitumor since the late 90s, in terms of synthetic
compounds of low molecular mass incorporating specific zinc-binding
groups, natural products and their derivatives. Through these
methods, new hope is emerging in the form of synthetic and
natural matrix metalloproteinase inhibitors for the prevention
and treatment of cancer.
[Back to top]
[Purchase
Article]
Circulating Biomarkers for the Diagnosis and Prognosis
of Heart Failure
D. Tousoulis, A.M. Kampoli, G. Siasos, E. Stefanadi, C.
Antoniades, A.G. Papavassiliou and C. Stefanadis
Despite substantial therapeutic advances, heart failure
remains a syndrome associated with high morbidity and mortality.
The management of heart failure remains challenging despite
the recent different therapeutic advances. The emergence of
cardiac biomarkers as increasingly effective clinical tools
suggests the potential of a new approach to the management
of patients with heart failure. A variety of circulating biomarkers
of diagnostic and prognostic utility in heart failure is currently
being studied in preclinical, observational and randomized
prospective studies. Of the various candidate biomarkers,
the greatest wealth of knowledge and clinical experience lies
with the B-type naturetic peptides. However, because individual
biomarkers may have limited sensitivity and specificity, a
multi-marker approach, using combinations of different biomarkers
that reflect different aspects of the pathophysiological milieu,
would contribute to better risk stratification and optimization
of therapy.
[Back to top]
[Purchase
Article]
Cardiovascular Effects of Losartan and Its Relevant
Clinical Application
Feichao Xu, Caiping Mao, Yali Hu, Can Rui, Zhice Xu and
Lubo Zhang
The renin-angiotensin system (RAS) plays an important role
in the homeostasis of the cardiovascular system and in the
development of cardiovascular diseases. An abnormal expression
or over activation of the local RAS in the heart and vasculature
system is one of the most common mechanisms in pathophysiological
processes in cardiovascular diseases. This also provides a
basis for medical prevention and treatments using chemical
approaches. Losartan is a selective nonpeptite antagonist
against type 1 angiotensin II receptors (AT1R), and has been
applied in medical treatments of a variety of cardiovascular
diseases, including essential hypertension. This article reviews
direct and indirect cardiovascular effects of losartan on
the heart and blood vessels. It summarizes the chemical basis
of AT1R for the action site of losartan, focuses on the mechanisms
underlying the action of losartan involved in both the heart
and vasculature, and reviews the information that may be helpful
in the development of new chemical candidates or approaches
in the war against cardiovascular diseases.
[Back to top]
[Purchase
Article]
Medicinal Chemistry Approaches for Glucokinase Activation
to Treat Type 2 Diabetes
Manojit Pal
Type 2 Diabetes (T2D), characterized by elevated levels
of blood glucose is a complex disease mainly caused by defects
in hepatic glucose balance and the failure of pancreatic β-cells
to secrete enough insulin to overcome insulin resistance.
Glucokinase (GK) is a member of hexokinase family of enzymes
that are responsible for the phosphorylation of glucose to
glucose-6-phosphate for further utilization in cells. It plays
a key role in glucose homeostasis in cells that express this
enzyme, such as β-cells
and hepatocytes. It promotes glycogen synthesis in the liver
and glucose-sensitive insulin release in the β-cell.
While hypoglycemia due to the increased insulin secretion
could be a potential concern it was hypothesized that a GK
activator with optimized properties would be able to both
blunt the postprandial glucose excursion and lower the fasting
blood glucose in T2D patients. As a result of intensive medicinal
chemistry efforts a number of small molecules have been discovered
as GK activators many of which showed antidiabetic effects
in animal models of T2D. Some of these activators have advanced
into human clinical studies. With the promising preclinical
data in hand, GK activators represent a promising and new
treatment option for T2D.
[Back to top]
[Purchase
Article]
Adenosine and Adenosine Receptors: Their Contribution
to Airway Inflammation and Therapeutic Potential in Asthma
M. Caruso, K. Varani, G. Tringali and R. Polosa
Growing evidence emphasizes that the purine nucleoside
adenosine plays an active role as local regulator in airway
inflammation and pulmonary diseases. The notion that increased
adenosine concentrations are associated with lung inflammation
indicates the importance of this signaling pathway, which
involves the activation of a family of cell surface G-protein
coupled receptor subtypes named as A1,
A2A, A2B
and A3. Recently, important
progress has been made to better clarify the role of these
receptors in a variety of inflammatory airway disorders including
asthma. As a consequence, new molecules with high affinity
and high selectivity for the human adenosine receptors subtypes
designed to control the airway inflammatory component of asthma
have been launched and are currently tested in clinical trials
as anti-asthma treatments. With the availability of these
molecules for testing in humans, the role of adenosine receptors
in asthma can now be validated.
[Back to top]
[Purchase
Article]
Role of Nuclear Steroid Receptors in Apoptosis
Joana D. Amaral, Susana Solá, Clifford J. Steer and Cecília M.P. Rodrigues
Nuclear steroid receptors (NSR) are ligand-activated transcription
factors that play a key role in a variety of vital physiological
phenomena including developmental or endocrine signaling,
reproduction, and homeostasis. In addition, they are implicated
in other important biological processes, such as apoptosis.
Modulation of apoptosis by NSR is mostly associated with control
of pro-apoptotic versus anti-apoptotic gene expression, and
includes both induction and prevention of apoptosis depending
on cell type. However, it is unclear how NSR can affect opposing
expression of the same gene in different cells. Of note, recently
described nongenomic mechanisms of NSR, in particular glucocorticoid
receptor translocation to mitochondria, were suggested to
be crucial steps for triggering apoptosis. NSR often act solely
as nuclear transporters of other regulatory molecules, thus
indirectly regulating several apoptosis-related genes. Curiously,
NSR are thought to cooperate with the anti-apoptotic endogenous
bile acid, ursodeoxycholic acid (UDCA), to prevent programmed
cell death. In fact, as cholesterol-derived molecules and
due to their chemical and structural similarities to steroid
hormones, bile acids also modulate NSR activation. Although
the precise link between NSR and UDCA remains unclear, we
have demonstrated that the bile acid requires NSR for translocation
to the cell nucleus as part of a ligand-receptor complex,
using a mechanism similar to that of steroid hormones. Interestingly,
other studies revealed that UDCA interacts with the glucocorticoid
receptor as a novel and selective NSR modifier. The huge diversity
of natural ligands and xenobiotics that bind to NSR and regulate
their function represents one of the most exciting drug targets
for potential therapeutic intervention. The next decade will
almost certainly unveil the remarkable role of NSR in modulating
cell fate in human health and disease.
[Back to top]
[Purchase
Article]
Design Strategies of Novel NNRTIs
to Overcome Drug Resistance
Peng Zhan, Xinyong Liu, Zhenyu Li, Christophe Pannecouque and Erik De Clercq
Nonnucleoside reverse transcriptase inhibitors (NNRTIs)
are very potent and most promising anti-AIDS drugs that specifically
inhibit HIV-1 reverse transcriptase (RT). However, to a great
extent, the efficacy of NNRTI drugs is impaired by rapid emergence
of drug-resistance mutations. Fortunately, detailed analysis
of a wide range of crystal structures of HIV-1 RT/NNRTI complexes
together with data on drug resistance mutations has identified
factors important for design of inhibitors and resilience
to mutations, such as, exhibiting conformational flexibility
and positional adaptability of NNRTIs, forming extensive main
chain hydrogen bonding, targeting highly conserved residues
in HIV-1 RT and possessing unconventional mechanisms for NNRTI-mediated
inhibition of RT. Besides, the plasticity of NNRTIs binding
pocket (NNIBP) also provides a broad space for the discovery
of new generations of NNRTIs. For instance, the composite
binding pocket, integrating all available crystal structure
information about the NNRTI binding site of HIV RT, was demonstrated
to be an effective tool to better understand the flexible
nature of the binding pocket and to identify specific inhibitors.
The RT/solvent interface proved to be an attractive site for
incorporating a moiety to improve water solubility and pharmacokinetics
or introducing a second pharmacophore to construct multifunctional
ligand. Totally, the characterization of NNRTIs and NNIBP
may help in the design of more effective drugs that are potent
toward wild type and drug-resistant strains of RT. In this
paper we attempt to translate the general knowledge gained
from a large number of related literature into a set of medicinal
chemistry strategies to improve the drug resistance profile
of NNRTIs.
|
