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Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 12, Number 26, 2005
Contents
Development of Lymphatic Vessels: Tumour Lymphangiogenesis
and Lymphatic Invasion Pp. 3043-3053
J. Wilting, T. Hawighorst, M. Hecht, B. Christ and M.
Papoutsi
[Abstract]
Neuropeptide-Derived Antimicrobial Peptides from Invertebrates
for Biomedical Applications Pp. 3055-3061
Michel Salzet
[Abstract]
Synthesis of Hydroxylated Cyclic β-Amino Acid
Derivatives Pp.3063-3083
Márta Palkó, Loránd Kiss and
Ferenc Fülöp
[Abstract]
A Yeast Extract High in Bioactive Peptides has a Blood-Pressure
Lowering Effect in Hypertensive Model Pp. 3085--3090
Osamu Kanauchi, Kiharu Igarashi, Rie Ogata, Keiichi Mitsuyama
and Akira Andoh
[Abstract]
Telomerase Inhibition and Cancer: Might Platinum Based
Drugs have a Future as Anti-telomerase Pharmacological Approach?
Pp. 3091-3102
Donato Colangelo and Domenico Osella
[Abstract]
Quorum Sensing Inhibition: Targeting Chemical Communication
in Gram-negative Bacteria Pp. 3103-3115
Tobias Persson, Michael Givskov and John Nielsen
[Abstract]
The Assessment of Platelet Activation in Antiplatelet
Drug
Development Pp. 3117-3125
Kiat T. Tan and Gregory Y.H. Lip
[Abstract]
Phosphate Isosteres in Medicinal Chemistry
Pp. 3127-3141
C.S. Rye and J.B. Baell
[Abstract]
RNA Interference as A Gene-Specific Approach for Molecular
Medicine Pp. 3143-3161
A. Grünweller and R.K. Hartmann
[Abstract]
Abstracts
[Back to top]
Development of Lymphatic Vessels:
Tumour Lymphangiogenesis and Lymphatic Invasion
J. Wilting, T. Hawighorst, M. Hecht, B. Christ and M.
Papoutsi
In human solid cancer, the lymph node status is the most
important prognostic indicator for the clinical outcome of
patients. Follow-up data has shown that about 80% of metastasis
follows an orderly pattern of progression via the lymphatic
network while about 20% systemic metastasis occurs, bypassing
the lymphatic system. Over the past few years, advances have
been made in understanding the cellular and molecular aspects
of physiological lymphangiogenesis and tumour-induced lymphangiogenesis,
and the majority of studies point out to a positive correlation
between tumour-induced lymphangiogenesis and lymphatic metastasis.
However, the impact of intra- and peritumoural lymphatics
on the tumour biology and the first steps of lymphatic metastasis,
i.e. the invasion of tumour cells into the lymphatic vessels,
are not well understood. We will give an outline of i. the
physiological process of lymphangiogenesis, ii. tumour-induced
lymphangiogenesis and lymphatic metastasis, iii. lymphatic
invasion and the common pathways of tumour-lymphangiogenesis
and lymphatic invasion. The growing interest in this topic
has brought up a number of new molecular players in the field,
which may provide the basis for a rational therapy against
the process of lymphatic dissemination of tumour cells.
[Back to top]
Neuropeptide-Derived Antimicrobial Peptides from Invertebrates
for Biomedical Applications
Michel Salzet
Since the beginning of the 20th century, important medicinal
progress has led medical doctors to think that the end of
devastating epidemics has arrived. In 1930, the discovery
of sulfamides and penicillin opened a wide area of applications
able to fight against bacterial infections. However, almost
all antibiotics were baffled by the great ability to adaptation
of bacteria (1) and the emergence of new bacterial agents,
discovered with up-dated technologies. The living world is
perpetually in co-evolution and since more than 3 billion
years, bacteria have developed resistance mechanisms to overcome
external aggressions. Thus, in the middle of the 80th century,
multi-resistant bacteria appeared and disseminated out from
hospitals. In this context, researches have been developed
in order to find new antimicrobial substances to destroy such
new types of bacteria. Thus, several groups have turned their
focus on invertebrates, which co-evoluad with human and have
appeared on the planet since a long time. Evidence of new
families of antimicrobial substances isolated from invertebrates
different to the classical cationic peptide family i.e.
dipeptides and anionic peptides been given. Moreover, these
molecules are also present in human and may serve in the innate
immune response as an important survival strategy.
[Back to top]
Synthesis of Hydroxylated Cyclic β-Amino
Acid Derivatives
Márta Palkó, Loránd Kiss and
Ferenc Fülöp
This review is intended to give a short summary of the developments
in the field of natural and synthetic alicyclic and heterocyclic
hydroxylated β-amino
acids and to focus on the main strategies that have been reported
for their synthesis. Given the medicinal and biological significance
of the hydroxylated β-amino
acids, an increasing volume of research is currently being
directed toward regio-, stereo- and enantioselective access
to this class of compounds.
[Back to top]
A Yeast Extract High in Bioactive Peptides has a Blood-Pressure
Lowering Effect in Hypertensive Model
Osamu Kanauchi, Kiharu Igarashi, Rie Ogata, Keiichi Mitsuyama
and Akira Andoh
It was reported that angiotensin-converting enzyme (ACE)
plays an important role in increasing blood pressure. Recently,
it was reported that several food hydrolysates have ACE inhibitory
effects in the spontaneous hypertensive rat (SHR) model and
mildly hypertensive subjects. Therefore, the anti-hypertensive
effects of brewer's yeast BY-G were investigated, which contains
many kinds of beneficial nutrients (vitamins, minerals, nucleic
acids, glutathione, amino acids, etc.). The aim of this study
was to evaluate the anti-hypertensive effects of BY-G and
its component peptides obtained by enzymatic treatment.
The peptide fraction KRF814 was obtained by the hydrolysate
of BY-G with alkaline protease and then treated with Amberlite
XAD-2. The KRF814, which has an inhibitory effect on ACE
in vitro, was obtained. BY-G and KRF814 were fed to male
SHR and showed significantly anti-hypertensive effects. KRF814
contained alanyl-phenylalanine (AF) and glycyl-phenylalanine
(GF), which significantly decreased systolic BP in the SHR
model. The active ingredients of KRF814, AF, and GF had about
60% of the potency of the positive control, which was captopril.
It is considered that intake of BY-G or its component peptides
as a functional food stuff might be beneficial for improving
BP in people with hypertension.
[Back to top]
Telomerase Inhibition and Cancer: Might Platinum Based
Drugs have a Future as Anti-telomerase Pharmacological Approach?
Donato Colangelo and Domenico Osella
Telomerase is a ribonucleoprotein polymerase that maintains
the length of telomeric DNA by adding hexameric units (TTAGGG)
to the ends of the chromosomes. This mechanism prevents replicative
senescence, thus conferring unlimited proliferative potential
to cells. Telomerase reactivation has been detected in most
human tumour tissue, indicating that the enzyme may be useful
as a specific tumour marker. The inhibition of telomerase
causes a progressive and critical reduction of telomeres,
leading to a potent signal for the blockage of cell proliferation
and the induction of apoptosis. Since normal somatic cells
lack telomerase activity, the anti-telomerase approach is
highly specific for tumour cells and metastases. Prolonged
treatment is required before enzyme deactivation causes the
telomeres to be shortened enough to induce senescence and
apoptosis. Therefore, the drugs employed in anti-telomerase
therapy should be of only moderate non-specific cytotoxicity.
Certain cis-Pt(II)-complexes have recently been shown
to be effective inhibitors of telomerase in both cell-free
and in vitro assays, most likely by targeting the
nucleobases of the RNA component of the enzyme.
[Back to top]
Quorum Sensing Inhibition: Targeting Chemical Communication
in Gram-negative Bacteria
Tobias Persson, Michael Givskov and John Nielsen
Quorum sensing (QS) systems comprise a new therapeutic
target potentially substitutive or complementary to traditional
antibiotic treatment of chronic diseases. One route to disrupt
the previously established interrelationship between pathogenesis
and QS is by blocking the dual functioning signal/receptor
transcriptional regulator in some clinically relevant Gram-negative
bacteria. The present review contains all reported compound
types that are currently known to inhibit the QS transcriptional
regulator in Gram-negative bacteria. These compounds are sub-divided
into two main groups, one comprising structural analogs of
the native signaling molecules and the other compounds lacking
structural resemblance. Biological activity is rationalized
on the basis of structure-activity relationships and structural
insight into the target protein.
[Back to top]
The Assessment of Platelet Activation in Antiplatelet
Drug
Development
Kiat T. Tan and Gregory Y.H. Lip
Platelet activation plays an important role in a wide range
of pathological conditions. For example, platelet activation
has been shown to be involved in the defence against parasitic
infection, the pathogenesis of atherosclerotic disease, and
various arterial and venous thrombotic diseases. Indeed, there
is considerable interest in the manipulation of platelet function
for therapeutic gain. It is for these reasons that there is
considerable interest in developing assays measuring in
vivo platelet activation.
Current modalities in the measurement of platelet activation
include Enzyme-linked Immunosorbent Assays (ELISA), platelet
flow cytometry and electron microscopy. It is proposed that
methods in measuring platelet activation can also be classified
into 'direct' and 'indirect' modalities, both of which have
their distinct advantages and disadvantages. Unfortunately,
there is at present no consensus on the ideal method of measuring
platelet activation. Thus, studies on platelet activation
should ideally include at least one of each of direct and
indirect modality of studying platelet activation. This review
provides an overview of basic platelet biology and the various
methods of measuring platelet activation, with an emphasis
on their role in drug development.
[Back to top]
Phosphate Isosteres in Medicinal Chemistry
C.S. Rye and J.B. Baell
The phosphate group is at the heart of an enormous number
of biological processes. The simple phosphorylation or dephosphorylation
of a protein can have a wide range of consequences, including
effects on its biological activity, its interaction with other
proteins, and on its subcellular location. Abnormal levels
of protein phosphorylation have been linked to a wide range
of diseases including cancer and diabetes. Consequently, proteins
that recognise the phosphate moiety have become an attractive
target for therapeutic development. The most prevalent medicinal
chemistry research examines the interactions of phosphorylated
tyrosine residues; however, the role of phosphate groups on
serine or threonine residues, in nucleotides, DNA and RNA,
on sugars, and lipid mediators such as lysophosphatidic acid
should not be overlooked. Investigations have focused on the
non-catalytic phosphotyrosine-recognising domains such as
Src homology 2 (SH2) and phosphotyrosine binding (PTB) domains,
as well as catalytic proteins such as protein tyrosine phosphatase
1B (PTP1B). The utilisation of the phosphate moiety as part
of an inhibitor is severely limited by the enzymatic lability
and poor cellular bioavailability of this highly charged recognition
element. The development of phosphate isosteres attempts to
address these issues by introducing a non-scissile bond and
utilizing groups with less charge that are still able to interact
favourably with the target protein in much the same way as
the phosphate group does. Many phosphate mimics retain the
phosphorus atom such as in the highly successful fluoromethylenephosphonates,
whereas others have lost the tetrahedral phosphate geometry
and are based on the combination of one or more carboxylate
groups that generally reduce the overall charge of the molecule.
This review focuses on the recent developments and the use
of phosphate isosteres in medicinal chemistry, covering roughly
the past four years.
[Back to top]
RNA Interference as A Gene-Specific Approach for Molecular
Medicine
A. Grünweller and R.K. Hartmann
The discovery of RNA interference (RNAi) in eukaryotic cells
has been the major recent breakthrough in molecular and cell
biology. RNAi machineries exert biological functions in gene
regulation, genome defense and chromatin architecture and
dynamics. The potential of RNAi to silence any gene of interest
in a highly specific and efficient manner via double-stranded
RNA (dsRNA) has literally revolutionized modern genetics.
RNAi-based functional genomics now permits, for the first
time, to evaluate the cellular role of individual gene products
on a genome-wide scale in higher organisms like mammals, presenting
an alternative to the generation of animal knockouts often
doomed to failure because of a lethal phenotype. RNAi has
had an enormous impact on the development of novel disease
models in animals, and it is likely that small interfering
RNAs (siRNAs), which are the trigger molecules for RNA silencing,
will become an invaluable tool for the treatment of genetic
diseases. First clinical trials, using siRNAs directed against
the vascular endothelial growth factor (VEGF) or one of its
receptors, have been initiated recently for the treatment
of age-related macular degeneration. Improving guidelines
for the rational design of siRNAs, based on recent progress
in understanding the mechanisms underlying RNAi, as well as
the introduction of chemical modifications into siRNAs are
expected to improve their pharmacokinetic and pharmacodynamic
properties for in vivo applications. Finally, successful
therapeutic application of RNAi will depend on the development
of improved siRNA delivery strategies that combine high specificity
and efficiency with a low immunostimulatory and tumorigenic
potential.
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