| Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 16, Number 19, 2009
Contents
Strategies to Improve the Efficacy of Platinum Compounds
Pp. 2355-2365
Giacomo Cossa, Laura Gatti, Franco Zunino
and Paola Perego
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Extracorporeal Shock Wave Therapy in Inflammatory
Diseases: Molecular Mechanism that Triggers Anti-Inflammatory
Action Pp. 2366-2372
Sofia Mariotto, Alessandra Carcereri de
Prati, Elisabetta Cavalieri, Ernesto Amelio, Ernst Marlinghaus
and Hisanori Suzuki
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Article]
Recent Advances on the Roles of NO in
Cancer and Chronic Inflammatory Disorders Pp.2373-2394
Jagat R. Kanwar, Rupinder K. Kanwar, Hannah
Burrow and Sara Baratchi
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Progress Towards the Identification of
New Aggrecanase Inhibitors Pp. 2395-2415
Francesca De Rienzo, Puneet Saxena, Federico
Filomia, Gianfranco Caselli, Fabrizio Colace, Luigi Stasi,
Antonio Giordani and Maria Cristina Menziani
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Iron Chelators in Medicinal Applications
- Chemical Equilibrium Considerations in Pharmaceutical Activity
Pp. 2416-2429
Thomas Manning, Greg Kean, Jessica Thomas,
Khaleh Thomas, Michael Corbitt, Donna Gosnell, Ronald Ware,
Sonya Fulp, Joey Jarrard and Dennis Phillips
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Article]
2-Arylbenzothiazole as a Privileged Scaffold
in Drug Discovery Pp. 2430-2440
A.A. Weekes and A.D. Westwell
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An Overview on Benzylisoquinoline Derivatives
with Dopaminergic and Serotonergic Activities Pp.
2441-2467
N. Cabedo, I. Berenguer, B. Figadère
and D. Cortes
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Article]
Fentanyl Analogs: Structure-Activity-Relationship
Study Pp. 2468-2474
S. Vuckovic, M. Prostran, M. Ivanovic, Lj.
Došen-Micovic, Z. Todorovic, Z. Nešic, R. Stojanovic,
N. Divac and Ž. Mikovic
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Article]
Current Evaluation of the Millennium
Phytomedicine- Ginseng (I): Etymology, Pharmacognosy, Phytochemistry,
Market and Regulations Pp. 2475-2484
Lee Jia and Yuqing Zhao
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Abstracts
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Strategies to Improve the Efficacy of Platinum Compounds
Giacomo Cossa, Laura Gatti, Franco Zunino
and Paola Perego
Platinum drugs are widely used in antitumour therapy
and are a cornerstone of the treatment of different solid
tumours. The pharmacological interest of cisplatin has led
to the design of many analogues to broaden the spectrum of
activity, reduce side effects, and overcome resistance. Although
the cis configuration was initially identified as
the only active one, trans-platinum complexes have
shown significant antitumour activity in preclinical models.
In addition to mononuclear platinum compounds, multinuclear
platinum complexes have been generated that are characterised
by a different mode of interaction with DNA. Since a major
limitation to the clinical efficacy of platinum compounds
is drug resistance, the most important feature of nonconventional
platinum drugs should be the capability of overcoming cellular
resistance. However, due to the multifactorial nature of clinical
resistance, which also involves pharmacological factors, the
optimisation of current platinum-based therapy also includes
the development of drug delivery approaches. The present review
focuses on recent studies on the molecular alterations of
tumour cells that are associated with resistance to platinum
drugs, the development of novel platinum drugs, and approaches
that may contribute to improve the efficacy of platinum-based
therapy.
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Extracorporeal Shock Wave Therapy in Inflammatory Diseases:
Molecular Mechanism that Triggers Anti-Inflammatory Action
Sofia Mariotto, Alessandra Carcereri de
Prati, Elisabetta Cavalieri, Ernesto Amelio, Ernst Marlinghaus
and Hisanori Suzuki
Shock waves (SW), defined as a sequence of single
sonic pulses characterised by high peak pressure (100 MPa),
a fast rise in pressure (<
10 ns) and a short lifecycle (10 μs),
are conveyed by an appropriate generator to a specific target
area at an energy density ranging from 0.03 to 0.11 mJ/mm2.
Extracorporeal SW (ESW) therapy was first used on patients
in 1980 to break up kidney stones. During the last ten years,
this technique has been successfully employed in orthopaedic
diseases such as pseudoarthosis, tendinitis, calcarea of the
shoulder, epicondylitis, plantar fasciitis and several inflammatory
tendon diseases. In particular, treatment of the tendon and
muscle tissues was found to induce a long-time tissue regeneration
effect in addition to having a more immediate anthalgic and
anti-inflammatory outcome. In keeping with this, an increase
in neoangiogenesis in the tendons of dogs was observed after
4-8 weeks of ESW treatment. Furthermore, clinical observations
indicate an immediate increase in blood flow around the treated
area. Nevertheless, the biochemical mechanisms underlying
these effects have yet to be fully elucidated.
In the present review, we briefly detail the physical properties
of ESW and clinical cases treated with this therapy. We then
go on to describe the possible molecular mechanism that triggers
the anti-inflammatory action of ESW, focusing on the possibility
that ESW may modulate endogenous nitric oxide (NO) production
either under normal or inflammatory conditions. Data on the
rapid enhancement of endothelial NO synthase (eNOS) activity
in ESW-treated cells suggest that increased NO levels and
the subsequent suppression of NF-κB
activation may account, at least in part, for the clinically
beneficial action on tissue inflammation.
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Recent Advances on the Roles of NO in Cancer and Chronic Inflammatory
Disorders
Jagat R. Kanwar, Rupinder K. Kanwar, Hannah
Burrow and Sara Baratchi
Nitric oxide (NO) is a short-life molecule produced
by the enzyme known as the nitric oxide synthase (NOS), in
a reaction that converts arginine and oxygen into citrulline
and NO. There are three isoforms of the enzyme: neuronal NOS
(nNOS, also called NOS1), inducible NOS (iNOS or NOS2), and
endothelial NOS (eNOS or NOS3). It is now known that each
of these isoforms may be expressed in a variety of tissues
and cell types. This paper is a review of the current knowledge
of various functions of NO in diseases. We discuss in more
detail its role in Cancer, the role of NO in myocardial pathophysiology,
in central nervous system (CNS) pathologies. Other diseases
such as inflammation, asthma, in chronic liver diseases, inflammatory
bowel disease (IBD), arthritis, are also discussed. This review
also covers the role of NO in cardiovascular, central nervous,
pancreas, lung, gut, kidney, myoskeletal and chronic liver
diseases (CLD). The ubiquitous role that the simple gas nitric
oxide plays in the body, from maintaining vascular homeostasis
and fighting infections to acting as a neurotransmitter and
its role in cancer, has spurred a lot of interest among researchers
all over the world. Nitric oxide plays an important role in
the physiologic modulation of coronary artery tone and myocardial
function. Nitric oxide from iNOS appears to be a key mediator
of such glial-induced neuronal death. The high sensitivity
of neurons to NO is partly due to NO causing inhibition of
respiration, rapid glutamate release from both astrocytes
and neurons, and subsequent excitotoxic death of the neurons.
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Progress Towards the Identification of New Aggrecanase Inhibitors
Francesca De Rienzo, Puneet Saxena, Federico
Filomia, Gianfranco Caselli, Fabrizio Colace, Luigi Stasi,
Antonio Giordani and Maria Cristina Menziani
Degenerative diseases are still a challenging issue
in clinical therapy; even though in several cases it is possible
to treat symptoms, drugs able to block disease progression
are lacking at present. Osteoarthritis (OA) and Rheumatoid
Arthritis (RA) are degenerative diseases leading to serious
cartilage destruction, affecting joint functions and giving
rise to restricted movement, pain and chronic disability.
Current clinical treatment for arthritis is confined to Non
Steroidal Anti-Inflammatory Drugs (NSAIDs), which are effective
in treating symptoms but fail to block the progression of
the disease. Matrix Metalloproteases (MMPs) inhibitors have
been clinically studied as possible drugs for cartilage degradation
prevention. However, their clinical use has been limited by
severe side-effects. Aggrecan, which plays a fundamental role
in maintaining the structural and mechanical properties of
cartilage, has recently been found to be specifically cleaved
by "aggrecanases". Aggrecanases are multidomain
zinc metalloproteases, different from MMPs, which cleave the
aggrecan within the interglobular domain (IGD). Aggrecan breakdown
at this site has been found to be crucial for cartilage degradation.
These new findings re-addressed the interest of the research
for new arthritis therapeutic agents focusing on aggrecanases
rather than on MMPs. This review is meant to provide a critical
appraisal of the ongoing developments of Zn-chelating and
non chelating aggrecanase inhibitors, with a particular emphasis
on the related structure-activity relationships (SARs), in
the light of the protein structural information recently made
available.
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Iron Chelators in Medicinal Applications - Chemical Equilibrium
Considerations in Pharmaceutical Activity
Thomas Manning, Greg Kean, Jessica Thomas,
Khaleh Thomas, Michael Corbitt, Donna Gosnell, Ronald Ware,
Sonya Fulp, Joey Jarrard and Dennis Phillips
Iron chelators are being examined as a potential
class of pharmaceutical agents to battle different types of
cancer as well as iron overload diseases. In recent studies,
iron binding species such as desferrioxamine, triapine, tachpyridine,
Dp44Mt, and PIH have been tested in cell line tests and clinical
trials. Using published chemical equilibrium values (stability
constants, equilibrium constants), it is argued that an iron
chelator cannot competitively remove iron from a heme-containing
biomolecule (i.e. hemoglobin (Hb), myoglobin) causing a cancerous
cell to die. This type of reaction (DFO(aq) + [Fe2+,3+-Hb]
→
[Fe2+,3+-DFO] + Hb) has been
proposed in a number of published studies using circumstantial
evidence. It is argued that iron chelators can potentially
interact with iron from ferritin or iron that has precipitated
or flocculated as oxyhydroxide under physiological pH’s.
It is argued that chelators can interfere with various physiological
processes by binding cations such as Ca2+,
Zn2+ or K+.
A number of siderophores and natural products that have the
ability to bind Fe2+/Fe2+
as well as other cations are discussed in terms of their potential
pharmaceutical activity as chelators. Chemical equilibria
between cations and pharmaceutical agents, which are rarely
quantitated in explaining medicinal mechanisms, are used to
show that chelators can bind and remove iron and other cations
from physiologically important systems required for cell survival
and propagation.
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2-Arylbenzothiazole as a Privileged Scaffold in Drug Discovery
A.A. Weekes and A.D. Westwell
Substituted 2-arylbenzothiazoles have emerged in recent
years as an important pharmacophore in a number of diagnostic
and therapeutic settings. Attractive features of drug candidates
based on this benzothiazole scaffold include their synthetic
accessibility, and synthetic approaches to 2-arylbenzothiazole-based
compounds will be reviewed here. Examples of 2-arylbenzothiazoles
endowed with diagnostic/therapeutic activity include the 2-(4-aminophenyl)benzothiazole
series, which has a remarkable activity profile in both the
potential non-invasive diagnosis of Alzheimer’s disease
and as antitumour agents.
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An Overview on Benzylisoquinoline Derivatives with Dopaminergic
and Serotonergic Activities
N. Cabedo, I. Berenguer, B. Figadère
and D. Cortes
Dopamine and serotonin are important neurotransmitters
in the mammalian central nervous system (CNS) involved in
numerous physiological and behavioural disorders such as schizophrenia,
major depression, anxiety, Parkinson’s and Huntington’s
diseases, and attention deficit hyperactivity disorder. Several
natural and synthetic benzylisoquinoline derivatives have
displayed affinity for dopamine and serotonin receptors in
nanomolar or micromolar ranges. This review covers the last
three decades of dopaminergic and serotonergic activities,
and especially focuses on structure-activity relationships
of natural and synthetic benzylisoquinoline derivatives. We
have included aporphines, 1-benzyltetrahydroisoquinolines,
bis-benzylisoquinolines, protoberberines, cularines and other
structural analogues. Further molecular modelling calculations
have been considered as important tools to not only obtain
structural information of both neurotransmitter receptors,
but to also identify their pharmacophore features. The development
of selective potential ligands like benzylisoquinoline derivatives
may help in the therapy of diseases related to CNS dysfunction.
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Fentanyl Analogs: Structure-Activity-Relationship Study
S. Vuckovic, M. Prostran, M. Ivanovic, Lj.
Došen-Micovic, Z. Todorovic, Z. Nešic, R. Stojanovic,
N. Divac and Ž. Mikovic
Fentanyl is the prototype of the 4-anilidopiperidine
class of synthetic opioid analgesics. This study was aimed
to review the structure-activity-relationship (SAR) of fentanyl
analogs substituted in the position 3, or 4 of the piperidine
ring. Pharmacological results show that the groups in position
3 of the piperidine ring, which are larger than methyl, severely
reduce the analgesic potency compared to fentanyl. It is likely
that the steric factor alone (i.e. voluminosity of
the group and cis/trans isomerism), rather than the
polarity and/or chemical reactivity, plays a crucial role
in the analgesic potency of this series. Although the duration
of action, in general, does not depend on the stereochemistry,
longer action of the most potent 3-alkyl fentanyl analogs
such as cis-3-methyl- and cis-3-ethyl fentanyl,
is more likely influenced by pharmacodynamic, rather than
pharmacokinetic variables. Also, it is possible that the introduction
of a functional group such as 3-carbomethoxy reduces the duration
of action by altering pharmacokinetic properties. SAR findings
obtained by evaluating the neurotoxic effects of fentanyl
analogs substituted in the position 3 of the piperidine ring
parallel the SAR findings on analgesia in regard to potency
and duration of action. This might suggest that similar receptors
are involved in producing both antinociceptive and neurotoxic
effects of these drugs. It appears that both the potency and
the duration of action in the series of fentanyl analogs substituted
in position 4 of the piperidine ring is influenced only by
the steric requirement and not by the chemical nature of the
substituent.
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Current Evaluation of the Millennium Phytomedicine- Ginseng
(I): Etymology, Pharmacognosy, Phytochemistry, Market and
Regulations
Lee Jia and Yuqing Zhao
The dawning of this millennium broke new ground in life science
and technology, presented us genomic and proteomic revolution,
nanotechnology innovation, and high performance liquid chromatography
coupled with tandem mass spectrometry (LC/MS/MS) used for
separating and identifying new chemical entities at pico-,
or even femto-concentrations. Applications of these high technologies
to the traditional Chinese medicine (TCM) opened a new chapter
in the ancient medicine, and prompted us to reevaluate the
thousand-year-old phytomedicine—
ginseng from current perspectives. We, therefore, collected
the latest information (mostly within 10 years) on ginseng,
and condensed the information into two parts of this review
serial. The present part covers etymology of ginseng, its
pharmacognosy (natural origin, physical appearance, chemical
properties, and specie identification), its cultivation and
processing-related metabolic changes in active ingredients,
standardized analytical methods used for quality control of
various ginseng products, modern analytical methods used to
identify and classify more than 100 chemical entities (many
were recently unfolded) derived from ginseng species and their
metabolites. The global markets and production of ginseng
and relevant government regulations are herein updated to
exchange information and understandings about current people’s
uses and cultivation of ginseng. The second part of the review
serial will classify all these 100 chemical entities separated
from various ginseng species into different groups based on
their structural similarities, and summarize bioactivities
of these entities. The second part of the review serial will
also focus on recent findings of ginseng pharmacology and
its clinical trials for various diseases, and brief side effects
of ginseng.
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