|
Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 13, Number 18, 2006
Contents
The Molecular Biology of TRAIL-Mediated Signaling and its
Potential Therapeutic Exploitation in Hematopoietic Malignancies
Pp. 2091-2100
Simone Boehrer, Daniel Nowak, Dieter Hoelzer, Paris S. Mitrou
and Kai Uwe Chow
[Abstract]
Development of Heparanase Inhibitors for Anti-Cancer
Therapy Pp. 2101-2111
Hua-Quan Miao, Hu Liu, Elizabeth Navarro, Paul Kussie
and Zhenping Zhu
[Abstract]
Prognostic Value of Leukocytosis in Acute Coronary
Syndromes: The Cinderella of the Inflammatory Markers
Pp. 2113-2118
J. Núñez, E. Núñez, J. Sanchis,
V. Bodí and A. Llàcer
[Abstract]
The Role of Insertion Allele of Angiotensin Converting
Enzyme Gene in Higher Endurance Efficiency and Some Aspects
of Pathophysiological and Drug Effects Pp. 2119-2126
M. Dékány, I. Harbula, I. Berkes, I. Györe,
A. Falus and J. Pucsok
[Abstract]
Diabetic Pregnancies: The Challenge of Developing
in a Pro Inflammatory Environment Pp. 2127-2138
A. Jawerbaum and E. González
[Abstract]
PET Tracers for Imaging of the Dopaminergic System
Pp. 2139-2153
Philip H. Elsinga, Kentaro Hatano and Kiichi Ishiwata
[Abstract]
The Features and Shortcomings for Gene Delivery
of Current Non-Viral Carriers Pp. 2155-2161
Kota Kodama, Yoshiki Katayama, Yoko Shoji and Hideki Nakashima
[Abstract]
Chemical Countermeasures for the Control of Bacterial
Biofilms: Effective Compounds and Promising Targets
Pp. 2163-2177
Dinty J. Musk Jr. and Paul J. Hergenrother
[Abstract]
Towards a Unifying Hypothesis of Alzheimer’s
Disease: Cholinergic System Linked to Plaques, Tangles and
Neuroinflammation Pp. 2179-2188
Kannan Sivaprakasam
[Abstract]
Cellular Mechanisms and Prospective Applications
of Hypericin in Photodynamic Therapy Pp. 2189-2204
Tobias Kiesslich, Barbara Krammer and Kristjan Plaetzer
[Abstract]
Isoniazid is Not a Lead Compound for its Pyridyl
Ring Derivatives, Isonicotinoyl Amides, Hydrazides, and Hydrazones:
A Critical Review Pp. 2205-2219
T. Scior and S.J. Garcés-Eisele
[Abstract]
Abstracts
[Back to top]
The Molecular Biology of TRAIL-Mediated Signaling
and its Potential Therapeutic Exploitation in Hematopoietic
Malignancies
Simone Boehrer, Daniel Nowak, Dieter Hoelzer, Paris
S. Mitrou and Kai Uwe Chow
Tumor necrosis factor apoptosis ligand (TRAIL) is a type
II membrane-bound ligand displaying expression in a broad
range of tissues and exhibiting a high grade of homology with
the cytotoxic Fas ligand. Interest in TRAIL grew after evidence
emerged, that induction of TRAIL-mediated signaling destroyed
malignant cells while sparing normal cells. Employing the
extrinsic pathway of apoptosis, TRAIL-stimulation is characterized
by initial adaptor recruitment and the subsequent activation
of caspases. Besides promoting apoptosis, stimulation of the
TRAIL receptors may also activate survival signals via
the transcription factor NF-κB.
Moreover, evaluation of the physiological roles of TRAIL-mediated
signaling pathways provides evidence for a regulatory function
within the immune system. Thus a complex picture of TRAIL-mediated
signaling evolves, underscoring the necessity to define its
modes of action while assessing its therapeutic potential.
This review outlines the current knowledge on the physiological
role of TRAIL and discusses its therapeutic potential with
particular focus on malignancies of the hematopoietic system.
[Back to top]
Development of Heparanase Inhibitors for
Anti-Cancer Therapy
Hua-Quan Miao, Hu Liu, Elizabeth Navarro, Paul Kussie
and Zhenping Zhu
Heparanase is an endo-beta-D-glucuronidase that
degrades heparan sulfate glycosaminoglycan side chains of
the proteoglycans in extracellular matrix and basement membrane.
Heparanase enzymatic activity is important in the promotion
of tumor angiogenesis, primary tumor growth, invasion, and
metastasis. Expression of heparanase in many tumor types conversely
correlates with prognosis. Much progress has been made in
studying the regulation of heparanase expression, processing
and activation. The interaction between heparanase and its
substrate heparan sulfate has been well characterized. The
fact that heparanase was identified as the single predominant
heparan sulfate-degrading enzyme in human cancer sparked considerable
interest in developing heparanase inhibitors for potential
therapeutic applications. Recent progress in drug development
led to several classes of heparanase inhibitors, including
chemically modified natural products, small molecule inhibitors,
and antibodies. Some of these inhibitors have demonstrated
potent activities to inhibit tumor angiogenesis, tumor progress,
or tumor metastasis. A leading compound, PI-88, is currently
being evaluated in clinical phase II trials in patients with
melanoma, liver, or lung cancers. This review summarizes the
recent progress in heparanase biochemical research and the
development of heparanase antagonists as novel anti-cancer
therapeutics.
[Back to top]
Prognostic Value of Leukocytosis in Acute
Coronary Syndromes: The Cinderella of the Inflammatory Markers
J. Núñez, E. Núñez, J.
Sanchis, V. Bodí and A. Llàcer
In recent years, numerous studies have validated
the role of inflammation in the pathogenesis of atherosclerosis.
Several of such studies have produced compelling evidence
that inflammation participates in both, the initiation and
perpetuation of the atherosclerotic process. Furthermore,
epidemiological observations have found basal white blood
cell (WBC) count is strongly associated with future cardiovascular
disease (CVD), highlighting the participation of leukocytes
in the pathogenesis of the ischemic damage that occurred during
an acute coronary event, in particularly during the acute
myocardial infarction (MI). Fundamentally, an acute MI triggers
a systemic response to a necrotic insult characterized by
leukocytosis and acute-phase protein synthesis. In this setting,
elevated WBC count plays a central role in the reparative
process that takes place to replace the necrotic tissue for
collagen. In addition to be a proxy for the intensity of the
peri-infarction inflammatory response, recent evidence has
also shown that an elevated WBC counts, measured during the
acute phase of MI, to be associated with adverse outcomes.
This relationship holds true even when adjusting for classical
prognostic variables some of which are surrogates for the
extension of the infarcted-area. WBC count prognostic value
in absence of necrosis marker elevation (like unstable angina),
however, remains unclear and controversial. Additionally,
and essentially due to its simplicity, cost-effectiveness
and wide availability, WBC count has drawn the attention of
researchers as a potential stratification tool in acute coronary
syndromes (ACS). However, a formal comparison is needed between
WBC count with other inflammatory markers such high-sensitive
C-reactive protein to fully characterize its diagnostic accuracy.
[Back to top]
The Role of Insertion Allele of Angiotensin
Converting Enzyme Gene in Higher Endurance Efficiency and
Some Aspects of Pathophysiological and Drug Effects
M. Dékány, I. Harbula, I. Berkes, I.
Györe, A. Falus and J. Pucsok
Background: None of the genetic markers are selectively
associated with elite athletes, but potential candidates are
found in the renin-angiotensin system, which plays a key role
in the regulation of cardiovascular physiology. The most extensively
examined gene in connection with the hemodynamics category
is the angiotensin converting enzyme (ACE). This review paper
has focused on ACE I/D allele polymorphism regarding the evidence
of the effects of physiological and pathophysiological drugs
and has completed with an original work in the exercise physiology.
Methods: In this study we examined genetic polymorphisms
of ACE in female (n=26) and male (n=24) athletes as well as
in a well-trained control group (n=24). MVVex,
VE and VO2max
were determined at rest and during an exhaustive step test.
Results: The frequency of the ACE I allele was significantly
higher (p<0.041) in the group showing a higher intensity
of breathing metabolism. The ACE D allele frequency was significantly
higher in the excellent endurance athletes group than in unsuccessful
athletes (p<0.054).
Conclusion: The ACE I allele is a genetic marker
for higher endurance efficiency in acute physical activity
and higher adaptation of the cardiovascular system. The measurement
of acute physical status needs to be completed with examination
of genotype, which is related to the athletic excellence also,
because the D allele could be associated with good performance
by endurance athletes in future world championships. Further
studies are needed to assess the view that the ACE D allele
has a significant role in athletic efficiency.
[Back to top]
Diabetic Pregnancies: The Challenge of Developing
in a Pro Inflammatory Environment
A. Jawerbaum and E. González
The maternal diabetic environment alters the embryo
and the feto-placental development. The results of these alterations
are: increased embryo resorption and malformation rates, placental
dysfunction, fetal alterations that lead to increased neonatal
morbidity and mortality rates, and also diseases that will
be evident later in the adult life of the newborn. The etiology
of these many maternal diabetes-induced complications are
not yet understood in full. In this review the role of maternal
diabetes as an inductor of a pro-inflammatory environment
that impairs embryo and placental development is discussed.
An overproduction of pro-inflammatory agents is found in the
uterus during implantation and the developing embryo and placenta
from experimental models of diabetes, as well as in placenta
from diabetic women. In these tissues there are increases
in reactive oxygen species, pro-inflammatory cytokines and
prostaglandins, nitric oxide and peroxynitrites. These pro-inflammatory
agents lead to the intrauterine activation of matrix metalloproteinases,
proteases involved in remodeling the extracellular matrix
during implantation and feto-placental development. Many of
these pro-inflammatory agents have overlapping mechanisms
of action and cross regulatory pathways that propagate the
inflammatory processes. Antioxidants, PPARγ
activators, and NF-κB
inhibitors are able to reduce the concentrations of these
agents in intrauterine gestational tissues. This article reviews
the current understanding of maternal diabetes-induced changes
in pro-inflammatory and anti-inflammatory pathways that affect
the embryo and placental development in maternal diabetes,
and stresses the need of a strict maternal control of the
pathology to prevent deleterious consequences in the offspring.
[Back to top]
PET Tracers for Imaging of the Dopaminergic
System
Philip H. Elsinga, Kentaro Hatano and Kiichi Ishiwata
The dopaminergic system plays a major role in neurological
and psychiatric disorders such as Parkinson’s disease,
Huntington’s disease, tardive dyskinea and schizophrenia.
Knowledge on altered dopamine synthesis, receptor densities
and status are important for understanding the mechanisms
underlying the pathogenesis and therapy of diseases. PET provides
a non-invasive tool to investigate these features in vivo,
provided the availability of suitable radiopharmaceuticals.
To investigate presynaptic function, PET-tracers have been
developed to measure dopamine synthesis and transport. For
the former the most commonly used tracers are 6-[18F]FDOPA
and 6-[18F]FMT,
whereas for the latter several 11C/18F-labeled
tropane analogues are being clinically used. Postsynaptically,
dopamine exerts actions through several subtypes of the dopamine
receptor. The dopamine receptor family consists of 5 subtypes
D1-D5.
In order to investigate the role of each receptor subtype,
selective and high-affinity PET-radioligands are required.
For the dopamine D1-subtype
the most commonly used ligand is [11C]SCH
23390 or [11C]NNC
112, whereas for the D2/D3-subtype
[11C]raclopride
is a common tracer. [18F]Fallypride
is a suitable PET-tracer for the investigation of extrapyramidal
D2-receptors.
For the other subtypes no suitable radioligands have been
developed yet.
This paper gives an overview of the current status on dopamine
PET-tracers and the development of new lead compounds as potential
PET-tracers by medicinal chemistry.
[Back to top]
The Features and Shortcomings for Gene Delivery
of Current Non-Viral Carriers
Kota Kodama, Yoshiki Katayama, Yoko Shoji and Hideki
Nakashima
Since the viral vector for gene therapy has serious
problems, including oncogenesity and other adverse effects,
non-viral carriers have attracted a great deal of attention.
Non-viral carriers are expected to achieve gene therapy without
serious side effects. However, the most critical issue of
gene delivery by non-viral carriers is the low-expression
efficiencies of the desired gene. In order to apply non-viral
carriers for gene therapy in practical clinical usage, further
understanding of the cellular barriers against gene delivery
is a prerequisite. Moreover, additional intelligent concepts
for gene delivery are also needed. We will summarize the features
and shortcomings of currently developed non-viral delivery
systems. Especially, we will address the current progress
of cationic lipids (lipoplex) and cationic polymers (polyplex)
in terms of transfection efficiency. Furthermore, our group
has developed a system that responds to the particular intracellular
signals of target disease cells. We have named this gene delivery
system a drug delivery system based on responses cellular
signal (D-RECS). We will introduce this new concept of intelligent
non-viral delivery system that our group recently developed.
[Back to top]
Chemical Countermeasures for the Control
of Bacterial Biofilms: Effective Compounds and Promising Targets
Dinty J. Musk Jr. and Paul J. Hergenrother
The pathogenic nature of many infectious bacteria is
enhanced by their ability to form surface-associated, protected
communities known as “biofilms.” Due to various
factors, bacteria in biofilm communities display significantly
greater resistance to traditional antimicrobial therapies
than their planktonic brethren. This resistance complicates
many common bacterial infections, resulting in recurrent ear
infections, bacterial endocarditis, chronic lung infection
in cystic fibrosis, infectious kidney stones, and surface
infection of implanted medical devices. Owing to the serious
nature of many biofilm-mediated infections and the near-complete
dearth of effective strategies for treating them, efforts
are underway to further understand the nature of bacterial
infections involving biofilms and to discover and develop
effective therapies to combat them. Particularly, several
classes of chemical compounds have shown promise in combating
biofilms when used in conjunction with traditional antimicrobials.
The vast majority of these compounds exert their anti-biofilm
properties through disruption of “quorum sensing,”
a common means of intercellular communication in bacterial
communities that allows coordinated expression of virulence
factors and facilitates formation of the oft-complex architecture
of mature bacterial biofilms. Other new chemical entities
are effective against biofilms without necessarily affecting
quorum sensing. This review summarizes salient research in
the development of effective chemical countermeasures for
Gram-negative and Gram-positive bacterial infections involving
biofilms.
[Back to top]
Towards a Unifying Hypothesis of Alzheimer’s
Disease: Cholinergic System Linked to Plaques, Tangles and
Neuroinflammation
Kannan Sivaprakasam
The central role of cholinergic system in Alzheimer’s
disease (AD) pathway is becoming increasingly significant
as reports linking the various components of cholinergic neurotransmission
with the other pathological hallmarks emerge. This review,
while addressing the molecular mechanisms associated with
the pathological hallmarks of the disease and their close
interactions, also makes an attempt to address the critical
question that evades an answer: Given the significant role
played by cholinergic system in AD pathway, why do the cholinergic-mechanism-based
drugs are not successful in reversing or arresting the disease
progress? Further, as molecules of diverse structural features
were shown to inhibit amyloid aggregation, an understanding
of the generic pathway of amyloid aggregation slowly emerges.
For the first time, a coherent view of amyloid aggregation
is presented in this review. The possible role of neuroinflammatory
response in the events leading to the degeneration of cholinergic
neurons is also discussed.
[Back to top]
Cellular Mechanisms and Prospective Applications
of Hypericin in Photodynamic Therapy
Tobias Kiesslich, Barbara Krammer and Kristjan Plaetzer
During the last decades, Photodynamic Therapy (PDT)
has been established as a powerful alternative approved by
health agencies of several countries for treatment of various
malignant and some non-malignant diseases. PDT makes use of
the light-induced destruction of target cells by formation
of cytotoxic products in the presence of a photosensitizing
agent and oxygen. The light-dependent tumor destructive properties
of Hypericin have drawn attention to its promising application
as a photosensitizer in the frame of PDT. Hypericin is a naturally
occurring secondary metabolite in plants of the Hypericum
genus, with Hypericum perforatum (St. John’s
wort) as it is a commonly known representative. This review
focuses on the cellular mechanisms of Hypericin-based phototoxicity
and provides an outlook for future application of Hypericin
as a fluorescing and photosensitizing agent for diagnosis
and treatment of cancerous diseases, respectively.
[Back to top]
Isoniazid is Not a Lead Compound for its
Pyridyl Ring Derivatives, Isonicotinoyl Amides, Hydrazides,
and Hydrazones: A Critical Review
T. Scior and S.J. Garcés-Eisele
The relationships between structure, disintegration and
antituberculotic in vitro activity were studied for
over 200 derivatives of isonicotinic acid hydrazide (isoniazid,
INH). Conclusive evidence reflects that many compounds do
not withstand the in vitro conditions. A pH dependant
partial hydrolysis to INH occurs in the case of hydrazones,
in analogy to well-known benzoic acid esters. Hydrazides and
amides are cleaved into isonicotinic acid. In general, antimycobacterial
potencies drop against INH except for two outliers probably
with additional unspecific toxicity of their residues. Analyzing
the complexity and heterogeneity of molecular events, trends
linked to hydrolysis are found when structural features are
clustered. Hammett sigma constants correlate to pKa
values possessing a twofold descriptive meaning: (i) the cardinal
increase of partial positive charge of the reaction center
towards nucleophilic water attack and (ii) the ionization
crucial for mycobacterial cell permeation through porins or
lipid barriers. We review the literature concluding that many
so-called “novel leads” are nothing else than
precursors of an INH-based scaffold. In addition, INH ring-substitution
or analogous backbones never achieve the efficiency of INH,
itself a prodrug, which accumulates in Mycobacterium tuberculosis
in form of its intrabacterial active principle(s) to which
it is an optimal transport vehicle, evidencing that INH is
not a promising lead compound at all.
|
