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Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 14, Number 17, 2007
Contents
Polyamines in the Brain: Distribution, Biological Interactions,
and their Potential Therapeutic Role in Brain Ischaemia
Pp. 1807-1813
Jun Li, Karen M. Doyle and Turgut Tatlisumak
[Abstract]
Therapeutic Targets in the ARF Tumor Suppressor Pathway
Pp. 1815-1827
Anthony J. Saporita, Leonard B. Maggi Jr., Anthony J.
Apicelli and Jason D. Weber
[Abstract]
Molecular Hybridization: A Useful Tool in the Design
of New Drug Prototypes Pp. 1829-1852
Cláudio Viegas-Junior, Amanda Danuello, Vanderlan
da Silva Bolzani, Eliezer J. Barreiro and Carlos Alberto Manssour
Fraga
[Abstract]
Hydroxylation of Hypoxia-Inducible Transcription Factors
and Chemical Compounds Targeting the HIF-α
Hydroxylases Pp. 1853-1862
K. Bruegge, W. Jelkmann and E. Metzen
[Abstract]
Whither Combine? New Opportunities for Receptor-Based
QSAR Pp. 1863-1877
Gerald H. Lushington, Jian-Xin Guo and Jenna L. Wang
[Abstract]
Uric Acid Reduction: A New Paradigm in the Management
of Cardiovascular Risk? Pp. 1879-1886
Jesse Dawson, Terry Quinn and Matthew Walters
[Abstract]
Relevance of Endothelial-Haemostatic Dysfunction in
Cigarette Smoking Pp. 1887-1892
Rossella R. Cacciola, Francesca Guarino and Riccardo Polosa
[Abstract]
Mechanism and Potential of the Growth-Inhibitory Actions
of Vitamin D and Analogs Pp. 1893-1910
G. Eelen, C. Gysemans, L. Verlinden, E. Vanoirbeek, P.
De Clercq, D. Van Haver, C. Mathieu, R. Bouillon and A. Verstuyf
[Abstract]
Abstracts
[Back to top]
Polyamines in the Brain: Distribution, Biological
Interactions, and their Potential Therapeutic Role in Brain
Ischaemia
Jun Li, Karen M. Doyle and Turgut Tatlisumak
The endogenous polyamines (spermine, spermidine, and putrescine)
are present at relatively high concentrations in the mammalian
brain and play crucial roles in a variety of aspects of cell
functioning. Stroke is the third most common cause of death
and the leading cause of disability among adults in the western
world. Brain polyamine levels change dramatically following
cerebral ischaemia. Polyamines may be involved in the pathophysiological
processes underlying brain ischaemia through several possible
mechanisms. These include direct effects on ion channels and
receptors modulating potassium, and most importantly calcium
trafficking, or through the production of toxic metabolites.
Considerable evidence shows that the non-competitive polyamine
antagonists, ifenprodil and eliprodil, are neuroprotective.
Interestingly, novel polyamine analogues, such as N1-dansylspermine,
BU36b, and BU43b, have also recently been shown to have neuroprotective
potential. The exact mechanisms of the neuroprotection afforded
by the polyamine antagonists and their clinical applicability
is worthy of further study.
[Back to top]
Therapeutic Targets in the ARF Tumor Suppressor Pathway
Anthony J. Saporita, Leonard B. Maggi Jr., Anthony J.
Apicelli and Jason D. Weber
One of the outstanding fundamental questions in cancer cell
biology concerns how cells coordinate cellular growth (or
macromolecular synthesis) with cell cycle progression and
mitosis. Intuitively, rapidly dividing cells must have some
control over these processes; otherwise cells would continue
to shrink in volume with every passing cycle, similar to the
cytoreductive divisions seen in the very early stages of embryogenesis.
The problem is easily solved in unicellular organisms, such
as yeast, as their growth rates are entirely dependent on
nutrient availability. Multicellular organisms such as mammals,
however, must have acquired additional levels of control,
as nutrient availability is seldom an issue and the organism
has a prodigious capacity to store necessary metabolites in
the form of glycogen, lipids, and protein. Furthermore, the
specific needs and specialized architecture of tissues must
constrain growth for growth’s sake; if not, the necessary
function of the organ could be lost. While certainly a myriad
of mechanisms for preventing this exist via initiating
cell death (e.g. apoptosis, autophagy, necrosis), these all
depend on some external cue, such as death signals, hypoxia,
lack of nutrients or survival signals. However there must
also be some cell autonomous method for surveying against
inappropriate growth signals (such as oncogenic stress) that
occur in a stochastic fashion, possibly as a result of random
mutations. The ARF tumor suppressor seems to fulfill that
role, as its expression is near undetectable in normal tissues,
yet is potently induced by oncogenic stress (such as overexpression
of oncogenic Ras or myc). As a result of induced expression
of ARF, the tumor suppressor protein p53 is stabilized and
promotes cell cycle arrest. Mutations or epigenetic alterations
of the INK4α/Arf
locus are second only to p53 mutations in cancer cells, and
in some cancers, alterations in both Arf and p53
observed, suggesting that these two tumor suppressors act
coordinately to prevent unwarranted cell growth and proliferation.
The aim of this review is to characterize the current knowledge
in the field about both p53-dependent and independent functions
of ARF as well as to summarize the present models for how
ARF might control rates of cell proliferation and/or macromolecular
synthesis. We will discuss potential therapeutic targets in
the ARF pathway, and some preliminary attempts at enhancing
or restoring the activity of this important tumor suppressor.
[Back to top]
Molecular Hybridization: A Useful Tool in the Design
of New Drug Prototypes
Cláudio Viegas-Junior, Amanda Danuello, Vanderlan
da Silva Bolzani, Eliezer J. Barreiro and Carlos Alberto Manssour
Fraga
Molecular hybridization is a new concept in drug design and
development based on the combination of pharmacophoric moieties
of different bioactive substances to produce a new hybrid
compound with improved affinity and efficacy, when compared
to the parent drugs. Additionally, this strategy can result
in compounds presenting modified selectivity profile, different
and/or dual modes of action and reduced undesired side effects.
So, in this paper, we described several examples of different
strategies for drug design, discovery and pharmacomodulation
focused on new innovative hybrid compounds presenting analgesic,
anti-inflammatory, platelet anti-aggregating, anti-infectious,
anticancer, cardio- and neuroactive properties.
[Back to top]
Hydroxylation of Hypoxia-Inducible Transcription Factors
and Chemical Compounds Targeting the HIF-α
Hydroxylases
K. Bruegge, W. Jelkmann and E. Metzen
The hypoxia-inducible transcription factors (HIFs) are central
components in the cellular responses to a lack of O2,
i.e. hypoxia. Homologs of the HIF system (HIF-1, -2 and -3)
are detectable in all nucleated cells of multicellular organisms.
Active HIFs are heterodimers (HIF-α/β).
In hypoxia the O2-labile
α-subunit
is translocated to the nucleus where it binds HIF-β.
Over 100 HIF target genes have already been identified. The
translational products of these genes increase O2
delivery to hypoxic tissues, such as erythropoietin which
stimulates the production of red blood cells, and they adapt
cellular metabolism to hypoxia, such as glycolytic enzymes.
HIFs are inactive in normoxia because of O2-dependent
enzymatic hydroxylation and subsequent degradation of their
α-subunit.
Three HIF-α
prolyl hydroxylases (PHD1, 2 and 3) initiate proteasomal degradation
while an asparaginyl hydroxylase (factor inhibiting HIF-1,
FIH-1) inhibits the function of the C-terminal transactivation
domain of HIF-α.
In addition to O2 and 2-oxoglutarate,
the HIF-α
hydroxylases require Fe2+
and ascorbate as co-factors. Products of glycolysis can act
as endogenous inhibitors of HIF hydroxylases which may lead
to sustained activation of HIFs in cancer cells. The cofactor
requirements define the routes to inhibition of the enzymes
when HIF activation is desirable. In particular, 2-oxoglutarate
analogues have emerged as promising tools for stimulation
of erythropoiesis and angiogenesis (“HIF-stabilizers”).
However, as the HIF system promotes the transcription of many
genes, and other 2-oxoglutarate dependent dioxygenases are
likely to be inhibited by the same analogues, careful evaluation
of the inhibitors seems mandatory prior to their clinical
use.
[Back to top]
Whither Combine? New Opportunities for Receptor-Based
QSAR
Gerald H. Lushington, Jian-Xin Guo and Jenna L. Wang
Receptor based QSAR methods represent a computational marriage
of structure activity relationship analysis and receptor structure
based design that is providing valuable pharmacological insight
to a wide range of therapeutic targets. One implementation,
called Comparative Binding Energy (COMBINE) analysis, is particularly
powerful by virtue of its explicit consideration of interatomic
interactions between the ligand and receptor as the QSAR variable
space. This review outlines the methodological basis for the
COMBINE model, contrasts it relative to other 3D QSAR techniques,
and discusses sample applications that illustrate recent key
innovations. One major development discussed is the rigorous
integration of multiple receptors into unified COMBINE models
for probing bioactivity trends as a function of amino acid
variation across a series of homologous protein receptors,
and as a function of conformational variation within one single
protein. Other important examples include a recent extension
of the method to account for covalent effects arising from
ligand binding, as well as successful application of a COMBINE
model to high throughput virtual screening. This review concludes
with discussions about possible future methodological refinements
and their applications, including potential extensions to
four-dimensional QSAR, and a potential role of quantum chemistry
in addressing covalent bonding effects and parametric adaptivity.
[Back to top]
Uric Acid Reduction: A New Paradigm in the Management
of Cardiovascular Risk?
Jesse Dawson, Terry Quinn and Matthew Walters
Uric acid is the end-product of purine catabolism. Hyperuricaemia
is implicated in disorders such as gout and urolithiasis and
recent epidemiological evidence suggests an association between
increasing uric acid levels and increased cardiovascular morbidity
and mortality. A direct causal role remains to be established
but recent studies of losartan, atorvastatin and fenofibrate
suggest that uric acid reduction contributes to attenuation
of cardiovascular risk. Furthermore, several small studies
of xanthine oxidase inhibition (the most common method of
uric acid reduction) have shown improvements in measures of
cardiovascular and endothelial function of a similar magnitude
to those of other proven preventative strategies.
This review introduces the epidemiological data, discusses
strategies to lower uric acid and outlines the available clinical
trial data supporting uric acid reduction as a potential and
novel method of reducing the burden of cardiovascular disease.
[Back to top]
Relevance of Endothelial-Haemostatic Dysfunction in
Cigarette Smoking
Rossella R. Cacciola, Francesca Guarino and Riccardo Polosa
Cigarette smoking plays a major role in the development of
atherosclerosis and is associated with increased morbidity
and mortality for coronary heart disease, stroke and peripheral
vascular disease. In spite of the abundance of epidemiological
evidence that links cigarette smoking to vascular disease,
the pathologic mechanisms for such interaction are not clear.
The endothelium is a major target organ that undergoes activation
when exposed to common vascular triggers, including hypertension,
hypercholesterolemia, hyperglycaemia and smoking. Changes
in endothelial function may lead to a dysfunctional vascular
phenotype characterized by anomalous responses of the vascular
tone, abnormal endothelial proliferation and prothrombotic
activation. Several studies have demonstrated that smoking
may alter endothelial function by a direct toxic effect and
consequently trigger haemostatic activation and thrombosis.
In this article we will review the evidence that loss of normal
endothelial function may result in a loss of the balance of
the haemostatic system and in changes of the platelet physiology
that may be relevant for the pathogenic effect of smoking
on the development of atherothrombosis.
[Back to top]
Mechanism and Potential of the Growth-Inhibitory Actions
of Vitamin D and Analogs
G. Eelen, C. Gysemans, L. Verlinden, E. Vanoirbeek, P.
De Clercq, D. Van Haver, C. Mathieu, R. Bouillon and A. Verstuyf
1α,25-Dihydroxyvitamin
D3 [1,25-(OH)2D3]
can exert its biological actions through binding with the
nuclear vitamin D receptor (VDR), a ligand-activated transcription
factor. Next to control of bone and mineral homeostasis, these
actions include an immunomodulatory effect and a potent growth-inhibitory,
antiproliferative or prodifferentiating action on a wide variety
of cell types. The molecular mechanisms underlying this antiproliferative
action form an intriguing research topic and they remain,
although thoroughly studied, not completely understood. Important
cell cycle regulators are involved such as cyclins, cyclin
dependent kinases and their corresponding inhibitors as well
as E2F transcription factors and accompanying pocket proteins.
Whether 1,25-(OH)2D3
influences the expression of all these proteins directly through
the nuclear VDR or rather in an indirect manner is not always
clear.
The antiproliferative action makes 1,25-(OH)2D3
a possible therapeutic tool to treat hyperproliferative disorders,
among which different types of cancer. Clinical application,
however, is severely hampered by calcemic effects such as
hypercalcemia, hypercalciuria and increased bone resorption.
Rational design of chemically modified 1,25-(OH)2D3-analogs
tries to overcome this problem. As such, several thousands
of analogs have been synthesized and evaluated, some of which
display the desired dissociation between beneficial antiproliferative
and unwanted calcemic effects. A number of those analogs are
‘superagonistic’ and have a several-fold stronger
antiproliferative action than the parent compound.
This review focuses on recent findings about the complex mechanisms
behind the antiproliferative and prodifferentiating effect
of 1,25-(OH)2D3.
Furthermore, the mode of action and possible clinical application
of chemically modified 1,25-(OH)2D3-analogs
will be discussed.
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