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Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 15, Number 15, 2008
Contents
From a Dull Enzyme to Something Else: Facts and Perspectives
Regarding Aldose Reductase Pp. 1452-1461
A. Del Corso, M. Cappiello and
U. Mura
[Abstract]
Non-Nucleoside Inhibitors of NS5B Polymerase Binding
to Allosteric Sites: 3D- QSAR and Molecular Docking Studies
Pp. 1462-1477
Hongyu Cao, Ran Cao, Huabei Zhang, Xuefang
Zheng and Dabin Gao
[Abstract]
Farnesyltransferase Inhibitors: A Detailed Chemical
View on an Elusive Biological Problem Pp. 1478-1492
Sérgio F. Sousa, Pedro A. Fernandes and
Maria João Ramos
[Abstract]
The Role of Glycogen Synthase Kinase-3β
in Normal Haematopoiesis, Angiogenesis and Leukaemia
Pp. 1493-1499
T. Holmes, T.A. O’Brien, R. Knight, R.
Lindeman, G. Symonds and A. Dolnikov
[Abstract]
Advances and Challenges in the Synthesis of Highly
Oxidised Natural Phenols with Antiviral, Antioxidant and Cytotoxic
Activities Pp. 1500-1519
Raffaele Saladino, Giampiero Gualandi, Angela
Farina, Claudia Crestini, Lucia Nencioni and Anna
Teresa Palamara
[Abstract]
What Does Systems Biology Mean for Drug Development?
Pp. 1520-1528
André Schrattenholz and Vukic
Šoškic
[Abstract]
Recent Advances in Antiviral Activity of Benzo/Heterothiadiazine
Dioxide Derivatives Pp. 1529-1540
Peng Zhan, Xinyong Liu and Erik
De Clercq
[Abstract]
Carriership of Factor V Leiden and Evolutionary
Selection Advantage Pp. 1541-1544
Pelle G. Lindqvist and Björn Dahlbäck
[Abstract]
Resveratrol and Ischemic Preconditioning in the
Brain Pp. 1545-1551
Ami P. Raval, Hung Wen Lin, Kunjan R. Dave, R.
Anthony DeFazio, David Della Morte, Eun Joo Kim and Miguel
A. Perez-Pinzon
[Abstract]
Abstracts
[Back to top]
From a Dull Enzyme to Something Else: Facts
and Perspectives Regarding Aldose Reductase
A. Del Corso, M. Cappiello and
U. Mura
Aldose Reductase (ALR2) is defined as the first enzyme
of the “polyol pathway”. As such, ALR2 would convert
glucose to sorbitol through an NADPH dependent reaction.
Considered a promoter of osmotic imbalance under hyperglycemic
conditions, the enzyme has been under intense investigation
as a critical target to prevent and control diabetic complications
through the inhibition of its activity. Further characterization
of ALR2 suggests its participation in cell detoxification
mechanisms through the reduction of toxic aldehydes. Moreover,
intriguing is the apparent involvement of the enzyme in the
signalling machinery of inflammatory cell response. Here,
the structural and functional assessment of ALR2 as an aldose/aldehyde
reducing enzyme, and its involvement in various aspects of
cell function from sugar metabolism to redox homeostasis and
cell signaling are presented.
[Back to top]
Non-Nucleoside Inhibitors of NS5B Polymerase Binding
to Allosteric Sites: 3D- QSAR and Molecular Docking Studies
Hongyu Cao, Ran Cao, Huabei Zhang, Xuefang
Zheng and Dabin Gao
Infection caused by hepatitis C virus (HCV) is a significant
world health problem for which novel therapies are in urgent
demand. Nonstructural (NS5B) viral proteins have emerged as
an attractive target for drug discovery efforts toward antiviral
for hepatitis C virus. Toward this target several series of
NS5B inhibitors that showed activity in the replicon assay
have been reported. In this article, we gave a report of the
NS5B allosteric sites and the corresponding non-nucleoside
inhibitors, which belong to different chemical classes. Then
using comparative molecular field analysis (CoMFA) and comparative
molecular similarity indices analysis (CoMSIA) methods, 3-dimension
quantitative structure-activity relationships (3D-QSAR) models
have been built with more than two hundred benzimidazole/indole
derivative inhibitors. These studies indicated that the QSAR
models were statistically significant and had high predictabilities
(CoMFA: q2=0.823, r2=0.942; CoMSIA:
q2=0.817, r2=0.935). The flexible docking
method, which was performed by the DOCK6.0 software, positioned
all of the inhibitors into the allosteric site to determine
the probable binding conformation. The CoMFA and CoMSIA models
based on the docking conformations also yielded statistically
significant and high predictive QSAR models (CoMFA: q2=0.509,
r2=0.768; CoMSIA: q2=0.582, r2=0.854).
Our models would offer help to better comprehend the structure-activity
relationships existent for this class of compounds and also
facilitate the design of new inhibitors with good chemical
diversity.
[Back to top]
Farnesyltransferase Inhibitors: A Detailed Chemical
View on an Elusive Biological Problem
Sérgio F. Sousa, Pedro A. Fernandes and
Maria João Ramos
Farnesyltransferase (FTase) is a zinc enzyme that has
been the subject of particular attention in anti-cancer research.
This enzyme promotes the addition of a farnesyl group from
farnesyl diphosphate (FPP) to a cysteine residue of a protein
substrate containing a typical -CAAX motif at the carboxyl
terminus.
Initial interest in FTase inhibition was prompted by the finding
that farnesylation was absolutely required for the oncogenic
forms of ras proteins to transform cells, as ras proteins
have been implicated in around 30% of all human cancers. This
discovery led to frenetic search for FTase inhibitors (FTIs),
with more than 400 patents registered in less than a decade.
However, despite the very promising initial results, the outcome
of Phase II and Phase III clinical trials was, is general,
rather disappointing, with the most advanced FTIs failing
to demonstrate anti-tumor activity in ras dependent cancers,
presumably because K-ras, the most frequently mutated form
of ras in human cancers, is able to bypass FTI blockade through
cross-prenylation by the related enzyme geranylgeranyltransferase
I (GGTase I). Surprisingly, several of these compounds were
later shown to have anti-tumor activity against non-ras dependent
cancers, launching the grounds for a new and exciting era
in FTIs research and development, although the precise target
for the FTIs activity of these compounds still remains unknown.
This review reports the recent progress in the field, presenting
a comprehensive summary of the most promising FTIs, in terms
of their chemical structure and properties, taking into account
the topology of the enzyme’s active-site, and the most
recent mechanistic results on the catalytic activity of FTase,
both at the theoretical and mechanistic level. These features
are presented in close linking with the available results
on the biological activity of these inhibitors, and with the
outcome of the most recent clinical trials.
[Back to top]
The Role of Glycogen Synthase Kinase-3β
in Normal Haematopoiesis, Angiogenesis and Leukaemia
T. Holmes, T.A. O’Brien, R. Knight, R.
Lindeman, G. Symonds and A. Dolnikov
Glycogen synthase kinase 3 beta (GSK-3β)
was one of the first kinases identified and studied, initially
for its role in the regulation of glycogen synthesis. Over
the past decade, interest in GSK-3β
has grown far beyond glycogen metabolism, and this is due
in large measure to the critical role that GSK-3β
plays in the regulation of many other cellular processes,
particularly cell proliferation and apoptosis. GSK-3β
has been shown to regulate the proteolysis and sub-cellular
compartmentalization of a number of proteins directly involved
in the regulation of cell cycling, proliferation, differentiation
and apoptosis. GSK-3β
also regulates the degradation of proteins that regulate gene
expression and thus affects a variety of important cell functions.
Specifically, GSK-3β
controls the degradation of β-catenin,
the main effector of Wnt that regulates haematopoiesis and
stem cell function. In this case GSK-3β
is a negative regulator of Wnt. In contrast, GSK-3β
positively regulates NF-κB,
another important biochemical pathway also involved in the
regulation of multiple aspects of normal and aberrant haematopoiesis.
GSK-3β
regulates degradation of IκB,
a central inhibitor of NF-κB.
In this way, GSK-3β
acts to control the resistance of leukaemic cells to chemotherapy
through the modulation of NF-κB,
a critical factor in maintaining leukaemic cell growth. In
addition, GSK-3β
regulates the pro-inflammatory activity of NF-κB.
As GSK-3β
is a pleiotropic regulator, inhibitors may increase the range
of novel anti-leukaemic and anti-inflammatory drugs that control
immune response.
[Back to top]
Advances and Challenges in the Synthesis of Highly
Oxidised Natural Phenols with Antiviral, Antioxidant and Cytotoxic
Activities
Raffaele Saladino, Giampiero Gualandi, Angela
Farina, Claudia Crestini, Lucia Nencioni and Anna
Teresa Palamara
Polyphenols are a family of organic compounds characterized
by a wide range of biological activities. Among natural polyphenols,
the products derived from shikimic and polyketide biogenic
pathways, such as lignans, neolignans, cardanols and flavonoids
are of special interest owing to their powerful antioxidant,
antitumoral, antimitotic, antiviral, cardiovascular and immunosuppressive
activity. The biological activity of polyphenols can be finely
tuned by the oxidation state of the molecule. Polyphenols
are subject to oxidative metabolism in the cell by cytochrome
p-450 dependent enzymes, mainly at reactive benzyl and aryl
positions of the molecule, to yield highly oxidised derivatives,
namely quinones, hydroquinones, semiquinones, catechols and
others, whose biological activity can greatly differ from
that of the parental compound. In fact, these derivatives
are characterized by peculiar antitumoral, antioxidant and
antiviral activities and show different chemical properties
toward nucleophiles and electrophiles active sites in the
cell. This behavior is dependent on the specific value of
the redox potential in the cell. The low concentration of
these metabolites in nature, and the difficulty to recover
them from mammalian cells or fluids require novel procedures
for their synthesis to collect adequate amounts of compounds
for biological assays. On the other hand, only a few attentions
has been devoted to design novel oxidative procedures for
the synthesis of highly oxidised polyphenols characterized
by higher biological activity. In this review, advances and
challenges in the synthesis of natural and semi-synthetic
highly oxidised polyphenols are reported focusing the attention
in the recent years. Data on the antiviral, antioxidant and
cytotoxic activities in vivo and in vitro
systems for natural and semi-synthetic highly oxidised polyphenols
are also reported, and the effect on the biological activity
due to the introduction of one or more oxygen atoms in different
reactive sites of the molecule, is discussed.
[Back to top]
What Does Systems Biology Mean for Drug Development?
André Schrattenholz and Vukic
Šoškic
The complexity and flexibility of cellular architectures
is increasingly recognized by impressive progress on the side
of molecular analytics, i.e. proteomics, genomics and metabolomics.
One of the messages from systems biology is that the number
of molecular species in cellular networks is orders of magnitude
bigger than anticipated by genomic analysis, in particular
by fast posttranslational modifications of proteins. The requirements
to manage external signals, integrate spatiotemporal signal
transduction inside an organism and at the same time optimizing
networks of biochemical and chemical reactions result in chemically
extremely fine tuned molecular entities. Chemical side reactions
of enzymatic activity, like e.g. random oxidative damage of
proteins by free radicals during aging constantly introduce
epigenetic alterations of protein targets. These events gradually
and on an individual stochastic scale, keep modifying activities
of these targets, and their affinities and selectivities towards
biological and pharmacological ligands.
One further message is that many of the key reactions in living
systems are essentially based on interactions of low affinities
and even low selectivities. This principle is responsible
for the enormous flexibility and redundancy of cellular circuitries.
So, in complex disorders like cancer or neurodegenerative
diseases, which are rooted in relatively subtle and multimodal
dysfunction of important physiologic pathways, drug discovery
programs based on the concept of high affinity/high specificity
compounds (“one-target, one-disease”), which still
dominate the pharmaceutical industry increasingly turn out
to be unsuccessful. Despite improvements in rational drug
design and high throughput screening methods, the number of
novel, single-target drugs fell much behind expectations during
the past decade and the treatment of “complex diseases”
remains a most pressing medical need.
Currently a change of paradigm can be observed with regard
to a new focus on agents that modulate multiple targets simultaneously.
Tar-geting cellular function as a system rather than on the
level of the single protein molecule significantly increases
the size of the drugable proteome and is expected to introduce
novel classes of multi-target drugs with fewer adverse effects
and toxicity. Multiple target approaches have recently been
used to design medications against atherosclerosis, cancer,
depression, psychosis and neurodegenerative diseases.
A focussed approach towards “systemic” drugs will
certainly require the development of novel computational and
mathematical concepts for appropriate modelling of complex
data and extraction of “screenable” information
from biological systems essentially ruled by deterministic
chaotic processes on a background of individual stochasticity.
[Back to top]
Recent Advances in Antiviral Activity of Benzo/Heterothiadiazine
Dioxide Derivatives
Peng Zhan, Xinyong Liu and Erik
De Clercq
Benzo/heterothiadiazine dioxides have been identified
as important fused heterocyclic systems possessing a broad
spectrum of biological activities and potential pharmacological
applications. Recently, a large number of structurally novel
compounds derived from these heterocycle scaffolds were identified
as antiviral agents. Especially, substituted benzo/heterothiadiazine
dioxide derivatives have been shown to inhibit the replication
of HCMV, VZV, HCV and HIV. Of particular interest, some potent
HCV polymerase inhibitors possess a benzothiadiazine dioxide
scaffold, which is critical for the anti-HCV potency through
strong hydrogen bond formation of the SO2NH group with the
active site of the enzyme, as shown by X-ray crystallography.
Also, some compounds belonging to the benzothiadiazine dioxide
class have been found to be potent antiviral agents against
HCMV and VZV. Moreover, some novel heterothiadiazine dioxide
derivatives have been synthesized and evaluated as potential
HIV inhibitors with lower toxicity and/or increased activity
against drug-resistant virus strains. No systematic review
is available in the literature on these thiadiazine derivatives
in the design of potent antiviral inhibitors. In this article,
we review the recent advances in the antiviral profile of
this kind of compounds, as well as the impact of structural
modifications and the structure-activity relationship (SAR).
[Back to top]
Carriership of Factor V Leiden and Evolutionary Selection
Advantage
Pelle G. Lindqvist and Björn Dahlbäck
Historically, lethal exsanguinations and severe infections
have been two major causes of maternal death. Gene mutations
that lower the risk of profuse hemorrhage or severe infections
would give a survival advantage. A single mutation of coagulation
factor V, known as FV Leiden (FVL), can be such a beneficial
mutation. FVL is common among Caucasians and today confers
an increased risk of thromboembolism. However, the high prevalence
of FVL (up to 15%) in the general population suggests that
it has given an evolutionary advantage. In this review, we
discuss possible mechanisms of the evolutionary survival advantage
associated with FVL. In women, FVL confers lower risk of blood
loss and profuse hemorrhage in association with delivery and
improves the hemoglobin status. In addition, FVL carriers
possibly have a survival advantage during sepsis. In conclusion,
the high prevalence of FVL may be the result of one or more
evolutionary selection advantages.
[Back to top]
Resveratrol and Ischemic Preconditioning in the Brain
Ami P. Raval, Hung Wen Lin, Kunjan R. Dave, R.
Anthony DeFazio, David Della Morte, Eun Joo Kim and Miguel
A. Perez-Pinzon
Cardiovascular pathologies in the French are not prevalent
despite high dietary saturated fat consumption. This is commonly
referred to as the “French Paradox” attributing
its anti-lipidemic effects to moderate consumption of red
wine. Resveratrol, a phytoalexin found in red wine, is currently
the focus of intense research both in the cardiovascular system
and the brain. Current research suggests resveratrol may enhance
prognosis of neurological disorders such as, Parkinson’s,
Huntington’s, Alzheimer’s diseases and stroke.
The beneficial effects of resveratrol include: antioxidation,
free radical scavenger, and modulation of neuronal energy
homeostasis and glutamatergic receptors/ion channels. Resveratrol
directly increases sirtuin 1 (SIRT1) activity, a NAD+
(oxidized form of nicotinamide adenine dinucleotide)-dependent
histone deacetylase related to increased lifespan in various
species similar to calorie restriction. We recently demonstrated
that brief resveratrol pretreatment conferred neuroprotection
against cerebral ischemia via SIRT1 activation. This neuroprotective
effect produced by resveratrol was similar to ischemic preconditioning-induced
neuroprotection, which protects against lethal ischemic insults
in the brain and other organ systems. Inhibition of SIRT1
abolished ischemic preconditioning-induced neuroprotection
in CA1 region of the hippocampus. Since resveratrol and ischemic
preconditioning-induced neuroprotection require activation
of SIRT1, this common signaling pathway may provide targeted
therapeutic treatment modalities as it relates to stroke and
other brain pathologies. In this review, we will examine common
signaling pathways, cellular targets of resveratrol, and ischemic
preconditioning-induced neuro-protection as it relates to
the brain.
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