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Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 14, Number 2, 2007
Contents
Towards Better Brain Management: Nootropics Pp. 123-131
Ruchi Malik, Abhijeet Sangwan, Ruchika Saihgal, Dharam Paul
Jindal and Poonam Piplani
[Abstract]
ATP-Sensitive Potassium Channel Openers and 2,3-Dimethyl-2-Butylamine
Derivatives Pp. 133-155
Hai Wang, Yuan Tang, Lin Wang, Chao-Liang Long and Ying-Li
Zhang
[Abstract]
Left Ventricular Hypertrophy: A Shift in Paradigm
Pp. 157-171
M.F.L. Meijs, L.J. de Windt, N. de Jonge, M.-J. M. Cramer,
M.L. Bots, W.P.Th.M. Mali and P.A. Doevendans
[Abstract]
Differentiation of Bone Marrow Stroma-Derived Mesenchymal
Cells Pp. 173-179
D. Benayahu, U.D. Akavia and I. Shur
[Abstract]
Role of Endogenous Inhibitors of Cytokine Signaling
in Allergic Asthma Pp. 181-189
Hiromasa Inoue, Satoru Fukuyama, Koichiro Matsumoto, Masato
Kubo, and Akihiko Yoshimura
[Abstract]
miRNAs in the Biology of Cancers and Viral Infections
Pp. 191-197
Man Lung Yeung, Yamina Bennasser and Kuan-Teh Jeang
[Abstract]
Medicinal Chemistry of Fetal Hemoglobin Inducers for
Treatment β-Thalassemia
Pp. 199-212
Roberto Gambari and Eitan Fibach
[Abstract]
Thiol Proteins, Redox Modulation and Parenchymal Lung
Disease Pp. 213-222
V.L. Kinnula, K.Vuorinen, H. Ilumets, P. Rytilä and
M. Myllärniemi
[Abstract]
Possible Effects of Early Treatments of Hsp90 Inhibitors
on Preventing the Evolution of Drug Resistance to Other Anti-Cancer
Drugs Pp. 223-232
Li Xiao, Parsa Rasouli and Douglas M. Ruden
[Abstract]
Virostatics: A New Class of Anti-Hiv Drugs
Pp. 233-241
F. Lori, A. Foli, L.M. Kelly and J. Lisziewicz
[Abstract]
Endothelial Dysfunction, Oxidative Stress and Inflammation
in Atherosclerosis: Beneficial Effects of Statins
Pp. 243-248
Vicente Lahera, Marian Goicoechea, Soledad García
de Vinuesa, María Miana, Natalia de las Heras, Victoria
Cachofeiro and José Luño
[Abstract]
Abstracts
[Back to top]
Towards Better Brain Management: Nootropics
Ruchi Malik, Abhijeet Sangwan, Ruchika Saihgal, Dharam Paul
Jindal and Poonam Piplani
The learning and memory deficits have been
recognized as severe and consistent neurological disorders
associated with numerous neurodegenerative states. Research
in this area has gained momentum only in the recent past after
the biochemical and physiological basis of these processes
have been understood. A considerable alteration in the neurotransmission
is a consistent finding in cognitive disorders. Therefore,
many therapeutic strategies to augment the concentration of
neurotransmitters in brain such as cholinergic agents, biogenic
amines and neuropeptides etc. have been evaluated in cognitive
deficits. CNS modulators are the type of antiamnesics that
act via modulation of the neurological processes underlying
memory storage. These include psychostimulants, excitatory
amino acids and most important of all “nootropics”.
Nootropics are a heterogeneous group of compounds of diverse
chemical composition and biological function that allegedly
facilitate learning and memory or overcome natural or induced
cognitive impairments. The literature survey incorporated
in this article hallmarks the success achieved in the design
and development of potential nootropic agents. Additionally,
this review is an attempt towards discussing various approaches
available to enhance memory, along with the classification
of the known memory enhancers, authors research work towards
various structural modifications carried out and the biological
screening.
[Back to top]
ATP-Sensitive Potassium Channel Openers
and 2,3-Dimethyl-2-Butylamine Derivatives
Hai Wang, Yuan Tang, Lin Wang, Chao-Liang Long and Ying-Li
Zhang
ATP-sensitive potassium (KATP) channels
have important functions through their coupling of cellular
energetic networks and their ability to decode metabolic signals,
and they are implicated in diseases of many organs. KATP
channels are formed by the physical association between the
inwardly rectifier potassium channels (Kir6.x) and the regulatory
sulfonylurea receptor subunit (SUR), which form a hetero-octameric
complex. Different subtypes of KATP channels exist
in various tissues. KATP channel openers (KCOs)
are classified into nine chemical families according to their
molecular structures: (1) benzopyrans, (2) cyanoguanidines,
(3) thioformamides, (4) pyrimidine derivatives, (5) pyridine
derivatives, (6) benzothiadiazines, (7) dihydropyridines,
(8) nicotinamide derivatives, and (9) aliphatic amines. Although
the model also predicts that KCOs have four co-binding areas,
it was hypothesized that the main contribution lies in the
binding domain of hydrophobicity of the side chain. A series
of compounds containing the skeleton of the aliphatic secondary
amines as a side chain was designed. It was found that N-isopropyl
2,3-dimethyl-2-butylamine (iptakalim, 91)
is a novel KCOs. Iptakalim regulates the pore selectively
of the inwardly rectifier potassium channel and dilates smaller
arteries, but has little effect on vasodilatation of the aorta.
Iptakalim administered p.o. has selective and long-lasting
antihypertensive effects in hypertensive animals and does
not induce tolerance, but has little effect on blood pressure
in normotensive animals. Meanwhile, it also reverses cardiovascular
remodeling and protects the brain and kidney against damage
caused by hypertension in animal models. Iptakalim is in phase
II clinical trials now and has a promising future as a treatment
for hypertension.
[Back to top]
Left Ventricular Hypertrophy: A Shift in
Paradigm
M.F.L. Meijs, L.J. de Windt, N. de Jonge, M.-J. M. Cramer,
M.L. Bots, W.P.Th.M. Mali and P.A. Doevendans
Observational studies have identified left ventricular
hypertrophy (LVH) as a strong, independent risk factor for
the development of heart failure (HF), coronary heart disease
and stroke. LVH develops in response to hemodynamic overload.
Classical conceptualization has it that LVH would start as
an adaptive, beneficial response in order to normalize wall
stress. With progression of the disease, deterioration to
maladaptive hypertrophy, and further on to HF could occur.
Recent experiments in animal models of pressure-overload and
myocardial infarction now challenge this concept by demonstrating
that blunting the hypertrophic response is actually associated
with preserved cardiac function, and with improved survival.
These findings may have profound therapeutical implications.
[Back to top]
Differentiation of Bone Marrow Stroma-Derived
Mesenchymal Cells
D. Benayahu, U.D. Akavia and I. Shur
Stem cell biology is a promising, fast-growing field
that aims to develop cell-based tools for the treatment of
a wide range of diseases. Special attention is paid to bone
marrow cells that play a role in the musculoskeletal system.
Bone marrow contains hematopoietic stem cells (HSCs) and stromal
cells that form the reticular network that supports HSCs formation.
Stromal cells also contain mesenchymal stem cells (MSCs) that
differentiate to various lineages.
The major obstacles in utilizing stem cells are identifying
these cells and following the signaling pathways that control
the cells’ fate. The interactions of stem cells with
an extracellular matrix and other cells create a tissue-specific
niche that is responsible for regulating cell differentiation.
It is important to identify biomarkers that will enable the
isolation, selection and expansion of stem cells in vitro
to allow their use for cell therapy. The study of stem cells’
differentiation is based on various techniques, including
the generation of antibodies to specific cellular sub-populations
and high throughput analysis at transcriptome and proteome
levels. Advances in transcriptome and proteome profiling will
establish the molecular signature and will allow the discovery
of the cell type specific differentiation programming. Such
analysis identified several proteins related to chromatin
remodeling factors, cell adhesion molecules and extracellular
matrix ligands that localize cells at the specific niche.
Detailed interpretation of the transcriptional and translational
expression patterns will provide understanding of key properties
of MSCs and allow their future use in regenerative medicine.
[Back to top]
Role of Endogenous Inhibitors of Cytokine
Signaling in Allergic Asthma
Hiromasa Inoue, Satoru Fukuyama, Koichiro Matsumoto, Masato
Kubo, and Akihiko Yoshimura
T helper 2 cytokines, including interleukin
(IL)-4, IL-5, and IL-13, play an important role in allergic
immune disorders, such as bronchial asthma. These cytokines
regulate diverse biological functions by binding to receptors
at the cell surface to activate complex signal transduction
pathways, including the Janus kinase-signal transducer and
activator of transcription (JAK-STAT) and the Ras-extracellular
signal-regulated kinase (ERK) signaling pathways. The suppressor
of cytokine signaling (SOCS) family proteins has been shown
to regulate the JAK-STAT pathway, and the Sprouty-related
EVH1-domain-containing protein (SPRED) family proteins regulate
the Ras-ERK pathway. SOCS3 and SOCS5 are predominantly expressed
in Th2 and Th1 cells, respectively, and they reciprocally
inhibit the Th1 and Th2 differentiation processes. SOCS3 also
has a role in Th3 differentiation. SPRED-1 is expressed in
hematopoietic cells, including eosinophils, and negatively
controls the eosinophil numbers and functions by modulating
IL-5 signaling. Here, we discuss the role of SOCS and SPRED
proteins in allergic asthma and explore the potential of these
proteins as targets for therapeutic strategies in allergic
asthma.
[Back to top]
miRNAs in the Biology of Cancers
and Viral Infections
Man Lung Yeung, Yamina Bennasser and Kuan-Teh Jeang
MicroRNAs (miRNAs) are non-coding small RNAs that
play important roles in a variety of biological pathways including
cellular proliferation and apoptosis. Recent studies have
linked the expression of selected miRNAs to carcinogenesis
and viral pathogenesis. Here, we will discuss examples of
roles served by cellular miRNAs and virus-encoded miRNAs in
the development of cancers and viral diseases.
[Back to top]
Medicinal Chemistry of Fetal Hemoglobin
Inducers for Treatment β-Thalassemia
Roberto Gambari and Eitan Fibach
In this review we summarize the achievements of
medicinal chemistry in the field of pharmacological approaches
to the therapy of β-thalassemia
using molecules able to stimulate the production of fetal
hemoglobin (HbF). We first describe the molecular basis of
the pathology and the biochemical rational of using HbF inducers
for therapy; we then outlined the in vitro and in
vivo experimental systems suitable for screening of such
potential drugs, and finally we describe the different classes
of compounds with emphasis on their advantages and disadvantages
in the treatment. The results of these reviewed studies indicate
that: (a) HbF inducers can be grouped in several classes based
on their chemical structure and mechanism of action; (b) clinical
trials with some of these inducers demonstrate that they are
effective in ameliorating the symptoms of β-thalassemia;
(c) a good correlation was found between HbF stimulation in
vivo and in vitro indicating that in vitro
testing might be predictive of the in vivo response;
(d) combined use of different inducers might maximize the
effect, both in vitro and in vivo. However,
(e) the response to HbF inducers, evaluated in vitro
and in vivo, is variable, and some patients might
be refractory to HbF induction by certain inducers; in addition,
(f) several considerations call for caution, including the
fact that most of the inducers exhibit in vitro cytotoxicity,
predicting side effects in vivo following prolonged
treatments.
[Back to top]
Thiol Proteins, Redox Modulation and Parenchymal
Lung Disease
V.L. Kinnula, K.Vuorinen, H. Ilumets, P. Rytilä and
M. Myllärniemi
The lung is a unique organ in terms of its direct
exposure to high levels of oxygen and reactive compounds.
Several parenchymal lung diseases (e.g. emphysema associated
with smoking and a number of fibrotic lung disorders) have
been proposed to be due to the exposure of the lung to exogenous
irritants leading to local redox imbalance in the alveolar
epithelium. The disease progression of emphysema/chronic obstructive
pulmonary disease (COPD) and fibrosis share several common
factors, such as the role of reactive oxygen species, disturbances
of the pulmonary thiol status and activation of growth factors
and tissue destructing proteases. Importantly in COPD or fibrosis,
medication does not provide any significant therapeutic effect.
This review concentrates on the key thiol (-SH)-regulated
mechanisms leading to the development of COPD and/or pulmonary
fibrosis and the major redox-regulated defense/oxidant repair
mechanisms, thioredoxin/peroxiredoxin and glutaredoxin protein
families in the lung. Redox-regulated proteins, both proteases
and oxidant repair enzymes, undergo conformational changes
during oxidative stress, a process that modulates their activation
or inactivation. In addition, some of the redox-regulated
proteins influence the metabolism of glutathione (GSH), a
major small molecular antioxidant of human lung, and participate
in the crosstalk between numbers of GSH associated enzymes
functioning in the detoxification pathways of human lung.
An understanding of the processes involved in oxidant-mediated
lung damage may provide the key to devising interventional
strategies that can actually prevent the progression of lung
parenchymal disease.
[Back to top]
Possible Effects of Early Treatments of
Hsp90 Inhibitors on Preventing the Evolution of Drug Resistance
to Other Anti-Cancer Drugs
Li Xiao, Parsa Rasouli and Douglas M. Ruden
Hsp90 is a chaperone that is critically important
for both cancer progression and tumor survival. Hsp90 is an
exciting target for anti-cancer drugs because most of the
proteins that interact with Hsp90 are known to be in the cell
cycle, signaling and chromatin-remodeling pathways. Recent
work in fungi has shown that reduction of Hsp90 activity dramatically
increases the efficacy of many fungicides. Furthermore, in
studies on the evolution of drug resistance in fungi, it has
been shown that high levels of Hsp90 increase the rate of
the development of fungicide resistance, whereby low levels
of Hsp90 decrease the rate of fungicide resistance. Similarly,
in humans and mammalian models, Hsp90 inhibitors have been
shown to act additively or synergistically with many other
cancer therapies for killing both solid tumors and leukemias.
Also, several recent studies have shown that Hsp90 inhibitors
potentiate the activity of drugs in cancer cells lines that
are otherwise resistant to the drug. However, during the evolution
of drug resistance in cancer cells, it has not yet been determined
whether early exposure to Hsp90 inhibitors slows the rate
of developing resistance to other anti-cancer drugs, as would
be expected from the fungal studies. In this review, we summarize
the effects of the Hsp90 inhibitors geldanamycin and its derivatives
with other anti-cancer drugs on killing cancer cells. We also
discuss other basic science and clinical studies that need
to be done to determine the optimum exposure regimens for
Hsp90 inhibitor treatments to maximize its cancer-killing
activities, and to minimize the evolution of resistance to
other anti-cancer drugs.
[Back to top]
Virostatics: A New Class of Anti-Hiv Drugs
F. Lori, A. Foli, L.M. Kelly and J. Lisziewicz
In this review we discuss the features of a new
class of antiretroviral combinations, namely “Virostatics”.
Virostatics are characterized by the combination of a drug
directly inhibiting virus production (viro), and
another drug indirectly inhibiting the virus by reducing cellular
proliferation (static). In particular, we will focus
on the combination of hydroxyurea and didanosine against HIV-1.
Hydroxyurea and didanosine synergize to control viral replication
and present with a favorable resistance profile, suppressing
several resistant quasi-species. Because virostatics target
essential cellular proteins, they exert an immune modulating
activity and reduce viral targets (CD4 T cells), possibly
with limited immunosuppressive effects. Importantly, a dose-finding
clinical study has shown that decreasing the dose of hydroxyurea
not only diminishes toxicity but also increases antiviral
potency. Therefore, the combination of hydroxyurea and didanosine
strikes a balance between viral suppression, drug-related
toxicity and viral escape, and could have a role both in induction
and maintenance therapy. In this review we would like to appraise
what is known about hydroxyurea and didanosine and specifically
address the major advantages, i.e. novel mechanism of action
leading to a new class of drugs and resistance profile providing
durability, as well as the major criticisms of this combination,
i.e. toxicity and reasons for prescribing a perceived immune
suppressant to immune compromised patients.
[Back to top]
Endothelial Dysfunction, Oxidative Stress
and Inflammation in Atherosclerosis: Beneficial Effects of
Statins
Vicente Lahera, Marian Goicoechea, Soledad García
de Vinuesa, María Miana, Natalia de las Heras, Victoria
Cachofeiro and José Luño
Atherosclerosis and its complications represent
the major cause of death in developed countries. Statins are
inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A [HMGCoA]
reductase and consequently inhibitors of cholesterol biosynthesis.
Statins have been described as the most potent class of drugs
to reduce serum cholesterol levels. In clinical trials, statins
are beneficial in primary and secondary prevention of coronary
heart disease. Statins, were initially designed as cholesterol-lowering
drugs. However, these drugs, besides their lipid-lowering
properties, exert a number of protective effects on the cardiovascular
system that emerged over the past years. The benefits observed
with statin treatment appear to be greater than that might
be expected from reduction in lipid levels alone, suggesting
effects beyond cholesterol lowering. These cholesterol-independent
effects have been called "pleiotropic”. The cholesterol-independent
or "pleiotropic" effects of statins involve improvement
of endothelial function, stability of atherosclerotic plaques,
decrease of oxidative stress and inflammation, and inhibition
of thrombogenic response. These pleiotropic effects of statins
have been proposed as key properties of these drugs to reduce
cardiovascular morbidity and mortality. The present review
will emphasize the molecular mechanisms underlying the effects
of statins on endothelial function and oxidative stress. In
particular, inhibition of small GTP-binding proteins, Rho,
Ras and Rac, which are regulated by isoprenoids [farnesyl
pyrophosphate and geranylgeranyl pyrophosphate], seems to
play an important role in mediating the pleiotropic effects
of statins.
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