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Mini-Reviews
in Medicinal Chemistry
ISSN: 1389-5575
Mini-Reviews in Medicinal
Chemistry
Volume 8, Number 7, June 2008
Contents
Chemokines as Pharmacological Targets Pp.
638-646
Emanuela Galliera, Massimiliano M. Corsi, Raffaella
Bonecchi, Massimo Locati and Alberto Mantovani
[Abstract]
Leukotrienes, Antileukotrienes and Asthma
Pp. 647-656
Paolo Montuschi
[Abstract]
Organoselenium Compounds in Cancer Chemoprevention
Pp. 657-668
Rajesh Naithani
[Abstract]
Critical Parameters for Genome Editing Using Zinc
Finger Nucleases Pp. 669-676
Todd D. Camenisch, Murray H. Brilliant and David
J. Segal
[Abstract]
Suppression of Cancer Invasiveness by Dietary
Compounds Pp. 677-688
Daniel Sliva
[Abstract]
Pharmacological Strategies for Neuroprotection
in Traumatic Brain Injury Pp. 689-701
J.S. Jennings, A.M. Gerber and M.L.
Vallano
[Abstract]
Development of 11β-HSD1
Inhibitors for the Treatment of Type 2 Diabetes Pp.
702-710
Clarence Hale and Minghan Wang
[Abstract]
The Development of Pro-Apoptotic Cancer Therapeutics
Pp. 711-718
Noha I. Ziedan, Hachemi Kadri and Andrew
D. Westwell
[Abstract]
On The Edge of Validation – Cancer Protease
Fibroblast Activation Protein Pp. 719-727
Beni B. Wolf, Clifford Quan, Thuy Tran, Christian
Wiesmann and Daniel Sutherlin
[Abstract]
Radiolabeled Glucocorticoids as Molecular Probes
for Imaging Brain Glucocorticoid Receptors by Means of Positron
Emission Tomography (PET) Pp. 728-739
Björn Steiniger, Torsten Kniess, Ralf Bergmann,
Jens Pietzsch and Frank R. Wuest
[Abstract]
Abstracts
[Back to top]
Chemokines as Pharmacological Targets
Emanuela Galliera, Massimiliano M. Corsi, Raffaella
Bonecchi, Massimo Locati and Alberto Mantovani
Chemokines play a key role in immune processes by controlling
leukocyte recruitment in physiological and pathological condition.
This review discusses the regulation of the chemokine system,
its role in human diseases, and its potential relevance as
a new pharmacological target.
[Back to top]
Leukotrienes, Antileukotrienes and Asthma
Paolo Montuschi
Leukotrienes (LTs), including LTB4
and cysteinyl-LTs (CysLTs) (LTC4 ,
LTD4 , and LTE4
), are potent inflammatory lipid mediators which
are derived from 5–lipoxygenase activity. CysLTs, which
stimulate CysLT1 and CysLT2
receptor subtypes, are functionally involved in the pathophysiology
of asthma. Selective CysLT1
receptor antagonists are effective anti-asthmatic drugs. CysLT1
receptor antagonists have been developed from leukotriene
structural analogs, analogs of FPL 55712, a chromone carboxylic
acid, and by random screening of corporate compound banks.
This review will examine the biosynthesis, metabolism and
mechanism of action of leukotrienes, their role in asthma,
the therapeutic implications of the leukotriene pathway inhibition
for asthma, and the medicinal chemistry strategies that have
been exploited in the design of potent and selective CysLT1
receptor antagonists.
[Back to top]
Organoselenium Compounds in Cancer Chemoprevention
Rajesh Naithani
Selenium is an important trace element involved in different
physiological functions of human body. Knowledge of selenium
in biology of cancer has increased at rapid rate especially
during last two decades. Basic research and clinical studies
involving animal models and more recently studies in human
strongly support the protective role of selenium against various
types of cancer. Selenium’s role as an essential nutrient
is as a result of its unique chemistry enabled by the presence
of selenium in selenoproteins. Epidemiological findings have
linked inadequate status of selenium to increased risk of
cancer. The protective action of selenium is a combination
of various mechanisms. Amongst all the diverse mechanism that
have been proposed some important ones are (a) Protective
role of selenoproteins / selenoenzymes (b) induction of apoptosis
(c) immune system effects (d) detoxification of antagonistic
metals (e) inactivation of nuclear transcription factor (f)
regulation of lipoxygenases (g) effect on advanced cancer
condition (h) reduction of oxidative stress (i) induction
of Phase II enzymes (j) androgen receptor down regulation
(k) inhibition of DNA adduct formation (l) cell cycle arrest.
The purpose of this review is to focus the recent development
in the field of cancer prevention utilizing selenium. The
metabolism of selenium compounds , carcinogenesis studies,
epidemiological data, and various proposed chemopreventive
mechanisms of selenium compounds along with results of human
intervention trials have been discussed.
[Back to top]
Critical Parameters for Genome Editing Using Zinc
Finger Nucleases
Todd D. Camenisch, Murray H. Brilliant and David
J. Segal
The possibility to make precise modifications to the
genome at high frequency holds tremendous potential for biotechnology,
conventional drug development and gene therapy. Homologous
recombination is a powerful method for introducing such modifications
in organisms such as mice. However, in mammals and plants,
the frequency of gene modification by homologous recombination
is quite low, precluding the therapeutic use of this methodology.
In the past few years, tremendous progress has been made in
overcoming one of primary barriers to efficient recombination,
namely the introduction of a targeted double-strand break
near the intended recombination site. This review will discuss
the advances in engineering custom zinc-finger nucleases and
their application in stimulating homologous recombination
in higher eukaryotic cells at efficiencies approaching 1 in
2 cells.
[Back to top]
Suppression of Cancer Invasiveness by Dietary Compounds
Daniel Sliva
Tumor invasion and cancer metastasis are interrelated
processes involving cell growth, cell adhesion, cell migration
and proteolytic degradation of tissue barriers, which are
mediated by aberrant intracellular signaling in cancer cells.
Natural (green tea polyphenols, soy isoflavones) or dietary
compounds (mushroom G. lucidum) markedly decreased
AP-1 and NF-κB
signaling and suppressed invasiveness of cancer cells. This
review will summarize alternative approaches for the inhibition
of invasive behavior of cancer cells by dietary compounds,
which can be considered in adjuvant or combination therapy
for the prevention and treatment of cancer metastasis.
[Back to top]
Pharmacological Strategies for Neuroprotection in
Traumatic Brain Injury
J.S. Jennings, A.M. Gerber and M.L.
Vallano
Traumatic brain injury affects over a million Americans
annually, but pharmacological therapy remains limited. Current
standards of care in acute, subacute and chronic phases of
injury are primarily supportive. This review discusses pharmacological
strategies and future directions in patient treatment emphasizing
pleiotropic agents targeting inflammation, oxidative damage,
and glutamate excitotoxicity.
[Back to top]
Development of 11β-HSD1
Inhibitors for the Treatment of Type 2 Diabetes
Clarence Hale and Minghan Wang
Glucocorticoid action is linked to the development of
obesity and insulin resistance. Inhibition of 11β-hydroxysteroid
dehydrogenase type 1 (11β-HSD1)
has been proposed as a strategy to suppress glucocorticoid
action in a tissue-specific manner. A large variety of 11β-HSD1
inhibitor classes are under investigation by the pharmaceutical
industry to treat type 2 diabetes and obesity.
[Back to top]
The Development of Pro-Apoptotic Cancer Therapeutics
Noha I. Ziedan, Hachemi Kadri and Andrew
D. Westwell
Resistance to apoptosis is one of the fundamental hallmarks
of cancer. Recently, the selective induction of apoptosis
in cancer cells has emerged as an exciting possibility for
the development of future selective cancer therapy. This review
will summarise the development of the major classes of small
molecule “proapoptotic” antitumour agents.
[Back to top]
On The Edge of Validation – Cancer Protease
Fibroblast Activation Protein
Beni B. Wolf, Clifford Quan, Thuy Tran, Christian
Wiesmann and Daniel Sutherlin
Numerous studies implicate the prolyl peptidase, fibroblast
activation protein (FAP) in tumorigenesis; however, FAP-selective
inhibitors have not yet been developed to fully validate FAP
as a therapeutic target. Herein, we review recent efforts
aimed at validating and inhibiting FAP for cancer therapy
and highlight future directions for successful targeting of
this prolyl peptidase.
[Back to top]
Radiolabeled Glucocorticoids as Molecular Probes for
Imaging Brain Glucocorticoid Receptors by Means of Positron
Emission Tomography (PET)
Björn Steiniger, Torsten Kniess, Ralf Bergmann,
Jens Pietzsch and Frank R. Wuest
Over the last two decades, numerous attempts have been
made to develop 11C- and
18F-labeled radiotracers
in order to study glucocorticoid receptor (GR)-mediated abnormalities
of the hypothalamus-pituitary-adrenocortical (HPA) axis function
and regulation in vivo by means of positron emission
tomography (PET). The present review addresses the research
efforts dealing with the design, radiosynthesis and radiopharmacological
evaluation of PET radiotracers for brain GR imaging. The underlying
problems such as metabolic instability, insufficient blood-brain-barrier
penetration and / or high non-specific binding will be discussed.
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