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Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 14, Number 1, 2007
Contents
The Medicinal Chemistry of Short Lactoferricin-Based Antibacterial
Peptides Pp. 1-18
B. E. Haug, M. B. Strøm and J. S. M. Svendsen
[Abstract] [Full
text article]
Radioligand Development for PET Imaging of β-Amyloid
(Aβ)-Current
Status Pp. 19-52
Lisheng Cai, Robert B. Innis and Victor W. Pike
[Abstract] [Full
text article]
Biocatalytic Approaches to Optically Active β-Blockers
Pp. 53-65
[Abstract] [Full
text article]
Airway Smooth Muscle Cell as Therapeutic Target of
Inflammation Pp. 67-76
Chi-Ming Hai
[Abstract] [Full
text article]
Contrast Agents and Applications to Assess Tumor Angiogenesis
In Vivo by Magnetic Resonance Imaging Pp.
77-91
F. Kiessling, B. Morgenstern and C. Zhang
[Abstract] [Full
text article]
Development of Low Molecular Weight CXCR4 Antagonists
by Exploratory Structural Tuning of Cyclic Tetra- and Pentapeptide
Scaffolds Towards the Treatment of HIV Infection, Cancer Metastasis
and Rheumatoid Arthritis Pp. 93-102
Hirokazu Tamamura, Hiroshi Tsutsumi, Hiroyuki Masuno and
Nobutaka Fujii
[Abstract] [Full
text article]
The Therapeutic Potential of Statins in Neurological
Disorders Pp. 103-112
G.K. Rajanikant, D. Zemke, M. Kassab and A. Majid
[Abstract] [Full
text article]
Structure and Functions of Influenza Virus Neuraminidase
Pp. 113-122
Jianzhi Gong, Wenfang Xu and Jie Zhang
[Abstract] [Full
text article]
Abstracts
[Back to top]
The Medicinal Chemistry of Short Lactoferricin-Based Antibacterial
Peptides
B. E. Haug, M. B. Strøm and J. S. M. Svendsen
[Full
text article]
This review discusses antibacterial peptides from
the perspective of development into clinically useful chemotherapeutic
drugs using short lactoferricin based peptides as examples.
The review shows how important features for antibacterial
activity can be identified and explored using the molecular
properties of a range of natural and non-natural amino acids.
The results have been further refined quantitatively using
a “soft-modelling” approach where important structural
parameters that influence the antibacterial activity of 15-residue
model peptides were identified. The review describes how this
knowledge is utilised to generate pharmacophores for antibacterial
efficacy. These pharmacophores turn out to be surprisingly
small and relatively consistent between typical Gram-negative
and Gram-positive bacteria leading to the discovery of a novel
class of short synthetic cationic antimicrobial peptides.
These compounds are found to have high antibacterial activity
against several bacterial strains that are resistant to commercial
antibiotics, and are promising as future clinical candidates
for treatment of infections caused by several clinically relevant
pathogens.
[Back to top]
Radioligand Development for PET Imaging
of β-Amyloid
(Aβ)-Current
Status
Lisheng Cai, Robert B. Innis and Victor W. Pike
[Full
text article]
Two of the main pathological hallmarks of Alzheimer’s
disease (AD) are neuritic plaques and neurofibrillary tangles.
Significant evidence supports a critical and probable causative
role of β
amyloid (Aβ)
plaque formation. Since neuroprotective treatments are typically
most effective at early stages of injury, the detection and
measurement of Aβ
load in living brain should be performed at early and perhaps
even presymptomatic stages of AD. Two primary targets of molecular
imaging research with positron emission tomography (PET) are
to develop surrogate markers (radioligands) for assessing
disease progression and for monitoring the efficacy of developmental
therapeutics. Here, we review the current status of radioligand
development for PET imaging of Aβ
aggregates. General structure-activity relationships have
emerged, including the identification of at least three different
ligand binding sites in various Aβ
aggregates and recognition of the general structural requirements
for ligand binding at each site. Also a few radioligands applicable
to imaging Aβ
plaques in living human brain with positron emission tomography
(PET) have emerged, including [11C]PIB, [11C]SB-13
and [18F]FDDNP.
[Back to top]
Biocatalytic Approaches to Optically Active β-Blockers
[Full
text article]
Beta-blockers are a very important group of drugs widely
used for the treatment of cardiovascular diseases. All aryloxyaminopropanols
are chiral and show different stereoselectivity in their pharmacodynamic
and pharmacokinetic properties for each enantiomer. The more
potent beta-adrenoceptor blocking activity is generally associated
with (S)-enantiomers. Most beta-blocking agents are
sold as racemates although (R)-enantiomers not only
show in some cases lack of activity but might be responsible
for undesirable effects.
Among reports on the direct enzymatic resolution of the most
representative beta-blocker propranolol, the most interesting
is N-acetylation method with commercially available
lipases to yield (S)-N-acetylpropranolol.
Another type of the one-step (S)-isomer biocatalytic
preparation from racemic mixture of propranolol is the biodegradation
with the fungus.
Biocatalytic methods of obtaining homochiral beta-blockers
that are focused on production of versatile precursors are
widely described in literature. The strategies based on the
use of glycidol and derivatives as C-3 synthones have been
shown to be extremely useful for the introduction of the 2-propanol
chain on the aromatic system.
Halohydrins are the established intermediates in the preparation
of optically active beta-blockers. Its resolution by esterhydrolases
has been used as a standard alternative in preparation of
the homochiral propranolol. Additionally, the enzymatic resolution
of the following intermediates was reported: 1-azido-3-aryloxy-2-propanols,
4-(1-aryloxy)-3-hydroxybutyric acid esters, glycerol and cyanohydrin
derivatives. However, even the highly enantioselective lipase-catalyzed
process can only provide 50% of the starting racemate in an
optically active form. An alternative method such as a reduction
of a prochiral ketone by various strains of yeast might quantitatively
provide an enantiomeric product with a yield greater than
50%. The reported substrates for microbial reductions were:
1-halo-aryloxypropan-2-ones and 1-acetoxy-aryloxypropan-2-ones.
[Back to top]
Airway Smooth Muscle Cell as Therapeutic Target
of Inflammation
Chi-Ming Hai
[Full
text article]
Airway inflammation is an outcome of complex interactions
of multiple cell types in an inflammatory network. In recent
years, it has become clear that a single target approach is
unlikely to be effective for the treatment of inflammatory
airway diseases such as asthma. This recognition suggests
an alternative approach of targeting multiple cell types and/or
mediators. Airway smooth muscle (ASM) cells are unique in
serving the dual function of bronchoconstriction and inflammation
in the airway system. ASM cells respond to a large array of
external stimuli such as acetylcholine, bradykinin, inflammatory
cytokines, and cyclic stretch with the expression of inflammatory
mediators such as cytokines and cyclooxygenase products. Ca2+
influx through voltage-gated and transient receptor potential
channels are important mechanisms of Ca2+-dependent
transcription in ASM cells. Calcineurin and Ca2+,
calmodulin-dependent kinase (CaMK) are Ca2+-sensitive
enzymes that regulate the activation of the two transcription
factors, nuclear factor of activated T-cells (NFAT) and cyclic
AMP response element binding protein (CREB). Erk1/2 and p38
mitogen-activated protein kinases are signaling enzymes that
couple receptor activation to gene transcription by phosphorylating
CREB and stabilizing mRNA against de-adenylation. CREB is
a unique transcription factor that is phosphorylated by both
CaMK II and Erk1/2 MAPK. Nuclear factor κB
(NFκB)
appears to be a universal transcription factor that regulates
the transcription of almost all inflammatory genes. Detailed
understanding of the cellular components and interactions
in the inflammatory network of the airway system may lead
to rational targeting of multiple cells and mediators in the
treatment of airway inflammation.
[Back to top]
Contrast Agents and Applications to Assess Tumor
Angiogenesis In Vivo by Magnetic Resonance Imaging
F. Kiessling, B. Morgenstern and C. Zhang
[Full
text article]
Angiogenesis plays a key role in the development of cancer
and is precondition for tumor growth, invasion and spread.
Therefore, numerous angiogenesis inhibitors have been developed,
of which some show potential to defeat cancer in preclinical
and clinical trials. However, response to antiangiogenic treatments
is often delayed and marked by high interindividual variability
making a closely mashed and efficient observation of the patient
necessary. Therefore, surrogate markers which specifically
catch early response to tumor therapy are highly desirable.
Functional parameters like relative blood volume, perfusion
and vessel permeability can be assessed using T1
and T2*-weighted dynamic contrast-enhanced (DCE)
MRI. Various reports are available on this topic but results
are controversial. During antiangiogenic therapies some authors
describe pronounced changes in blood volume: others find effects
only on vessel permeability or perfusion. These conflictive
observations can be attributed to the different tumor models,
therapies, measurement techniques and contrast agents (CA).
Particularly the choice of the optimal CA is considered to
be essential for a successful characterization of tumor angiogenesis.
Often therapy effects on vessel permeability only become apparent,
when blood pool CA are used. This article reviews the current
state of DCE and molecular MRI of angiogenesis. Besides a
general introduction of the different measurement and postprocessing
methods and its previous applications, design, structure and
use of different types of CA are the main focus of this article.
[Back to top]
Development of Low Molecular Weight CXCR4 Antagonists
by Exploratory Structural Tuning of Cyclic Tetra- and Pentapeptide
Scaffolds Towards the Treatment of HIV Infection, Cancer Metastasis
and Rheumatoid Arthritis
Hirokazu Tamamura, Hiroshi Tsutsumi, Hiroyuki Masuno
and Nobutaka Fujii
[Full
text article]
The chemokine receptor, CXCR4, is a GPCR that transduces
signals of its endogenous ligand, CXCL12 (stromal cell-derived
factor-1, SDF-1). The CXCL12-CXCR4 system plays an important
role in the migration of progenitors during embryologic development
of the cardiovascular, hemopoietic, central nervous systems,
etc. This system has recently been proven to be involved in
several problematic diseases, including HIV infection, cancer
cell metastasis, leukemia cell progression, rheumatoid arthritis
(RA) and pulmonary fibrosis. Thus, CXCR4 is thought to be
an important therapeutic target to overcome the above diseases.
Fourteen-mer peptides, T140 and its analogs, were previously
found to be specific CXCR4 antagonists that were characterized
as HIV-entry inhibitors, anti-cancer-metastatic agents, anti-chronic
lymphocytic/acute lymphoblastic leukemia agents and anti-RA
agents. Based on our knowledge of pharmacophores of T140,
CXCR4 antagonists, such as FC131, were previously found by
the efficient utilization of cyclic pentapeptide libraries.
This review article focuses on our recent research on the
development of low molecular weight CXCR4 antagonists including
FC131 analogs, in which structural tuning of the cyclic peptide
ring and chemical modifications were performed for an increase
in potency and a reduction of the peptide character.
[Back to top]
The Therapeutic Potential of Statins in Neurological
Disorders
G.K. Rajanikant, D. Zemke, M. Kassab and A. Majid
[Full
text article]
Statins are currently among the most commonly prescribed
agents for the prevention of cardiovascular disease. Statins
reduce serum cholesterol levels by reversibly inhibiting 3-hydroxy-3-methylglutaryl
coenzyme A reductase, the rate-limiting enzyme in cholesterol
biosynthesis, in the nanomolar range. Mounting evidence suggests
that in addition to their vascular effects such as stabilization
of atherosclerotic plaques and decreased carotid intimal–medial
thickness, statins have additional properties such as endothelial
protection via actions on the nitric oxide synthase system
as well as antioxidant, anti-inflammatory and anti-platelet
effects. These effects of statins might have potential therapeutic
implications in various neurological disorders such as stroke,
Alzheimer's disease, Parkinson’s disease, multiple sclerosis
and primary brain tumors. In this review, the major protective
mechanisms of statins and their applicability to the treatment
of neurological disease are summarized. Although further experiments
are required, currently available data would seem to indicate
that clinical trials to determine the safety and efficacy
of statins in a number of disorders are warranted.
[Back to top]
Structure and Functions of Influenza Virus Neuraminidase
Jianzhi Gong, Wenfang Xu and Jie Zhang
[Full
text article]
Influenza is a disease that deeply affects millions of
people every year. There has not been any drug effective against
all strains. Neuraminidase (NA) is the major surface glycoprotein
of the influenza virus, which possesses critical enzymatic
activity and has been considered as a suitable target for
designing agents against influenza viruses. Here we review
the structure and functions of this enzyme and touch upon
the structure-activity relationship (SAR) of existing influenza
neuraminidase inhibitors (NAIs).
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