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Mini-Reviews
in Medicinal Chemistry
ISSN: 1389-5575
Mini-Reviews in Medicinal
Chemistry
Volume 8, Number 5, May 2008
Contents
Novel Anti-Angiogenic Compounds for Application in
Tumor Therapy – COP9 Signalosome-Associated Kinases
as Possible Targets Pp. 421-428
Chris Braumann, Judith Tangermann, Christoph A. Jacobi, Joachim
M. Müller and Wolfgang Dubiel
[Abstract]
Polyphenols as Potential Inhibitors of Amyloid
Aggregation and Toxicity: Possible Significance to Alzheimer’s
Disease Pp. 429-435
S. Bastianetto, S. Krantic and R. Quirion
[Abstract]
Condensed and Hydrolysable Tannins as Antioxidants
Influencing the Health Pp. 436-447
Vit Koleckar, Katerina Kubikova, Zuzana Rehakova, Kamil
Kuca, Daniel Jun, Ludek Jahodar and Lubomir Opletal
[Abstract]
Gene Expression Profiles in Breast Cancer to
Identify Estrogen Receptor Target Genes Pp. 448-454
M.A. Nagai and M.M. Brentani
[Abstract]
Novel Beta-Lactam Antibiotics Derivatives: Their
New Applications as Gene Reporters, Antitumor Prodrugs and
Enzyme Inhibitors Pp. 455-471
Bengang Xing, Jianghong Rao and RongRong Liu
[Abstract]
Methylene Blue and Vasoplegia: Who, When, and
How? Pp. 472-490
S. Peter Stawicki, Carrie Sims, Babak Sarani, Michael
D. Grossman and Vicente H. Gracias
[Abstract]
Future Target Molecules for Influenza Treatment
Pp. 491-495
N. Uchide and H. Toyoda
[Abstract]
E-Cadherin Upregulation as a Therapeutic Goal in Cancer
Treatment Pp. 496-518
E.W. Howard, K.D. Camm, Y.C. Wong and X.H. Wang
[Abstract]
Reactivity-Based Drug Discovery Using Vitamin
B6-Derived
Pharmacophores Pp. 519-528
Georg T. Wondrak
[Abstract]
Carotenoids and Prostate Cancer Risk Pp.
529-537
C.Y.F. Young, H.-Q. Yuan, M.-L. He and J.-Y. Zhang
[Abstract]
Abstracts
[Back to top]
Novel Anti-Angiogenic Compounds for Application in Tumor Therapy
– COP9 Signalosome-Associated Kinases as Possible Targets
Chris Braumann, Judith Tangermann, Christoph A. Jacobi, Joachim
M. Müller and Wolfgang Dubiel
Preclinical studies revealed that curcumin, the yellow
curry pigment, emodin, a compound derived from grapes, and
taurolidine, derived from a biogenic amino acid, and some
of their structural homologs possess anti-angiogenic and cancer
chemopreventive properties. Whereas curcumin and emodin can
act via inhibition of COP9 signalosome-associated
kinases, taurolidine blocks protein biosynthesis.
[Back to top]
Polyphenols as Potential Inhibitors of Amyloid Aggregation
and Toxicity: Possible Significance to Alzheimer’s Disease
S. Bastianetto, S. Krantic and R. Quirion
Beta-amyloid (Aβ)likely
plays a pivotal role in the etiology of Alzheimer’s
disease (AD). Consequently, Aβ
associated pathways are targets for the development of possible
effective AD therapies. This review first updates strategies
aimed at the inhibition of Aβ
formation and then discusses the role of food-derived polyphenols
as putative anti-amyloid drugs.
[Back to top]
Condensed and Hydrolysable Tannins as Antioxidants Influencing
the Health
Vit Koleckar, Katerina Kubikova, Zuzana Rehakova, Kamil
Kuca Daniel Jun, Ludek Jahodar and Lubomir Opletal
Natural polyphenols are a wide class of secondary plant
metabolites and represent an abundant antioxidant component
of human diet. An important, but often neglected group of
natural polyphenols, are tannins. This review offers a general
description of chemistry of both hydrolysable and condensed
tannins (proanthocyanidins), the mechanisms of their antioxidation
action, like free radical scavenging activity, chelation of
transition metals, inhibition of prooxidative enzymes and
lipid peroxidation. The mechanisms of action of antibacterial,
antiviral, anticarcinogenic, cardiovascular system preventing,
and antiinflammatory effects as well as the absorption, metabolic
fate and positive in vivo effects of tannins are
enclosed.
[Back to top]
Gene Expression Profiles in Breast Cancer to Identify Estrogen
Receptor Target Genes
M.A. Nagai and M.M. Brentani
The estrogens play important role in the homeostatic
maintenance of several target tissues including those in the
mammary gland, uterus, bone, cardiovascular system, and brain.
Most of estrogen’s action is thought to be mediated
through its nuclear estrogen receptors, ERα
and ERβ ,
which are members of the nuclear receptor superfamily that
act as ligand-induced transcription factors. Acting via its
receptors, estrogen also plays an essential role in the development
and progression of human breast cancer. The ER and progesterone
receptor (PR), which are regulated by estrogen via ER, have
been used as prognostic markers in the clinical management
of breast cancer patients. However, the prognosis of a patient
with ER+/PR+ breast cancer can be highly variable and a significant
proportion of hormone receptor positive breast cancers does
not respond to endocrine therapy. The identification of estrogen
receptor target genes may improve our understanding of the
role played by estrogens in breast cancer making it possible
to better tailor hormone treatments and improve a patient’s
response to hormonal therapy. In this review, we explore the
literature for data regarding the identification of estrogen
receptor-regulated genes in breast cancer cell lines and breast
tumor biopsies using high throughput technologies such as
serial analysis of gene expression (SAGE) and cDNA microarrays.
[Back to top]
Novel Beta-Lactam Antibiotics Derivatives: Their New Applications
as Gene Reporters, Antitumor Prodrugs and Enzyme Inhibitors
Bengang Xing, Jianghong Rao and RongRong Liu
Since the antibiotic properties of penicillin were first
noticed in the beginning of last century, beta-lactam based
antibiotics have been well developed as miracle drugs for
the therapy of bacterial infectious diseases in clinics. Recently,
these “old” antibiotics and their relevant derivatives
have also found new applications as gene reporters, anti-cancer
prodrugs and enzyme inhibitors. In this review, we will introduce
the latest developments in the study of these new applications
based on literatures reported over the last decade. The first
section covers the recent developments of β-lactam
antibiotics as drugs against bacteria, the second section
briefly discusses the occurrence of bacterial resistance and
mechanistic studies of β-lactam
resistance in bacteria, the third section presents the current
development of fluorogenic cephalosporin based β-lactam
probes for real-time imaging of gene expression, and the fourth
section describes relevant studies on β-lactam
based substrates as anti-tumor prodrugs. Beta-lactam substrates
as protease inhibitors will be also described in the fifth
section. The final section summarizes future perspectives
for β-lactam
antibiotic derivatives as scaffolds in the fields of molecular
imaging, drug delivery and enzymatic assays.
[Back to top]
Methylene Blue and Vasoplegia: Who, When, and How?
S. Peter Stawicki, Carrie Sims, Babak Sarani, Michael
D. Grossman and Vicente H. Gracias
Systemic inflammatory response can be associated with
clinically significant and, at times, refractory hypotension.
Despite the lack of uniform definitions, this condition is
frequently called vasoplegia or vasoplegic syndrome (VS),
and is thought to be due to dysregulation of endothelial homeostasis
and subsequent endothelial dysfunction secondary to direct
and indirect effects of multiple inflammatory mediators. Vasoplegia
has been observed in all age groups and in various clinical
settings, such as anaphylaxis (including protamine reaction),
sepsis, hemorrhagic shock, hemodialysis, and cardiac surgery.
Among mechanisms thought to be contributory to VS, the nitric
oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway appears
to play a prominent role. In search of effective treatment
for vasoplegia, methylene blue (MB), an inhibitor of nitric
oxide synthase (NOS) and guanylate cyclase (GC), has been
found to improve the refractory hypotension associated with
endothelial dysfunction of VS. There is evidence that MB may
indeed be effective in improving systemic hemodynamics in
the setting of vasoplegia, with reportedly few side effects.
This review describes the current state of clinical and experimental
knowledge relating to MB use in the setting of VS, highlighting
the potential risks and benefits of therapeutic MB administration
in refractory hypotensive states.
[Back to top]
Future Target Molecules for Influenza Treatment
N. Uchide and H. Toyoda
Induction of apoptosis and pro-inflammatory cytokine
gene expression in influenza virus-infected cells activates
production of toxic superoxide by macrophages. Pyrrolidine
dithiocarbamate and nordihydroguaiaretic acid inhibit influenza
virus proliferation and scavenge superoxide. These results
suggest that they can be potential candidates for a drug of
choice for influenza chemotherapy.
[Back to top]
E-Cadherin Upregulation as a Therapeutic Goal in Cancer Treatment
E.W. Howard, K.D. Camm, Y.C. Wong and X.H. Wang
We review the role of E-cadherin in cancer progression,
and its therapeutic restoration as a strategy to suppress
metastasis. We subsequently discuss E-cadherin upregulating
drugs, proposing a schema for restoring E-cadherin by targeting
its epigenetic and transcriptional regulators. These pathways
will likely provide significant future treatment breakthroughs
against cancer metastasis.
[Back to top]
Reactivity-Based Drug Discovery Using Vitamin B6-Derived
Pharmacophores
Georg T. Wondrak
Endogenous reactive intermediates including photoexcited
states of tissue chromophores, reactive oxygen species (ROS),
reactive carbonyl species (RCS), transition metal ions, and
Schiff bases have been implicated in the initiation and progression
of diverse human pathologies including tumorigenesis, atherosclerosis,
diabetes, and neurodegenerative disease. In contrast to structure-based
approaches that target macromolecules by selective ligands,
reactivity-based drug discovery uses chemical reagents as
therapeutics that target reactive chemical species involved
in human pathology. Reactivity-based design of prototype agents
that effectively antagonize, modulate, and potentially even
reverse the chemistry underlying tissue damage from oxidative
and carbonyl stress therefore holds great promise in delivering
significant therapeutic benefit. Apart from its established
role as an essential cofactor for numerous enzymes, a large
body of evidence suggests that B6-vitamers
contain reactive pharmacophores that mediate therapeutically
useful non-vitamin drug actions as potent antioxidants, metal
chelators, carbonyl scavengers, Schiff base forming agents,
and photosensitizers. Based on the fascinating chemical versatility
of B6 -derived pharmacophores,
B6 vitamers are therefore
promising lead compounds for reactivity-based drug design.
[Back to top]
Carotenoids and Prostate Cancer Risk
C.Y.F. Young, H.-Q. Yuan, M.-L. He and J.-Y. Zhang
Chemoprevention is presumably one of most effective means
to combat prostate cancer (PCa). Patients usually require
more than a decade to develop a clinically significant Pca,
therefore, an ideal target for chemoprevention. This review
will focus on recent findings of a group of naturally occurring
chemicals, carotenoids, for potential use in reducing PCa
risk.
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