| Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 16, Number 30, 2009
Contents
Angiogenesis Inhibitors and Vascular Disrupting Agents in
Non-Small Cell Lung Cancer Pp. 3919-3930
A. Rossi, P. Maione, M.L. Ferrara, P.C. Sacco, C. Schettino,
M.A. Bareschino and C. Gridelli
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The Effects of Insulin and Insulin-Like Growth
Factors on Tumor Vascularization: New Insights of Insulin-Like
Growth Factor Family in Cancer Pp. 3931-3942
S. Orciari, S. Di Nuzzo, R. Lazzarini, P. Caprari, A.
Procopio and A. Catalano
[Abstract] [Purchase
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Plant Polyphenols and Tumors: From Mechanisms
to Therapies, Prevention, and Protection Against Toxicity
of Anti-Cancer Treatments Pp. 3943-3965
L.G. Korkina, C. De Luca, V.A. Kostyuk and S.
Pastore
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Medicinal Chemistry of Paclitaxel and its Analogues
Pp. 3966-3985
Y. Fu, S. Li, Y. Zu, G. Yang, Z. Yang, M. Luo, S. Jiang,
M. Wink and
T. Efferth
[Abstract] [Purchase
Article]
Systemic Sclerosis at the Cellular Level: Molecular
Pathways of Pathogenesis and its Implication on Future Drug
Design Pp. 3986-3995
S.W. Schulz and C.T. Derk
[Abstract] [Purchase
Article]
The Antibacterial Effect of a Proline-Rich Antibacterial
Peptide A3-APO Pp. 3996-4002
F. Rozgonyi, D. Szabo, B. Kocsis, E. Ostorházi,
G. Abbadessa, M. Cassone, J.D. Wade and L. Otvos,
Jr.
[Abstract] [Purchase
Article]
Staphylococcus aureus: The
Toxic Presence of a Pathogen Extraordinaire Pp.
4003-4019
E.A. Larkin, R.J. Carman, T. Krakauer and B.G.
Stiles
[Abstract] [Purchase
Article]
Natriuretic Peptides in Septic Patients Pp.
4020-4031
M. Piechota, M. Barylski, S. Hannam, D.P. Mikhailidis,
J. Rysz and M. Banach
[Abstract] [Purchase
Article]
QSAR Modeling for Quinoxaline Derivatives using Genetic
Algorithm and Simulated Annealing Based Feature Selection Pp.
4032-4048
P. Ghosh and M.C. Bagchi
[Abstract] [Purchase
Article]
Abstracts
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Angiogenesis Inhibitors and Vascular Disrupting Agents in
Non-Small Cell Lung Cancer
A. Rossi, P. Maione, M.L. Ferrara, P.C. Sacco, C. Schettino,
M.A. Bareschino and C. Gridelli
Most patients diagnosed with non-small cell lung cancer
(NSCLC) have advanced disease. Chemotherapy has apparently
reached a plateau of effectiveness in improving survival in
this subgroup of patients. Considerable efforts have been
initiated to identify novel targets for new biological agents
which may be safely and effectively administered to NSCLC
patients. New blood vessel formation, known as angiogenesis,
is a fundamental event in the process of tumor growth and
metastatic dissemination. The vascular endothelial growth
factor (VEGF) and its receptors play an essential role in
tumor proliferation. Approaches to limit VEGF activity include
monoclonal antibodies (mAbs) and small molecules inhibiting
the corresponding receptor-tyrosine kinase activity. Bevacizumab,
an anti-VEGF recombinant humanized mAb, is the first targeted
agent which, when combined with chemotherapy, has shown superior
efficacy versus chemotherapy alone as first-line treatment
of advanced NSCLC. Future clinical developments of bevacizumab
in NSCLC treatment include the combination with other targeted
therapies in advanced disease, and the integration into the
combined modality approaches for the treatment of early and
locally advanced disease stages. Vandetanib, a small molecule
targeting VEGF tyrosine-kinase activity, due to first indications
of antitumor activity and the excellent toxicity profile seems
to be a promising agent for the treatment of advanced NSCLC.
Other antiangiogenic drugs, such as sorafenib, sunitinib,
VEGF Trap and a new class named ‘vascular
disrupting agents’,
which includes ASA404, are being tested in ongoing clinical
trials which will further define their role in the management
of NSCLC.
This paper reviews the state of the art and the future developments
of the main antiangiogenic agents in the treatment of NSCLC
patients.
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The Effects of Insulin and Insulin-Like Growth
Factors on Tumor Vascularization: New Insights of Insulin-Like
Growth Factor Family in Cancer
S. Orciari, S. Di Nuzzo, R. Lazzarini, P. Caprari, A.
Procopio and A. Catalano
It is currently believed that the development of a clinically
relevant tumor needs new vessel formation provided by both
angiogenesis (primary involving endothelial cells) and postnatal
vasculogenesis (primary involving bone marrow-derived cells).
Clearly, it is important to identify factors that help to
enhance the growth and “health”
of tumors, as well as their further vascularization. The Insulin
and Insulin-like Growth Factors (IGFs) systems play a key
role in cellular metabolism, differentiation, proliferation,
transformation and apoptosis, during normal and malignant
growth. Moreover, these molecules seem essential in promoting
tumor vascularization. Due to the complexity of these systems,
the review has been focused on the role of insulin and IGFs
signaling in the regulation of tumor angiogenesis and postnatal
vasculogenesis. Since targeting on IGF for cancer therapy
is rapidly becoming a clinical reality, a better understanding
of IGFs-mediated pathways has a relevant impact, providing
new insights to help the design of newly developed drugs.
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Plant Polyphenols and Tumors: From Mechanisms to Therapies,
Prevention, and Protection Against Toxicity of Anti-Cancer
Treatments
L.G. Korkina, C. De Luca, V.A. Kostyuk and S.
Pastore
Polyphenolic molecules produced by higher plants in response
to biotic and abiotic stresses exert numerous effects on tumorigenic
cell transformation, and on tumor cells in vitro
and in vivo, and may interact with conventional anti-tumor
therapies. In the present review, we collected and critically
discussed data on: (i) redox-dependent and redox-independent
mechanisms underlying cytotoxic/cytostatic effects of PPs
and their metabolites towards tumor cells and cytoprotection
of normal cells; (ii) mechanisms of anti-angiogenic and anti-metastatic
action of PPs; (iii) PPs-associated phototoxicity against
tumor cells and photoprotection of non-tumor cells; (iv) PPs
effects on drug-metabolizing enzymes as a basis for their
synergism or antagonism with chemotherapy; (v) molecular pathways
leading to tumor chemoprevention by PPs; and (vi) PPs as protectors
against toxic effects of chemo-, radio-, and photodynamic
therapies.
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Medicinal Chemistry of Paclitaxel and its Analogues
Y. Fu, S. Li, Y. Zu, G. Yang, Z. Yang, M. Luo, S. Jiang,
M. Wink and T. Efferth
Paclitaxel belongs to the most successful anticancer drugs
developed and utilised during the past two decades. Nevertheless,
the development of resistance of tumor cells and severe side
effects in the patients require further improvement of the
drug. In this review, we provide a detailed overview of the
state-of-the-art in the medicinal chemistry of paclitaxel
and its analogues. A number of strategies have been explored
to obtain sufficient amounts of paclitaxel for clinical use
from natural resources. Semi-synthesis from its precursor,
10-deacetylbaccatin III, which can be extracted from Taxus
leavesturned out as the most appropriate method for commercial
production. So far, many paclitaxel derivatives have been
synthesized, and their effect on microtubules stabilization
and cytotoxicity were investigated in terms of structure-activity
relationships (SAR). One of them, docetaxel, was approved
as a more potent anticancer agent than paclitaxel towards
a variety of tumor types. This review summarizes current possibilities
to harvest sufficient amount of drugs from natural sources,
including the production of taxanes in bioreactors and synthetic
approaches for paclitaxel and its analogues, their mechanism
of action and structure-activity relationships. In addition,
future developments and perspectives for this class of compounds
are outlined.
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Systemic Sclerosis at the Cellular Level: Molecular
Pathways of Pathogenesis and its Implication on Future Drug
Design
S.W. Schulz and C.T. Derk
Endothelial cell abnormalities and the effects on the surrounding
microvasculature is a focal point in the pathogenesis of Systemic
Sclerosis disease and may even be the sentinel event for the
initiation of this disorder. A better understanding of these
processes may improve our understanding of the pathophysiology
of Systemic Sclerosis and more specifically the vasculopathy
observed. Such knowledge will help us to further current treatments
options and design novel therapies for Systemic Sclerosis
and other fibrotic disorders.
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The Antibacterial Effect of a Proline-Rich Antibacterial
Peptide A3-APO
F. Rozgonyi, D. Szabo1, B. Kocsis, E. Ostorházi,
G. Abbadessa, M. Cassone, J.D. Wade and L. Otvos,
Jr.
Antimicrobial resistance is an emerging worldwide concern
in light of the widespread antimicrobial drug use in humans,
livestock and companion animals. The treatment of life-threatening
infections is especially problematic because clinical strains
rapidly acquire multiple-drug resistance. Antimicrobial peptides
have long been considered to be viable alternatives to small
molecule antibiotics. However, the peptides’
parenteral use is frequently hampered by inadequate safety
margins and rapid renal clearance leaving them suitable only
for topical applications. The proline-rich peptide A3-APO
represents a family of a new class of synthetic dimers that
kill bacteria by a dual mode of action and carry domains for
interaction with both the bacterial membrane and an intracellular
target. From a series of designer antibacterial peptides,
A3-APO emerged as a viable preclinical candidate by virtue
of its superior ability to disintegrate the bacterial membrane,
inhibit the 70-kDa heat shock protein DnaK alone or in synergy
with small molecule antibiotics, lack of eukaryotic toxicity
and withstand proteolytic degradation in body fluids. As many
other proline-rich peptides, A3-APO binds to the C-terminal
helical lid of bacterial DnaK and inhibits chaperone-assisted
protein folding in bacteria but not in mammalian Hsp70. In
this review, the structure, pharmacokinetic properties, antimicrobial
spectrum of peptide A3-APO and its in vivo metabolite
are summarized and the in vitro and in vivo
antimicrobial effects (antimicrobial susceptibilities, postantibiotic
effects, resistance induction) are discussed in detail.
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Staphylococcus aureus: The Toxic
Presence of a Pathogen Extraordinaire
E.A. Larkin, R.J. Carman, T. Krakauer and B.G.
Stiles
Staphylococcus aureus is a facultative, Gram-positive
coccus well known for its disease-causing capabilities. In
particular, methicillin and vancomycin resistant strains of
S. aureus (MRSA and VRSA, respectively) isolated
globally represent daunting medical challenges for the 21st
Century. This bacterium causes numerous illnesses in humans
such as food poisoning, skin infections, osteomyelitis, endocarditis,
pneumonia, enterocolitis, toxic shock, and autoimmune disorders.
A few of the many virulence factors attributed to S. aureus
include antibiotic resistance, capsule, coagulase, lipase,
hyaluronidase, protein A, fibronectin-binding protein, and
multiple toxins with diverse activities. One family of protein
toxins is the staphylococcal enterotoxins (SEs) and related
toxic shock syndrome toxin-1 (TSST-1) that act as superantigens.
There are more than twenty different SEs described to date
with varying amino acid sequences, common conformations, and
similar biological effects. By definition, very low (picomolar)
concentrations of these superantigenic toxins activate specific
T-cell subsets after binding to major histocompatibility complex
class II. Activated T-cells vigorously proliferate and release
proinflammatory cytokines plus chemokines that can elicit
fever, hypotension, and other ailments which include a potentially
lethal shock. In vitro and in vivo models are available for
studying the SEs and TSST-1, thus providing important tools
for understanding modes of action and subsequently countering
these toxins via experimental vaccines or therapeutics. This
review succinctly presents the pathogenic ways of S. aureus,
with a toxic twist. There will be a particular focus upon
the biological and biochemical properties of, plus current
neutralization strategies targeting, staphylcoccocal superantigens
like the SEs and TSST-1.
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Natriuretic Peptides in Septic Patients
M. Piechota, M. Barylski, S. Hannam, D.P. Mikhailidis,
J. Rysz and M. Banach
The natriuretic peptide family is comprised of atrial natriuretic
peptide (ANP), brain natriuretic peptide (BNP), C-type natriuretic
peptide (CNP), dendroaspis natriuretic peptide –
DNP and urodilatin. They play a role in the diagnosis of several
diseases, especially those involving the cardiovascular system.
Sepsis is a complex condition that can lead to multiorgan
failure, shock and death. The number of people developing
sepsis is still increasing (approximately 750,000 cases of
sepsis occur annually in the USA).
Both ANP and pro-ANP have attracted interest as new markers
for sepsis. Reports indicate that ANP or BNP levels are elevated
in septic patients. However, many mechanisms are still unexplained.
This situation is complicated by the fact that contradictory
results have been published. There are several reasons for
this controversy including differences in the techniques used
to assay natriuretic peptides. Nevertheless, natriuretic peptides
might eventually prove useful for the diagnosis and/or the
treatment of septic patients.
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QSAR Modeling for Quinoxaline Derivatives using Genetic
Algorithm and Simulated Annealing Based Feature Selection
P. Ghosh and M.C. Bagchi
With a view to the rational design of selective quinoxaline
derivatives, 2D and 3D-QSAR models have been developed for
the prediction of anti-tubercular activities. Successful
implementation of a predictive QSAR model largely depends
on the selection of a preferred set of molecular descriptors
that can signify the chemico–biological
interaction. Genetic algorithm (GA) and simulated annealing
(SA) are applied as variable selection methods for model development.
2D-QSAR modeling using GA or SA based partial least squares
(GA-PLS and SA-PLS) methods identified some important topological
and electrostatic descriptors as important factor for tubercular
activity. Kohonen network and counter propagation artificial
neural network (CP-ANN) considering GA and SA based feature
selection methods have been applied for such QSAR modeling
of Quinoxaline compounds. Out of a variable pool of 380 molecular
descriptors, predictive QSAR models are developed for the
training set and validated on the test set compounds and a
comparative study of the relative effectiveness of linear
and non-linear approaches has been investigated. Further analysis
using 3D-QSAR technique identifies two models obtained by
GA-PLS and SA-PLS methods leading to anti-tubercular activity
prediction. The influences of steric and electrostatic field
effects generated by the contribution plots are discussed.
The results indicate that SA is a very effective variable
selection approach for such 3D-QSAR modeling.
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