| Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 17, Number 21, 2010
Contents
Blockade of Furin Activity and Furin-Induced
Tumor Cells Malignant Phenotypes By The Chemically Synthesized
Human Furin Prodomain Pp.
2214-2221
A. Basak, A. Chen, N. Scamuffa, D. Mohottalage, S. Basak
and A.-M. Khatib
[Abstract] [Supplementary
Material] [Purchase
Article] [PMID:
20459383 PubMed - indexed for MEDLINE]
New Insights on the Antitumoral Properties of Prodiginines
Pp. 2222-2231
R. Pérez-Tomás and M. Viñas
[Abstract] [Purchase
Article] [PMID:
20459382 PubMed - indexed for MEDLINE]
RAGE: A Multi-Ligand Receptor Unveiling Novel Insights in
Health and Disease Pp.
2232-2252
P. Alexiou, M. Chatzopoulou, K. Pegklidou and
V.J. Demopoulos
[Abstract]
[Purchase
Article] [PMID:
20459381 PubMed - indexed for MEDLINE]
Molecular and Biochemical Features of the Mitochondrial Enzyme
Ornithine Transcarbamylase: A Possible New
Role as a Signaling Factor Pp. 2253-2260
Mauricio Díaz-Muñoz and Rolando
Hernández-Muñoz
[Abstract]
[Purchase
Article] [PMID:
20459380 PubMed - indexed for MEDLINE]
Pharmacological Strategies to Contend Against Myocardial
Reperfusion Damage: Diverse Chemicals for Multiple
Targets Pp. 2161-2273
F. Correa, E. Martínez-Abundis, S. Hernández-Reséndiz,
N. García, M. Buelna-Chontal, F. Arreguín
and C. Zazueta
[Abstract]
[Purchase
Article] [PMID:
20459379 PubMed - indexed for MEDLINE]
Mesenchymal Stem Cells in Cartilage Repair: State
of the Art and Methods
to monitor Cell Growth, Differentiation and Cartilage Regeneration
Pp. 2274-2291
J. Galle, A. Bader, P. Hepp, W. Grill, B. Fuchs,
J.A. Käs, A. Krinner, B. Marquaß, K.
Müller, J. Schiller, R.M. Schulz, M. von Buttlar, E.
von der Burg, M. Zscharnack and M. Löffler
[Abstract]
[Purchase
Article] [PMID:
20459378 PubMed - indexed for MEDLINE]
Editor’s
Choice
Synthetic Membrane-Targeted Antibiotics Pp. 2292-2300
S.K. Vooturi and S.M. Firestine
[Abstract]
[Purchase
Article] [PMID:
20459377 PubMed - indexed for MEDLINE]
Synthesis and Structure-Activity Relationships of
Skin Ceramides Pp. 2301-2324
J. Novotný, A. Hrabálek and K.
Vávrová
[Abstract]
[Purchase
Article] [PMID:
20459376 PubMed - indexed for MEDLINE]
Abstracts
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[Purchase
Article] [PMID:
20459383 PubMed - indexed for MEDLINE]
Blockade of Furin Activity and Furin-Induced Tumor
Cells Malignant Phenotypes By The Chemically Synthesized Human
Furin Prodomain
A. Basak, A. Chen, N. Scamuffa, D. Mohottalage, S. Basak
and A.-M. Khatib
[Supplementary
Material]
Processing of cancer-associated precursor proteins such as
growth factors by the Proprotein Convertase furin is an important
cellular process for acquisition of malignant phenotype and
metastatic potential of tumor cells. Furin is inhibited by
its own prodomain protein which also plays role in the folding
of mature furin. Herein, the complete 83-mer furin prodomain
protein was chemically synthesized for the first time by solid
phase peptide chemistry and its effects on furin activity
and tumor cells malignant phenotypes were evaluated. It inhibited
furin activity in a competitive manner with low nanomolar
inhibition constant (Ki).
Expression of furin prodomain cDNA in tumor cells or cells
incubated with the corresponding protein blocked furin-cleavage
of proPDGF-A. This was associated with significant reduction
in tumor cells proliferation, migration as well as invasion.
Interestingly shorter synthetic furin prodomain peptides derived
from either its primary or secondary activation site alone
weakly inhibited furin and displayed limited effects on tumor
cells. This suggests that the combined presence of the above
two prodomain segments is crucial for prodomain’s potent
furin-inhibitory and hence anticancer activities.
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[Purchase Article] [PMID:
20459382 PubMed - indexed for MEDLINE]
New Insights on the Antitumoral Properties of Prodiginines
R. Pérez-Tomás and M. Viñas
Apoptosis is involved in the action of several (and perhaps
all) cancer-chemotherapeutic agents. Prodiginines are a family
of natural red pigmented secondary metabolites, produced by
different bacteria and most of them are characterized by a
common pyrrolylpyrromethene skeleton. The biosynthesis of
prodigiosin and derivatives has been extensively studied in
Serratia marcescens. S. marcescens is a Gramnegative bacterium
belonging to Enterobacteriaceae. Prodiginines show numerous
biological activities pointing out immunosuppressive and anticancer
properties. Some prodiginines displayed apoptotic effects
in vitro and antitumor activity in vivo.
Their cytotoxic effect is attributed to the presence of the
C-6 methoxy substituent. The A-pyrrole ring plays a key role
in both the copper nuclease activity and the cytotoxicity
of prodiginines. Here we review the main characteristics of
prodigiosin and their derivatives as well as the most prominent
pharmacological activity of prodiginines and related compounds,
including novel synthetic PG-derivatives with lower toxicity
like GX15-070 (Obatoclax). The molecular targets of prodiginines
are discussed and the mechanism of action for these molecules
is a current topic in biomedicine with a real therapeutica
potential in the clinic.
[Back to top] [Purchase
Article] [PMID:
20459381 PubMed - indexed for MEDLINE]
RAGE: A Multi-Ligand Receptor Unveiling Novel Insights in
Health and Disease
P. Alexiou, M. Chatzopoulou, K. Pegklidou and
V.J. Demopoulos
Receptor for advanced glycation end products (RAGE) is expressed
in a range of cell types such as endothelial cells, smooth
muscle cells, mesangial cells, mononuclear phagocytes and
certain neurons. It is a multi-ligand receptor and a member
of the immunoglobulin superfamily of cell surface molecules.
Its repertoire of ligands includes advanced glycation end
products (AGEs), amyloid fibrils, amphoterin and S100/calgranulins.
This variety of ligands allows RAGE to be implicated in a
wide spectrum of pathological conditions such as diabetes
and its complications, Alzheimer’s disease, cancer and
inflammation. Additionally, genetic polymorphisms in the RAGE
gene may have impact on the functional activity of the receptor.
It becomes obvious that RAGE pathway is a complicated one
and the question of whether blockade of RAGE is a feasible
and safe strategy for the prevention/treatment of chronic
diseases is gradually gaining the attention of the pharmaceutical
community.
In this review the biology of RAGE and the triggered signaling
cascades involved in health and disease will be presented.
Additionally, its potential as an attractive pharmacotherapeutic
target will be explored by pointing out the pharmacotherapeutic
agents that have been developed for RAGE blockade.
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[Purchase
Article] [PMID:
20459380 PubMed - indexed for MEDLINE]
Molecular and Biochemical Features of the Mitochondrial
Enzyme Ornithine Transcarbamylase: A Possible New Role as
a Signaling Factor
Mauricio Díaz-Muñoz and
Rolando Hernández-Muñoz
Ornithine transcarbamylase (OTC; EC 2.1.3.3) is a one-carbon-unit
transferring enzyme that synthesizes citrulline using ornithine
and carbamoylphosphate as substrates. It is involved in the
metabolic transformation of arginine and proline, and it participates
in the urea cycle in vertebrates and in the formation of putrescine
in plants. Its enzymatic reaction is consistent with a ping-pong
mechanism. OTC is expressed in a large variety of organisms
from bacteria to mammals. Its gene can be regulated by glucocorticoids
and other transcriptional factors such as C/EBP and HNF-4.
The functional enzyme exists mostly as a trimer with an approximate
molecular weight of 38 kDa. Inborn errors associated with
a deficiency of OTC activity cause mainly urea cycle-related
disorders, and lead to hyperammonemic states that may become
lethal.
In humans and experimental animals, OTC is localized in the
mitochondrial matrix, mainly in the liver, but it is also
in the intestinal epithelial cells. Some states of hepatotoxicity
are associated with hepatocyte disruption and release of OTC
into the bloodstream. However, recent evidence suggests that
during active cell proliferation (e.g., during liver regeneration),
OTC is also released from the hepatic tissue but without apparent
damage. In this situation, extracellular and circulating hepatic
OTC could be playing a different role, possibly functioning
as a signaling molecule.
[Back to top] [Purchase
Article] [PMID:
20459379 PubMed - indexed for MEDLINE]
Pharmacological Strategies to Contend Against Myocardial
Reperfusion Damage: Diverse Chemicals for Multiple
Targets
F. Correa, E. Martínez-Abundis, S. Hernández-Reséndiz,
N. García, M. Buelna-Chontal, F. Arreguín
and C. Zazueta
Acute
myocardial infarction is a frequent and disabling disease.
Paradoxically, reperfusion, the most effective treatment to
reduce infarct size, can both protect and kill. Although reperfusion
protects by preventing lesions occurring during prolonged
ischemia, it causes damage because reflow is associated with
an unbalance between oxygen availability and metabolic demand,
altered ionic homeostasis, and reactive oxygen species (ROS)
generation. Recently, more players in myocardial reperfusion
injury have been described: protein kinase C (PKC) and members
of the MAP kinase, which activate downstream cascades that
may activate intricate processes compromising cardiac recovery
after ischemia. All together, such mechanisms promote endothelial
and vascular dysfunction, sequels of impaired blood flow,
metabolic and contractile dysfunction, dysrhythmia, cellular
necrosis and apoptosis. Different pharmacological agents,
as well as mechanical strategies, have been used to challenge
the outcome of the complex interactions among these mechanisms
and with others. In this review, we focused on the potential
of different compounds used in animal models and in the clinical
practice to improve the prognosis after post-ischemic reperfusion.
We also review mechanisms activated during reperfusion injury
and the structure-activity relationship between some of the
cardioprotective chemicals and their cellular targets.
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[Purchase
Article] [PMID:
20459378 PubMed - indexed for MEDLINE]
Mesenchymal Stem Cells in Cartilage Repair: State
of the Art and Methods to monitor Cell Growth, Differentiation
and Cartilage Regeneration
J. Galle, A. Bader, P. Hepp, W. Grill, B. Fuchs, J.A. Käs,
A. Krinner, B. Marquaß, K. Müller, J. Schiller,
R.M. Schulz, M. von Buttlar, E. von der Burg, M. Zscharnack
and M. Löffler
Degenerative joint diseases caused by rheumatism, joint dysplasia
or traumata are particularly widespread in countries with
high life expectation. Although there is no absolutely convincing
cure available so far, hyaline cartilage and bone defects
resulting from joint destruction can be treated today by appropriate
transplantations. Recently, procedures were developed based
on autologous chondrocytes from intact joint areas. The chondrocytes
are expanded in cell culture and subsequently transplanted
into the defect areas of the affected joints. However, these
autologous chondrocytes are characterized by low expansion
capacity and the synthesis of extracellular matrix of poor
functionality and quality. An alternative approach is the
use of adult mesenchymal stem cells (MSCs). These cells effectively
expand in 2D culture and have the potential to differentiate
into various cell types, including chondrocytes. Furthermore,
they have the ability to synthesize extracellular matrix with
properties mimicking closely the healthy hyaline joint cartilage.
Beside a more general survey of the architecture of hyaline
cartilage, its composition and the pathological processes
of joint diseases, we will describe here which advances were
achieved recently regarding the development of closed, aseptic
bioreactors for the production of autologous grafts for cartilage
regeneration based on MSCs. Additionally, a novel mathematical
model will be presented that supports the understanding of
the growth and differentiation of MSCs. It will be particularly
emphasized that such models are helpful to explain the well-known
fact that MSCs exhibit improved growth properties under reduced
oxygen pressure and limited supply with nutrients.
Finally, it will be comprehensively shown how different analytical
methods can be used to characterize MSCs on different levels.
Besides discussing methods for non-invasive monitoring and
tracking of the cells and the determination of their elastic
properties, mass spectrometric methods to evaluate the lipid
compositions of cells will be highlighted.
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[Purchase
Article] [PMID:
20459377 PubMed - indexed for MEDLINE]
Synthetic Membrane-Targeted Antibiotics
S.K. Vooturi and S.M. Firestine
Antimicrobial resistance continues to evolve and
presents serious challenges in the therapy of both nosocomial
and community-acquired infections. The rise of resistant strains
like methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant
Staphylococcus aureus (VRSA) and vancomycin-resistant enterococci
(VRE) suggests that antimicrobial resistance is an inevitable
evolutionary response to antimicrobial use. This highlights
the tremendous need for antibiotics against new bacterial
targets. Agents that target the integrity of bacterial membrane
are relatively novel in the clinical armamentarium. Daptomycin,
a lipopeptide is a classical example of membrane-bound antibiotic.
Nature has also utilized this tactic. Antimicrobial peptides
(AMPs), which are found in all kingdoms, function primarily
by permeabilizing the bacterial membrane. AMPs have several
advantages over existing antibiotics including a broad spectrum
of activity, rapid bactericidal activity, no cross-resistance
with the existing antibiotics and a low probability for developing
resistance. Currently, a small number of peptides have been
developed for clinical use but therapeutic applications are
limited because of poor bioavailability and high manufacturing
cost. However, their broad specificity, potent activity and
lower probability for resistance have spurred the search for
synthetic mimetics of antimicrobial peptides as membrane-active
antibiotics. In this review, we will discuss the different
classes of synthetic membrane-bound antibiotics published
since 2004.
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[Purchase
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20459376 PubMed - indexed for MEDLINE]
Synthesis and Structure-Activity Relationships of
Skin Ceramides
J. Novotný, A. Hrabálek and K.
Vávrová
Ceramides are a complex group of lipids that has gained much
attention as cell signaling molecules and skin barrier constituents.
In the skin, these sphingolipids form a major part of the
stratum corneum intercellular lipid matrix, which is the barrier
for penetration of most compounds. The development of such
a protective layer was a critical step in the evolution of
life on a dry land. Moreover, prominent skin diseases such
as psoriasis and atopic dermatitis are associated with diminished
ceramide levels and may be effectively improved by exogenous
ceramides or their analogues. Since ceramides are not obtained
from natural sources in pure form, they are of synthetic interest
since 1950's. In this review, we describe sphingosine syntheses
from 1998 until 2008, and the synthetic approaches to the
unique epidermal ceramides, including the 6-hydroxysphingosine-based
ones, the alpha- and omega-hydroxy forms and the omega-acyloxy
species. Moreover, the structural requirements of ceramides
for a competent skin barrier are discussed, including acyl
chain length, trans double bond, acyl alpha-hydroxyl,
stereochemistry, omega-linoleyloxy species and ceramide conformation.
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