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Mini-Reviews
in Medicinal Chemistry
ISSN: 1389-5575
Mini-Reviews in Medicinal
Chemistry
Volume 6, Number 12, December 2006
Contents
Structure and Design of Polycationic Carriers For Gene Delivery
Pp. 1285-1298
Geoffrey A. Pietersz, Choon-Kit Tang and Vasso Apostolopoulos
[Abstract]
Carbohydrate-Based Scaffolds in Drug Discovery
Pp. 1299-1309
Bernd Becker, Glenn C. Condie, Giang Thanh Le and Wim
Meutermans
[Abstract]
Chondroitin Sulphate: Antioxidant Properties and Beneficial
Effects Pp. 1311-1320
G.M. Campo, A. Avenoso, S. Campo, A.M. Ferlazzo and A.
Calatroni
[Abstract]
New Insights into the Regulation of Liver Inflammation
and Oxidative Stress Pp. 1321-1330
Natàlia Ferré and Joan Clària
[Abstract]
The Adiponectin Signaling Pathway as a Novel Pharmacological
Target Pp. 1331-1340
Xuming Mao, Jenny Y. Hong and Lily Q. Dong
[Abstract]
Recent Progress in the Field of β-(1,3)-Glucans
and New Applications Pp. 1341-1349
Karine Descroix, Vincent Ferrières, Frank Jamois,
Jean-Claude Yvin and Daniel Plusquellec
[Abstract]
Prothrombotic Potential of NSAID in Ischemic Heart
Diesase Pp. 1351-1355
Florian Krötz, Nicole Hellwig, Thomas M. Schiele,
Volker Klauss and Hae-Young Sohn
[Abstract]
Carbohydrate Antigens: Synthesis Aspects and Immunological
Applications in Cancer Pp. 1357-1373
Teresa Freire, Sylvie Bay, Sophie Vichier-Guerre, Richard
Lo-Man and Claude Leclerc
[Abstract]
The Function of the Selective Inhibitors of Cycloxygenase
2 Pp. 1375-1381
Yepeng Luan and Wenfang Xu
[Abstract]
Targeting Calmodulin in Reversing Multi Drug Resistance
in Cancer Cells Pp. 1383-1389
Y.C. Mayur, S. Jagadeesh and K.N. Thimmaiah
[Abstract]
Abstracts
[Back to top]
Structure and Design of Polycationic Carriers For Gene Delivery
Geoffrey A. Pietersz, Choon-Kit Tang and Vasso Apostolopoulos
The development of safe and effective gene delivery methods
is a major challenge to enable gene therapy or DNA vaccines
to become a reality. Currently there are two major approaches
for delivery of genetic material, viral and non-viral. The
majority of on-going clinical trials in gene therapy or DNA
vaccines use retroviruses and adenoviruses for delivering
genetic materials. Viral delivery systems are far more effective
than non-viral delivery however there are concerns regarding
toxicity, immunogenicity and possible integration of viral
genetic material into the human genome. Given the negative
charge of the phosphate backbone of DNA, polycationic molecules
have been the major focus as carriers of DNA. There are several
physiological barriers to overcome for effective systemic
delivery of DNA. The ideal vector must be stable in the systemic
circulation, escape the reticuloendothelial system, able to
extravasate tissues, enter the target cell, escape lysosomal
degradation and transport DNA to the nucleus to be transcribed.
With increasing understanding of the physicochemical properties
essential to overcome the various barriers, it is possible
to apply rational design to the cationic carriers. A number
of poly-amino acids, cationic block co-polymers, dendrimers
and cyclodextrins have been rationally designed to optimize
gene delivery. This review will discuss approaches that have
been used to design various synthetic polycations with enhanced
DNA condensing ability, serum stability and endosomolytic
capability for efficient gene transfer in vitro and
in vivo.
[Back to top]
Carbohydrate-Based Scaffolds in Drug Discovery
Bernd Becker, Glenn C. Condie, Giang Thanh Le and Wim
Meutermans
Carbohydrates have been proven as valuable scaffolds to display
pharmocophores and the resulting molecules have demonstrated
useful biological activity towards various targets including
the somatostatin receptors (SSTR), integrins, HIV-1 protease,
matrix metalloproteinases (MMP), multidrug resistance-associated
protein (MRP), and as RNA binders. Carbohydrate-based compounds
have also shown antibacterial and herbicidal activity.
[Back to top]
Chondroitin Sulphate: Antioxidant Properties and Beneficial
Effects
G.M. Campo, A. Avenoso, S. Campo, A.M. Ferlazzo and A.
Calatroni
Most biological molecules exhibit more than one function.
In particular, many molecules have the ability to directly/indirectly
scavenge free radicals and thus act in living organisms as
antioxidant. During oxidative stress, the increase of these
molecules levels seems to be a biological response that in
synergism with the other antioxidant defence systems may protect
cells from oxidation. Among these structures, chondroitin
sulphate is a biomolecule which has increasingly focused the
interest of many research groups due to its antioxidant activity.
This review briefly summarises the action of chondroitin sulphate
in reducing molecular damage caused by free radicals and associated
oxygen reactants.
[Back to top]
New Insights into the Regulation of Liver Inflammation
and Oxidative Stress
Natàlia Ferré and Joan Clària
Pro-inflammatory lipid mediators (i.e. eicosanoids), cytokines
(i.e. TNF-α)
and reactive oxygen species are targets of interest in the
regulation of liver inflammation and oxidative stress. In
the current review, we summarize recent advances in the pharmacological
modulation of these pathways with especial emphasis on the
participation of Kupffer cells, the liver resident macrophages
and the cell type most directly related to the production
of inflammatory mediators in this organ.
[Back to top]
The Adiponectin Signaling Pathway as a Novel Pharmacological
Target
Xuming Mao, Jenny Y. Hong and Lily Q. Dong
There appear to be compelling evidences presenting adiponectin
as a key regulator of energy homeostasis. Over the past 10
years, much work has been done to identify the molecular mechanisms
by which adiponectin functions in the body. We and other groups
have demonstrated that adiponectin activates multiple signaling
pathways, which mediate its anti-diabetic, anti-atherogenic
and anti-inflammatory functions. Comprehensive analysis of
the mechanism of adiponectin action may allow us to elucidate
the etiology of metabolic syndrome associated diseases including
diabetes and cardiovascular diseases, where dysfunction of
adiponectin may contribute to pathogenesis of diseases. While
regulation of adiponectin gene expression or secretion remains
an interesting topic in studies of cell metabolism, further
intensive studies are necessary to illustrate the molecular
mechanisms. Importantly, identification of molecules in the
adiponectin signaling pathways and in the regulation of adiponectin
gene expression may provide novel targets for therapeutic
drugs.
[Back to top]
Recent Progress in the Field of β-(1,3)-Glucans
and New Applications
Karine Descroix, Vincent Ferrières, Frank Jamois,
Jean-Claude Yvin and Daniel Plusquellec
β-(1,3)-Glucans
are widely distributed within microorganisms or seaweeds in
which they act as membrane components or for energy storage,
respectively. Since these glucans are not biosynthesized by
mammals, they are likely to activate the immune system of
their host. Since the discovery of their positive involvement
as immunomodulator agents, numerous studies were published
all around the glycosciences. These works deal with purification
procedures, analytical chemistry, synthetic processes, chemical
modification of the natural polysaccharides, determination
of their physicochemical properties, and assessment of their
biological and medicinal effects through in vitro
and in vivo studies. This article aims at presenting
some recent results linked to β-(1,3)-glucans
through two closely connected points of view, i.e. biology
and chemistry. Biological aspects will be focused more particularly
on discovery of some receptors present on immunocompetent
cells and scope and limitations of chemical synthesis and/or
modifications will be described. Moreover, this paper will
also introduce some new chemo-enzymatic synthetic methods
using wild-type or mutant glycosidases and will be extended
to novel opportunities of applications of β-(1,3)-glucans
in nanotechnology resulting from a better understanding of
their self-assembling propensity in aqueous media.
[Back to top]
Prothrombotic Potential of NSAID in Ischemic Heart
Diesase
Florian Krötz, Nicole Hellwig, Thomas M. Schiele,
Volker Klauss and Hae-Young Sohn
Non-steroidal anti-inflammatory drugs (NSAID) target the enzyme
cyclooxygenase (COX) thus affording relieve from pain, inflammation
or fever. As COX-dependently formed prostanoids not only mediate
signals involved in inflammation and pain, but also regulate
important physiological cardiovascular functions, some NSAID
have recently been reported to be associated with arterial
thrombosis or hypertension. This is in contrast to the well-known
antiplatelet effects of low-dose aspirin, but in coherence
with the specific effects of some NSAID on prostanoid formation
in the vasculature. A correlation between the intake of selective
inhibitors of the cyclooxygenase 2 (COX-2) isoform and atherothrombotic
events has recently been established. Large retrospective
analyses of clinical data have repeatedly shown this effect
and in some cases have also observed potential hazards for
other, rather non-selective NSAID. This review evaluates potential
prothrombotic effects of NSAID in vascular ischemic disease
in comparison to low-dose aspirin and selective COX-2 inhibitors
and discusses pathophysiological backgrounds for such observations.
[Back to top]
Carbohydrate Antigens: Synthesis Aspects and Immunological
Applications in Cancer
Teresa Freire, Sylvie Bay, Sophie Vichier-Guerre, Richard
Lo-Man and Claude Leclerc
Tumor Associated Carbohydrate Antigens (TACAs) constitute
powerful tools as tumor markers and as targets for anticancer
immunotherapy. In this review, methods of production of glycopeptide-based
vaccines, as well as results of preclinical and clinical studies
in cancer patients are discussed.
[Back to top]
The Function of the Selective Inhibitors of Cycloxygenase
2
Yepeng Luan and Wenfang Xu
Cyclooxygenase plays a pivotal role in the transformation
of the arachidonic acid to prostaglandins (PGs) and thromboxane.
It is composed of two kinds of enzymes, namely cyclooxygenase
1 (COX-1) and cyclooxygenase 2 (COX-2). Cyclooxygenase 1 is
the constructive enzyme whereas the cyclooxygenase 2 is the
inducible enzyme. Inhibiting cyclooxygenase 1 is always associated
with some undesirable side-effects, while inhibiting cyclooxygenase
2 can result in therapeutic effect. This has led the researchers
to strive for searching the selective inhibitors inhibiting
the COX-2 instead of COX-1. It is very well known that pain
and inflammation are alleviated through the inhibition of
COX-2 inhibitors such as Aspirin, which has resulted in the
recent years, in the emergence of a range of COX-2 inhibitors.
Moreover, while evaluating the functions of the COX-2 inhibitions,
their significant role in treating glaucoma, preventing and
suppressing cancer through their inhibitory activity was clearly
revealed and many studies further demonstrated that COX-2
is not only related to the inflammation of peripheral tissues
but also to the inflammation manifested in the central nervous
system. In addition, the nervous disorders also found an effective
treatment with the administration of COX-2 inhibitors. The
above-mentioned findings delineate the role of the COX-2 inhibitors
as promising agents to be exploited in the treatment of many
illnesses. This review will elucidate the functions of the
COX-2 inhibitors briefly and introduce some common selective
inhibitors of COX-2.
[Back to top]
Targeting Calmodulin in Reversing Multi Drug Resistance
in Cancer Cells
Y.C. Mayur, S. Jagadeesh and K.N. Thimmaiah
Calmodulin is a Ca2+ binding protein
found in many eukaryotic cells. It is one of the most important
intracellular mediators of Ca2+-dependant signaling
in eukaryotic cells. It regulates diverse processes including
mitosis, muscle contraction and nucleotide metabolism by modulating
the activity of at least 30 different target enzymes in a
calcium-dependant manner. Calmodulin plays an important role
in the regulation of processes, such as the assembly and disassembly
of microtubules by controlling protein kinase activities,
by exerting an indirect influence upon a wide variety of cellular
processes. It is observed that multi-drug resistant cells
have a greater intracellular concentration of calcium than
non-resistant cells which contributes to their increased sensitivity
to calmodulin antagonism compared with that of non resistant
cells. Calmodulin mediated processes can be effectively inhibited
by a variety of pharmacological agents of different chemical
structures, eg:The calcium channel blocker verapamil and antipsychotic
drugs like the Phenothiazines. Many bioisosteres of phenothiazines
like phenoxazines and acridones have been prepared and these
have also shown very good calmodulin antagonism. These calmodulin
antagonists have been shown to modulate multi-drug resistance
(MDR) in cancer cells. This review highlights concepts of
identification and optimization of new inhibitors of calmodulin
in reversing MDR in cancer cells.
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