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Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 15, Number 10, 2008
Contents
Oxidatively Damaged DNA Repair Defect in Cockayne
Syndrome and its Complementation by Heterologous Repair Proteins
Pp. 940-953
Guido Frosina
[Abstract]
Current Developments in the Synthesis and Biological
Activity of Aza-C-Nucleosides: Immucillins and Related Compounds
Pp. 954-967
Pedro Merino, Tomas Tejero and Ignacio Delso
[Abstract]
Granulocyte Colony-Stimulating Factor
(G-CSF) for Cardio- and Cerebrovascular Regenerative Applications
Pp. 968-977
Rainer Klocke, Michael T. Kuhlmann, Sergiu Scobioala,
Wolf-Rüdiger Schäbitz and Sigrid Nikol
[Abstract]
ANTI-ADHESION Evolves To a Promising Therapeutic
Concept in Oncology Pp. 978-990
R. Schmidmaier and P. Baumann
[Abstract]
Anti-Infective and Anti-Tumor Agents Based on
the Depletion of Immune Suppressive Effects Pp. 991-996
Naohiro Seo, Hiromichi Yamashiro and Toshimasa Tadaki
[Abstract]
Arbidol: A Broad-Spectrum Antiviral Compound
that Blocks Viral Fusion Pp. 997-1005
Y.S. Boriskin, I. A. Leneva, E.-I. Pécheur and
S. J. Polyak
[Abstract]
Non-Steroidal Targets in the Diagnosis and Treatment
of Endometriosis 1006-1017
C.M. Kyama, A. Mihalyi, P. Simsa, J.M. Mwenda, C. Tomassetti,
C. Meuleman and T.M. D’Hooghe
[Abstract]
Pharmacophore-Based Virtual Screening
Pp.1018-1024
Hongmao Sun
[Abstract]
Melanin-Concentrating Hormone Receptor 1 Antagonists:
A New Perspective for the Pharmacologic Treatment of Obesity
Pp. 1025-1043
Gildardo Rivera, Virgilio Bocanegra-García, Silvia
Galiano, Nuria Cirauqui, Javier Ceras, Silvia Pérez,
Ignacio Aldana and Antonio Monge
[Abstract]
Abstracts
[Back to top]
Oxidatively Damaged DNA Repair Defect in Cockayne Syndrome
and its Complementation by Heterologous Repair Proteins
Guido Frosina
Cockayne syndrome (complementation groups A and B) is
a rare autosomal recessive DNA repair disorder characterized
by photosensitive skin and severely impaired physical and
intellectual development. The Cockayne syndrome A and B proteins
intervene in the repair of DNA modifications that block the
RNA polymerase in transcribed DNA sequences (transcription-coupled
repair). Recent results suggest that they also have a more
general role in the repair of oxidative DNA base modifications.
Although the phenotypical consequences of defective repair
of oxidatively damaged DNA in Cockayne syndrome are not determined,
accumulation of oxidized lesions might contribute to delay
the physical and intellectual development of these patients.
To conceive new therapeutic strategies for this syndrome,
we are investigating whether the oxidatively damaged DNA repair
defect in Cockayne syndrome might be complemented by heterologous
repair proteins, such as the Escherichia coli formamidopyrimidine-DNA
glycosylase and endonuclease III. The complementation studies
may shed light on the important lesions for the Cockayne syndrome
phenotype and offer new tools for future therapies aimed at
counteracting the consequences of oxidatively damaged DNA
accumulation.
[Back to top]
Current Developments in the Synthesis and Biological Activity
of Aza-C-Nucleosides: Immucillins and Related Compounds
Pedro Merino, Tomas Tejero and Ignacio Delso
This review will describe the recent advances in the
field of aza-C-nucleosides with a particular emphasis on immucillins
and related compounds. The review will cover both chemical
and biological aspects concerning their preparation and/or
occurrence in Nature as well as their biological properties
which include glycosidase, glycosyl transferase, and nucleoside
hydrolase and phosphorylase inhibition, among others. These
enzymatic inhibitory properties are the basis for the potential
use of the title compounds in viral and parasitic infections,
cancer and genetic disorders.
[Back to top]
Granulocyte Colony-Stimulating Factor (G-CSF) for Cardio-
and Cerebrovascular Regenerative Applications
Rainer Klocke, Michael T. Kuhlmann, Sergiu Scobioala,
Wolf-Rüdiger Schäbitz and Sigrid Nikol
The cytokine granulocyte colony-stimulating factor (G-CSF)
is produced by numerous cell types including immune and endo-thelial
cells. G-CSF binding to its receptor G-CSF-R which belongs
to the cytokine receptor type I family depends on the interaction
of alpha-helical motifs of the former and two fibronectin
type III as well as an immunoglobulin-like domain of the latter.
It activates several signalling transduction pathways including
PI3K/Akt, Jak/Stat and MAP kinase, thereby promoting survival,
proliferation, differentiation and mobilisation of haematopoietic
stem and progenitor cells. Accordingly, recombinant human
(rh)G-CSF has been extensively used in clinical haematology
and oncology to enable bone marrow transplantation or to treat
chemotherapy-associated neutropenia.
Using animal models it has been recently shown that G-CSF,
alone or in combination with other cytokines such as stem
cell factor (SCF), causes an accumulation of bone marrow-derived
cells in the infarcted heart which, however, do not differentiate
into cardiac cells. Nevertheless, since beneficial effects
on structural and functional properties were observed in animal
models of cardiac, brain and hindlimb ischaemia other mechanisms
of G-CSF action must be operative. Recent evidence suggests
paracrine effects mediated by the immigrated bone marrow-derived
cells and/or direct effects of the cytokine on resident G-CSF-R
expressing cells. In both cases these may include promotion
of cellular survival, proliferation and differentiation. First
clinical studies in patients with myocardial infarction, heart
failure and stroke have been accomplished and are reviewed
in this paper.
[Back to top]
ANTI-ADHESION Evolves To a Promising Therapeutic Concept in
Oncology
R. Schmidmaier and P. Baumann
Adhesion is a hallmark of haematological and solid cancer
cells. All five classes of cell adhesion molecules (CAM) –
integrins, cadherins, immunoglobulin-like CAMs, selectins
and CD44s – are characteristically dysregulated in human
cancer. Adhesion enables and promotes cancer-defining biological
processes like growth, survival, migration, extravasation,
homing, and metastasis. Furthermore, cell adhesion mediates
drug resistance (CAM-DR) in multiple myeloma, malignant lymphoma,
acute and chronic leukaemias, as well as in pancreatic cancer,
neuroblastoma, small cell and non-small cell lung cancer,
mesothelioma, colorectal carcinoma, and breast cancer. Cell
adhesion protects from death by radiation, genotoxic chemotherapy,
or targeted pathway inhibitors. Adhesion molecules are overexpressed
on drug resistant cells (e.g. multiple myeloma or prostate
cancer). Very recently, several cell adhesion mediated survival
pathways have been elucidated, with key mediators being LFA-1,
VLA-4, FAK, ILK, Src, PI3K, Akt, Ras, MEK, Erk, HMG-CoA reductase,
Rho, Rho kinase, PKC, and NFκB.
Because the surface and the intracellular targets are now
known and because specific compounds are becoming increasingly
available, first clinical trials regarding ANTI-ADHESION therapies
are ongoing. However, in comparison to the comprehensive preclinical
and clinical knowledge about CAMs, the number of drugs developed
thusfar is quite low. ANTI-ADHESION strategies include targeting
of surface antigens, inhibition of cell adhesion associated
pathways, inhibition of CAM-DR, and targeted drug delivery.
As ANTI-ADHESION is based on general characteristics of cancer
cells independent of specific disease entities or treatment
modalities, it may become a successful, low-toxic and broadly
applicable concept in cancer treatment.
[Back to top]
Anti-Infective and Anti-Tumor Agents Based on the Depletion
of Immune Suppressive Effects
Naohiro Seo, Hiromichi Yamashiro and Toshimasa Tadaki
Aggressive immunity characterized by the motion of cytotoxic
T lymphocytes (CTLs), T helper (Th) 1 cells, and natural killer
(NK) cells is the first line of defense against intracellular
microorganism invasion and tumor formation. In patients with
infectious diseases and tumors, aggressive immunity is often
attenuated by immune suppressive effects provided by regulatory
T (Treg) cells including CD4+
CD25+ forkhead-box (fox)
p3+ T cells, T regulatory
(Tr) 1, Th3, and a subpopulation of γδ-type
of T cell receptor-expressing T (γδ
T) cells. It has been demonstrated that Treg cells down-regulate
aggressive immunity by direct cell interactions and suppressive
cytokines (e.g., interleukin (IL)-10, transforming growth
factor (TGF)-β).
Today, instead of synthesizing chemical agents with serious
side effects, protein agents, catalytic oligonucleotides,
and natural medicines involved in the elimination of Treg
cell-mediated suppressive responses for the restoration of
aggressive immunity are expected to be alternatives as a mild
clinical remedy against microorganism invasion and tumors.
[Back to top]
Arbidol: A Broad-Spectrum Antiviral Compound that Blocks Viral
Fusion
Y.S. Boriskin, I. A. Leneva, E.-I. Pécheur and
S. J. Polyak
Arbidol (ARB; ethyl-6-bromo-4-[(dimethylamino)methyl]-5-hydroxy-1-methyl-2-[(phenylthio)methyl]-indole-3-carboxylate
hydrochloride monohydrate), is a Russian-made potent broad-spectrum
antiviral with demonstrated activity against a number of enveloped
and non-enveloped viruses. ARB is well known in Russia and
China, although to a lesser extent in western countries. Unlike
other broad-spectrum antivirals, ARB has an established molecular
mechanism of action against influenza A and B viruses, which
is different from that of available influenza antivirals,
and a more recently established mechanism of inhibition of
hepatitis C virus (HCV). For both viral infections the anti-viral
mechanism involves ARB inhibition of virus-mediated fusion
with target membrane and a resulting block of virus entry
into target cells. However, ARB inhibition of fusion exploits
different ARB modalities in case of influenza viruses or HCV.
This review aims to summarize the available evidence of ARB
effects against different groups of viruses, also, to compare
various aspects of ARB anti-fusion mechanisms against influenza
virus and HCV (with reference to different stringency of pH-dependence
of these two viral fusogens) and to discuss further prospects
for ARB and its improved derivatives of the parent compounds.
[Back to top]
Non-Steroidal Targets in the Diagnosis and Treatment of Endometriosis
C.M. Kyama, A. Mihalyi, P. Simsa, J.M. Mwenda, C. Tomassetti,
C. Meuleman and T.M. D’Hooghe
Endometriosis, a chronic gynecologic disease frequently
resulting in chronic pelvic pain, severe dysmenorrhoea, and
subfertility, is defined as the presence of endometrial tissue
at extrauterine locations, most commonly on the peritoneum
and ovaries. Conclusive diagnosis requires laparoscopic surgery
followed by histological confirmation. The treatment options
-at present- are limited to hormonal therapies and/or surgical
ablation of the lesions, and are characterized by high recurrence
rates, significant side-effects and limited duration of administration.
The pathogenesis of endometriosis is still unclear and numerous
immunological and inflammatory factors have been suggested
to be involved in the development of the disease, including
interleukin (IL)-1, IL-2, IL-6, IL-8, IL-12, tumour necrosis
factor –alpha (TNF-α),
regulated on activation, normal T-Cell expressed and secreted
(RANTES) and its receptor cognate chemokine receptor 1 (CCR1),
peroxisome proliferator activated receptors (PPARs), matrix
metalloproteinases (MMPs) and cyclooxygenase (COX). Another
crucial mechanism in endometriosis is the vascularisation
of the endometriotic lesions, with a key role for vascular
endothelial growth factor (VEGF). Recently, protease activated
receptors (PARs), mitogen-activated protein kinases (MAPKs)
and tyrosine kinases have also been associated with the pathophysiology
of endometriosis.
The aim of this article is to discuss molecules that have
recently been found to have connections with the pathogenesis
of endometriosis, as potential targets to develop new methods
for noninvasive diagnosis and for novel medical management
of this disease. This review also critically addresses how
these molecules can be tested in basic, preclinical and clinical
research, the status of this research and the importance of
potential side effects.
[Back to top]
Pharmacophore-Based Virtual Screening
Hongmao Sun
Virtual screening (VS) is an important component of cheminformatics
and molecular modeling. An abundance of structural information,
indicated by both the ever-increasing availability of 3-dimensional
(3D) protein structures and the readiness of free conformational
databases of commercially available compounds, such as ZINC,
supplies a broad platform for VS. At the same time, new technology
enables the implementation of more accurate and sophisticated
pharmacophore models and the screening of millions of compounds
within a manageable period. Therefore, VS is expected to play
a more important role in future drug discovery efforts. This
paper will examine and compare the advantages and disadvantages
of VS against experimental high-throughput screening (HTS).
It will also evaluate pharmacophore-based VS against docking-based
VS. The strategies leading to successful pharmacophore-based
VS are outlined, including how to enumerate a conformational
database efficiently, how to select chemical features for
a specific pharmacophore model, how to incorporate excluded
volumes to enhance the geographical restrictions, and how
to optimize a pharmacophore model. Successful examples of
pharmacophore-based VS will be presented.
[Back to top]
Melanin-Concentrating Hormone Receptor 1 Antagonists: A New
Perspective for the Pharmacologic Treatment of Obesity
Gildardo Rivera, Virgilio Bocanegra-García, Silvia
Galiano, Nuria Cirauqui, Javier Ceras, Silvia Pérez,
Ignacio Aldana and Antonio Monge
Obesity is a chronic disease characterized by the accumulation
of excess adipose tissue associated with an increased risk
of multiple morbidities and mortality. At the present time,
only three drugs have been approved by the Food and Drug Administration
(FDA) for the treatment of obesity. Agonists and antagonists
of some of the substances implicated in the regulation of
energy homeostasis represent opportunities for anti-obesity
drug development. The most promising targets are alpha-melanocyte
stimulating hormone (alpha-MSH) receptors, cannabinoid receptors,
the 5-hydroxytryptamine (5-HT) receptors and melanin-concentrating
hormone (MCH) receptors. MCH receptors could be major potential
targets for the treatment of obesity. Many pharmaceutical
companies have described MCH-R1 antagonists that have appeared
over the past year. Recently, two compounds went into phase
I clinical trials that evaluate MCH receptor antagonists as
a new perspective for the pharmacologic treatment of obesity.
In this review, structure-activity relationships (SAR) in
the development of MCH-R1 antagonists are provided.
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