|
Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 15, Number 14, 2008
Contents
Anticancer Drug Discovery Targeting DNA Hypermethylation
Pp. 1350-1375
Niefang Yu and Mingrong Wang
[Abstract]
Procarbazine – A Traditional Drug in the
Treatment of Malignant Gliomas Pp. 1376-1387
Rainer Goerne, Ulrich Bogdahn and
Peter Hau
[Abstract]
Progress in the Development of Matrix Metalloproteinase
Inhibitors Pp. 1388-1395
GuoGang Tu, WengFang Xu, HuiMing Huang and
ShaoHua Li
[Abstract]
NO Signaling Through cGMP in Renal Tissue Fibrosis
and Beyond: Key Pathway and Novel Therapeutic Target
Pp. 1396-1406
Yingrui Wang-Rosenke, Hans-H. Neumayer and
Harm Peters
[Abstract]
Old Friends in New Constellations - the Hematopoetic
Growth Factors G-CSF, GM-CSF, and EPO for the Treatment of
Neurological Diseases Pp. 1407-1411
M.H. Maurer, W.-R. Schäbitz and
A. Schneider
[Abstract]
Anti-Infective Treatment of Bacterial Urinary
Tract Infections Pp. 1412-1427
F.M.E. Wagenlehner, A. Pilatz, K.G. Naber,
G. Perletti, C.M. Wagenlehner and W. Weidner
[Abstract]
Cannabinoid CB1 and CB2 Receptor Ligand Specificity
and the Development of CB2-Selective Agonists Pp.
1428-1443
John C. Ashton, Jason L. Wright, John M. McPartland
and Joel D.A. Tyndall
[Abstract]
The Chromogranin A-Derived Vasostatins: New Players
in the Endocrine Heart Pp. 1444-1451
B. Tota, T. Angelone, R. Mazza and M.C.
Cerra
[Abstract]
Abstracts
[Back to top]
Anticancer Drug Discovery Targeting DNA Hypermethylation
Niefang Yu and Mingrong Wang
DNA methyltransferases (DNMTs) are important regulators
of gene transcription and their roles in carcinogenesis have
been a topic of considerable interest in the last few years.
Diverse classes of chemical compounds including nucleotide
analogues, adenosine analogues, aminobenzoic derivatives,
polyphenols, hydrazines, phthalides, disulfides and antisenses
are being discovered and evaluated as DNMT inhibitors targeting
DNA hypermethylation. Among them, 5-Azacytidine 5
and Decitabine 6 were launched recently.
Several other compounds are under clinical trials. Some of
these compounds were discovered from structure-based drug
design. These compounds exert their DNA methylation inhibitory
by different mechanisms. This review will present a brief
account of various DNA methyltransferases and their biological
functions, with focus on actuality of design and synthesis
of various inhibitors of DNA hypermethylation as anticancer
drugs.
[Back to top]
Procarbazine – A Traditional Drug in the Treatment
of Malignant Gliomas
Rainer Goerne, Ulrich Bogdahn and
Peter Hau
The methylhydrazine derivative Procarbazine (PCZ) as monotherapy
or in combination with CCNU and vincristine (PCV) was evaluated
in a vast number of clinical trials and is still used in patients
with high-grade and low-grade gliomas. The compound is an
antineoplastic agent with multiple sites of action. It inhibits
incorporation of small DNA precursors, as well as RNA and
protein synthesis. PCZ can also directly damage DNA through
an alkylation reaction. The drug is not cross-resistant with
other mustard-type alkylating agents. As PCZ was in almost
all trials used in a combination with CCNU and Vincristin,
the efficacy can only be evaluated in the view of the PCV
regimen. The published data suggest a role of PCV as a salvage
regimen, especially in oligodendroglial tumors; however, well
designed studies with high evidence are rare in all entities.
This article summarizes the existing data with the goal to
define the role of PCZ/PCV in modern neurooncology.
[Back to top]
Progress in the Development of Matrix Metalloproteinase
Inhibitors
GuoGang Tu, WengFang Xu, HuiMing Huang and
ShaoHua Li
Matrix metalloproteinases (MMPs) are a family of zinc-dependent
proteinases involved in the degradation and remodeling of
extracellular matrix proteins that are associated with the
tumorigenic process. MMPs promote tumor invasion and metastasis,
regulating host defense mechanisms and normal cell function.Thus,
MMP inhibitors (MMPIs) are expected to be useful for the treatment
of diseases such as cancer, osteoarthritis, and rheumatoid
arthritis. A vast number of MMPIs have been developed in recent
years.With the failure of these inhibitors in clinical trials,more
efforts have been directed to the design of specific inhibitors
with different Zn-binding groups. This review summarizes the
current status of MMPIs, the design of small molecular weight
MMPIs , a brief description of available threedimensional
MMP structures, a review of the proposed therapeutic utility
of MMPIs, and a clinical update of compounds that have entered
clinical trials in humans.
[Back to top]
NO Signaling Through cGMP in Renal Tissue Fibrosis
and Beyond: Key Pathway and Novel Therapeutic Target
Yingrui Wang-Rosenke, Hans-H. Neumayer and
Harm Peters
Nitric oxide (NO) produced by endothelial NO synthase (NOS)
in low concentrations is a unique messenger molecule with
key homeostatic functions concerning the prevention of pathological
vascular and tissue changes such as increases in blood pressure,
platelet degranulation, mononuclear cell infiltration, cell
proliferation and extracellular matrix protein accumulation.
This is in contrast to high levels of NO derived from inducible
NOS which act as detrimental effector molecules and free radicals
in immune response. Deficiency in NO´s protective signaling
actions is a major characteristic in numerous experimental
and human disease situations. The main function of the NO
signaling pathway is activation of the soluble guanylate cyclase
(sGC) enzyme with subsequent generation of cyclic guanosine
monophosphate (cGMP) as a second messenger and downstream
mediator. In the past, attempts to overcome deficiency in
endothelial NO effects were focused primarily on increasing
the supply with the NO precursor L-arginine or on the use
of directly NO-releasing compounds. The clinical impact of
these strategies, however, was rather limited. Recent state-of-the-art
studies have revealed that NO signaling is highly regulated
at the transcriptional level and that deficiency in NO signaling
correlates closely with pathological changes. In parallel
efforts, novel pharmacological compounds which specifically
enhance NO/cGMP signaling have been developed and have demonstrated
remarkable efficacy in experimental disease settings. In this
review, we summarize the current state of knowledge on the
impairment of NO/cGMP signaling and about its pharmacological
stimulation. In the first part, experimental renal fibrosis,
i.e. the tandem rat model of acute anti-thy1 glomerulonephritis
and progressive anti-thy1 renal fibrosis will serve as a paradigm
for introducing this new and exciting field. In the second
part, we will address the most recent findings on NO signaling
in non-renal diseases. Together, these results point out that
deficiency in NO/cGMP is a common key pathway as well as a
novel therapeutic target in a number of diseases.
[Back to top]
Old Friends in New Constellations - the Hematopoetic
Growth Factors G-CSF, GM-CSF, and EPO for the Treatment of
Neurological Diseases
M.H. Maurer, W.-R. Schäbitz and
A. Schneider
Currently, growth factors which have been identified in hematopoiesis
and angiogenesis are re-considered as therapeutical agents
in a number of neurological diseases, mainly neurodegenerative
disorders like Parkinson's Disease, amyotrophic lateral sclerosis
(ALS), or cerebrovascular events such as stroke. Among these
growth factors, erythropoietin (EPO) and granulocyte colony-stimulating
growth factor (G-CSF) are the most prominent. With regard
to neurological disease, EPO has been tested in clinical trials
for potential use in stroke, schizophrenia, and addiction,
G-CSF is currently under clinical investigation for stroke
treatment. The major advantage of these growth factors is
their well-described pharmacological behavior and their clinical
use over several years. A number of mechanisms of action in
the CNS have been identified that are probably important for
the beneficial action of these factors in animal models of
disease, the most relevant relating to neuroprotection, neuroplasticity
and stem cell growth and differentiation. In this review,
we will discuss the current efforts and prerequisites of novel
growth factor therapies for neurodegenerative diseases with
regard to their possible mechanism of action on the molecular
level and their effects on brain-derived stem cell populations.
Additionally, we will describe the necessities for future
research before such therapies can be envisioned.
[Back to top]
Anti-Infective Treatment of Bacterial Urinary
Tract Infections
F.M.E. Wagenlehner, A. Pilatz, K.G. Naber,
G. Perletti, C.M. Wagenlehner and W. Weidner
Bacterial urinary tract infections (UTI) are frequently found
in the outpatient as well as in the nosocomial setting. The
bacterial UTI can be stratified into uncomplicated and complicated
UTI. Antibiotic resistance is continuously increasing in uncomplicated
as well as complicated UTI. In uncomplicated UTI efforts are
made to use antibiotic substances exclusively for this indication.
In complicated UTI as broad spectrum antibiotics are increasingly
used, the higher the antimicrobial resistance rates are reported.
There are two predominant aims in the antimicrobial treatment
of both uncomplicated and complicated UTI: 1.) rapid and effective
response to therapy, prevention of complications and prevention
of recurrence in the individual patient treated, and 2.) prevention
of emergence of resistance to anti-infective agents in the
microbial environment.
The use of antibiotics has to keep up with the continuous
change in antimicrobial resistance and the tailored needs
in the individual patient. Antibiotic substances therefore
need to become evaluated for each indication and continuously
followed for clinical usage.
The knowledge of structure-activity relationships of antimicrobial
substances and bacterial resistance mechanisms to antibiotics
help to use antibiotics better in daily routine and design
new derivatives and substances.
The aim of this review is to describe the chemistry and structure-activity
relationships of current antibiotics and promising substances
in development for the treatment of UTI.
[Back to top]
Cannabinoid CB1 and CB2 Receptor Ligand Specificity
and the Development of CB2-Selective Agonists
John C. Ashton, Jason L. Wright, John M. McPartland
and Joel D.A. Tyndall
Cannabinoids in current use such as nabilone activate
both CB1 and CB2 receptors. Selective CB2 activation may provide
some of the therapeutic effects of cannabinoids, such as their
immuno-modulatory properties, without the psychoactive effects
of CB1 activation. Therefore, cannabinoid CB2 receptors represent
an attractive target for drug development. However, selective
and potent CB2 agonists remain in development. CB1 and CB2
differ considerably in their amino acid sequence and tertiary
structures. Therefore, clinical development of potent and
selective CB2 agonists is probable. Mutational and ligand
binding studies, functional mapping, and computer modelling
have revealed key residues and domains in cannabinoid receptors
that are involved in agonist and antagonist binding to CB1
and CB2. In addition, CB2 has undergone more rapid evolution,
and results for ligand binding and efficacy cannot be automatically
extrapolated from rat or mouse CB2 to human. Furthermore,
loss of CB1 affinity is a crucial property for CB2-selective
ligands, and although rat CB1 is 97% homologous with human
CB1, critical differences do exist, with potential for further
exploitation in drug design. In this paper we briefly review
previous cannabinoid receptor models and mutation/binding
studies. We also review binding affinity ratios with respect
to CB1 and CB2. We then employ our own models to illustrate
key cannabinoid receptor residues and binding subdomains that
are involved in these differences in binding affinities and
discuss how these might be exploited in the development of
CB2 specific ligands. Published reports for species specific
binding affinities for CB2 are scarce, and we argue that this
needs to be corrected prior to the progression of CB2 agonists
f rom pre-clinical to clinical research.
[Back to top]
The Chromogranin A-Derived Vasostatins: New Players
in the Endocrine Heart
B. Tota, T. Angelone, R. Mazza and M.C.
Cerra
Over the last 50 years, increasing evidence has documented
the ability of cardiac non-neuronal cells to synthesize and
release catecholamines (CAs) and the vasorelaxant natriuretic
peptides (NPs), which both regulate cardiovascular homeostasis
in health and disease. This knowledge has firmly established
the concept of the heart as an endocrine organ. The contents
of this frame have been richly expanded by the identification
of an increasing number of intracardiac endocrine modulators,
including Chromogranin-A (CgA) and its derived peptides. In
the rat heart, CgA is co-stored and co-released with Atrial
NP (ANP) in non-adrenergic myoendocrine atrial cells as well
as in atrial and ventricular Purkinje fibres. In the ventricular
myocardium of the human hypertrophic and dilated heart, CgA
co-localizes with B-type NP (BNP). CgA is the precursor of
biologically active peptides produced by proteolytic cleavage.
One of them, the human recombinant 1-76 CgA-derived vasostatin-1
(VS-1), is an inhibitor of cardiac contraction and relaxation,
a non-competitive counter-regulator of β-adrenergic
stimulation and a protecting agent in ischemic preconditioning.
Therefore, it may function as a cardiocirculatory homeostatic
stabilizer, particularly in the presence of intense adrenergic
stimuli, e. g. under stress responses. Since in patients with
chronic heart failure circulating CgA levels increase up to
10-20 nM, depending on the severity of the disease and are
independent prognostic indicators of mortality, knowledge
on the physio-pathological significance of locally produced
and/or circulating CgA-derived peptides, as attemped in this
synopsis, may pave the way for clinically-oriented cardiovascular
applications.
|
