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Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 13, Number 6, 2006
Contents
Cancer Stem Cells and Therapeutic Perspectives Pp.
603-607
E. Galmozzi, F. Facchetti and CAM La Porta
[Abstract]
NO-Releasing Hybrids of Cardiovascular Drugs Pp.
609-625
A. Martelli, S. Rapposelli and V. Calderone
[Abstract]
Pharmacology and Physiopathology of the Brain Endothelin
System: An Overview Pp. 627-638
Sergio Schinelli
[Abstract]
Novel Strategies for the Design of New Potent and Selective
Human A3 Receptor Antagonists: An Update Pp.
639-645
S. Moro, F. Deflorian, M. Bacilieri and G. Spalluto
[Abstract]
Recognition and Activation of Ryanodine Receptors
by Purines Pp. 647-657
Armando Butanda-Ochoa, Germund Höjer, Verónica
Morales-Tlalpan and Mauricio Díaz-Muñoz
[Abstract]
Cyclooxygenase Inhibitory Natural Products: Current
Status Pp. 659-678
Sanjay M. Jachak
[Abstract]
Antimicrobial Peptides with Unusual Amino Acid Compositions
and Unusual Structures Pp. 679-696
N. Sitaram
[Abstract]
New Methods for Medicinal Chemistry – Universal
Gene Cloning and Expression Systems for Production of Marine
Bioactive Metabolites Pp. 697-710
Walter C. Dunlap, Marcel Jaspars, Daslav Hranueli, Christopher
N. Battershill, , Jurica Zucko, Stephen H. Wright and Paul
F. Long
[Abstract]
Medical Applications of Macrocyclic Polyamines
Pp. 711-727
Feng Liang, Shuhui Wan, Zheng Li, Xiaoqin Xiong, Li Yang,Xiang
Zhou and Chengtai Wu
[Abstract]
Erratum
Pp. 729
Abstracts
[Back to top]
Cancer Stem Cells and Therapeutic
Perspectives
E. Galmozzi, F. Facchetti and CAM La Porta
The cancer stem cell hypothesis suggests that neoplastic
clones are maintained exclusively by a rare fraction of cells
with stem cell proprieties. Stem cells are defined as cells
which are able to both extensively self-renew and differentiate
into progenitors. Furthermore, stem cells are also attractive
candidates as origin of cancers, as in their long lifespan
mutations and epigenetic changes they can increase allowing
for increasing evolution toward malignancy.
Herein, we discuss the evidences reported in literature on
existence of cancer stem cells in several tumors and mechanisms
of the extrinsic and intrinsic circuitry controlling stem
cell fate as well as their possible connections to cancer.
In particular, the review will focus on recent results on
conserved Polycomb Group (PcG) gene family, an epigenetic
chromatin modifiers involved in cancer development and also
in the maintenance of embryonic and adult stem cells. There
are two distinct multiprotein PcG complexes identified, Polycomb
repressive complex (PRC) 1 and 2. The fact that either PRC1
Bmi1 than PRC2 SU(Z)12 components are implicated
in self-renewal stem cells and up-regulated in several kind
of human cancer, confirm the importance of (de)regulation
of the PcG genes in cancer and stem cell biology. Moreover,
Bmi1 and SU(Z)12 are downstream target of Sonic hedgehog
(Shh) and Wnt signaling respectively, providing for a connection
between epigenetic change regulators (PcG) and developmental-signaling
pathways.
Finally, potential therapies using inhibitors acting on cancer
stem cell population such as cyclopamine, an inhibitor of
hedgehog signalling, 6-bromoindirubin-3'-oxime (BIO) which
acts on GSK3 and inhibitors of β-catenin
signaling such as exisulind and the tyrosine-kinase inhibitor
STI571/Gleevac/imatinib will also discuss.
[Back to top]
NO-Releasing Hybrids of Cardiovascular Drugs
A. Martelli, S. Rapposelli and V. Calderone
Nitric oxide (NO) is an endogenous compound, which plays
a fundamental role in the modulation of the function of the
cardiovascular system, where it induces vasorelaxing and antiplatelet
responses, mainly through the stimulation of guanylate cyclase
and the increase of cGMP. Many drugs of common, time-honoured
clinical use (for example, glycerol trinitrate and all the
vasodilator nitrites and nitrates) act via the release of
exogenous NO, thus mimicking the effects of the endogenous
factor.
In the last few years, a revision of the “one-compound-one-target”
paradigm has led pharmacologists and pharmaceutical chemists
to develop new classes of molecules which combine different
pharmacodynamic properties. This innovative pharmacological/pharmaceutical
strategy has produced hybrid drugs, with a dual mechanism
of action: a) the slow release of nitric oxide and b) another
fundamental pharmacodynamic profile.
These drugs have been obtained by inserting appropriate NO-donor
chemical groups (i.e. nitrate esters, nitrosothiols, etc.),
linked to a known drug, by means of a variable spacer moiety.
These new pharmacodynamic hybrids present the advantage of
combining a basic mechanism of action (for example, cyclooxygenase
inhibition, beta-antagonism or ACE inhibition) with a slow
release of NO, which may be useful either to reduce adverse
side effects (for example, the gastrotoxicity of NSAIDs),
or to improve the effectiveness of the drug (for example,
conferring direct vasorelaxing and antiplatelet effects on
an ACE-inhibitor).
The aim of this review is to present the chemical features
of NO-releasing hybrids of cardiovascular drugs, and to explain
the pharmacological improvements obtained by the addition
of the NO-donor properties.
[Back to top]
Pharmacology and Physiopathology of the
Brain Endothelin System: An Overview
Sergio Schinelli
The endothelin system, consisting of three peptides, two
peptidases and two G-protein coupled receptors, is widely
expressed in the brain cell types and brain-derived tumor
cell lines. The stimulation of endothelin receptors elicits
a variety of short- and long-term changes at cellular level
but the effects of the pharmacological modulation of the endothelin
system in brain physiology and pathophysiology are, at the
present time, poorly understood. Altered expression of endothelins
(ETs) in reactive astrocytes has been observed in many pathological
conditions of the human brain, such as infarcts, lacunae,
traumatic conditions, Alzheimer's disease and inflammatory
diseases of the brain. In addition, recent studies have shown
that endothelin antagonists might inhibit growth and induce
cell death in human melanoma cells in vitro and in
vivo, and have emphasized a possible role of endothelin
peptides as autocrine or paracrine factor in the proliferation
and dissemination of tumor cell lines. Given the fact that
brain cell and a variety of brain tumor cell lines express
functional endothelin receptors, further studies are warranted
to demonstrate a possible therapeutic role of endothelin agonists
and antagonist in the pharmacological treatment of brain-related
diseases and brain tumors.
[Back to top]
Novel Strategies for the Design of New Potent and
Selective Human A3 Receptor Antagonists: An Update
S. Moro, F. Deflorian, M. Bacilieri and G. Spalluto
A computer-aided approach has been developed in order to
understand the molecular pharmacology of human A3R,
and specifically, to lead to the discovery and structural
refinement of new, potent and selective human A3R
antagonists. This review focuses on our combined target-based
and ligand-based drug design strategy, recently applied to
provide more accurate information about the recognition mode
on human A3R of some pyrazolotriazolopyrimidine
and triazoloquinoxalinone analogs. The 3D rhodopsin-based
homology model of human A3R has represented the
starting point of our approach. A high throughput molecular
docking method on the considered antagonists has allowed us
to generate a receptor-based pharmacophore model. A novel
“Y-shaped” pharmacophore binding motif has been
proposed for both pyrazolotriazolopyrimidine and triazoloquinoxalinone
derivatives. Moreover, related receptor-based 3D-QSAR analysis
has been carried out to provide a suitable tool for prediction
of the antagonists binding affinity on human A3R.
[Back to top]
Recognition and Activation of Ryanodine Receptors
by Purines
Armando Butanda-Ochoa, Germund Höjer, Verónica
Morales-Tlalpan and Mauricio Díaz-Muñoz
Ryanodine receptor (RyR) is a tetrameric, high molecular
weight protein that functions as a calcium release channel.
It plays a key role in phenomena such as signal transduction,
excitation-contraction and excitation-secretion coupling.
Hyperthermia maligna, central core disease and myocardial
infarction have been related with RyR dysfunction. RyR is
present as three isoforms in vertebrates: RyR 1 mainly localized
in skeletal muscle, RyR 2 in cardiac muscle, and RyR 3 in
nervous system. RyR is regulated by a number of physiological
and pharmacological factors. Main physiological modulators:
calcium, kinases and phosphatases, redox state and energy
charge. Main pharmacological regulators: caffeine, dantrolene,
ruthenium red, heavy metals and ryanodine.
Purines have to do with both, physiological and pharmacological
regulation of the RyR activity. So far, the mechanisms of
RyR activation by ATP and caffeine have been described in
detail using [3H]-ryanodine binding assays and
unitary channel activity recorded in planar lipid bilayers.
However, some questions remain to be addressed and are at
present aim of active scrutiny: How many sites for purines
are present in the RyR? Is the same site recognized by nucleotides
and methylxanthines? What differences exist among the interaction
between RyR and purine bases, nucleosides and nucleotides?
Are the phosphate groups important for the recognition of
nucleotides? Is the sugar moiety important for the recognition
of nucleosides? The review article will examine the most recent
specialized literature about the mechanism of activation of
RyR by purines with emphasis on reports with approaches of
structure-function and structure-activation.
[Back to top]
Cyclooxygenase Inhibitory Natural Products: Current
Status
Sanjay M. Jachak
Non-steroidal anti-inflammatory drugs (NSAIDs) are of huge
therapeutic benefit in the treatment of rheumatoid arthritis
and various types of inflammatory conditions. The target for
these drugs is cyclooxygenase (COX), a rate-limiting enzyme
involved in the conversion of arachidonic acid into inflammatory
prostaglandins. COX-2 selective inhibitors are believed to
have the same anti-inflammatory, anti-pyretic and analgesic
activities as that of nonselective inhibitor NSAIDs with little
or none of the gastrointestinal side effects. Thus, in the
last 6-7 years several selective COX-2 inhibitors including
coxibs were discovered and introduced into clinic. Recent
reports evidence that selective COX-2 inhibitor such as rofecoxib,
can lead to thrombotic cardiovascular events through inhibition
of prostacyclin formation in the infracted heart. This has
resulted in withdrawal of rofecoxib from the clinic in September
2004. Moreover, the COX-2/COX-1 selectivity ratio is vital
in the design of COX-2 inhibitory drugs, as it is clear from
rofecoxib, which is more than 50-fold COX-2 selective. After
looking at all above mentioned facts, natural product-based
compounds seem better as these compounds are generally supposed
to be devoid of severe side effects. The literature indicates
that natural product-based compounds are mainly COX-1 selective.
Through minor semi-synthetic changes in the structures, their
selectivity towards COX-2 can be increased. The present review
article addresses natural product COX inhibitors of plant
and marine origin, reported during last ten years and their
advantages, possible leads for further development and current
status. In addition we describe our experience in the characterization,
design and synthesis of potential natural COX inhibitors.
[Back to top]
Antimicrobial Peptides with Unusual Amino Acid Compositions
and Unusual Structures
N. Sitaram
Antimicrobial peptides, which constitute an important component
of innate immunity in animal and plant kingdom, are ubiquitously
distributed in nature. However, they differ widely in their
sizes, sequences and structures. On the basis of their structure
they have been broadly classified into three classes: a) linear
peptides with propensity for amphiphilic α-helical
structure, b) peptides with β
or αβ
structure stabilized by different number of disulfide bridges
and c) peptides with over-representation of certain amino
acids or unusual structures. Although considerable amount
of work has been done on peptides of all the three classes,
recent reviews have emphasized on peptides belonging to the
first two classes. The present review focuses on the peptides
belonging to the third group. The antimicrobial peptides discussed
in this article include aromatic amino acid-rich peptides,
(Pro-Arg)-rich peptides, unusual defensins and defensin-like
molecules, unusual antimicrobial peptides from amphibians,
bacteriocins with unusual structure and anionic antimicrobial
peptides.
[Back to top]
New Methods for Medicinal Chemistry – Universal
Gene Cloning and Expression Systems for Production of Marine
Bioactive Metabolites
Walter C. Dunlap, Marcel Jaspars, Daslav Hranueli, Christopher
N. Battershill, , Jurica Zucko, Stephen H. Wright and Paul
F. Long
Natural products from symbiotic or commensal associations
between marine invertebrate and microbial organisms show exceptional
promise as pharmaceuticals in many therapeutic areas. An economic
and sustainable global market supply due to difficulty of
synthesis is cited as the main obstacle for exploitation of
these otherwise exciting marine bioactive compounds [1]. Different
strategies have been evoked to overcome this impediment as
long-term harvesting of wild stocks from the environment is
considered unsound, and other modes of production based on
biosynthesis, such as aquaculture, have not yet been proven
as reliable [2]. One option is to clone the genes encoding
the biosynthetic expression of a lead metabolite into a surrogate
host suitable for industrial-scale fermentation. To facilitate
this goal we are developing a universal system to clone and
express genes responsible for biosynthesis of natural products
from both eukaryotic and prokaryotic partners of marine symbioses.
The ability to harness the complete meta-transcriptome of
entire biosynthetic pathways is particularly valuable where
the biogenesis of a target natural product occurring within
a complex symbiotic association is unclear.
[Back to top]
Medical Applications of Macrocyclic Polyamines
Feng Liang, Shuhui Wan, Zheng Li, Xiaoqin Xiong, Li Yang,Xiang
Zhou and Chengtai Wu
Macrocyclic polyamines comprise a special group of heterocycles
that bind different guests. Over the past decade, medical
interest has focused on macrocyclic polyamines owning to their
chemical and biological properties. The discovery and development
of the bicyclam AMD3100 highlighted the clinical potential
of such compounds in AIDS, cancer and stem-cell mobilization.
Many macrocyclic polyamines and their transition metal complexes
had the cytotoxic activities to tumors through binding DNA,
cleaving DNA, crosslinking DNA, or depleting the endogenous
ATP levels of the tumor cells. Furthermore, macrocyclic polyamines
also could be labeled with metal ionic radii and have applications
in cancer radioimmunotherapy and in vivo magnetic
resonance imaging (MRI). The current rational design, and
medical applications of macrocyclic polyamines will be reviewed
in this manuscript.
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