| Mini-Reviews
in Medicinal Chemistry
ISSN: 1389-5575
Mini-Reviews in Medicinal
Chemistry
Volume 7, Number 6, June 2007
Contents
Allosteric Enhancers for A1
Adenosine Receptor Pp. 559-569
Pier Giovanni Baraldi, Maria Antonietta Iaconinoto, Allan
R. Moorman, Maria Dora Carrion, Carlota Lopez Cara, Delia
Preti, Olga Cruz López, Francesca Fruttarolo, Mojgan
Aghazadeh Tabrizi and Romeo Romagnoli
[Abstract]
Natural Peroxy Anticancer Agents Pp.
571-589
Valery M. Dembitsky, Tatyana A. Gloriozova and Vladimir
V. Poroikov
[Abstract]
New Perspectives in the Management of Secondary Hyperparathyroidism
Pp. 591-598
Francesco Locatelli, Monica Limardo and Giuseppe Pontoriero
[Abstract]
Back to the Future: COX-2 Inhibitors for Chemoprevention
and Cancer Therapy Pp. 599-608
Fazlul H. Sarkar, Shreelekha Adsule, Yiwei Li and Subhash
Padhye
[Abstract]
A Search for Inhibitors of S100B, a Member of the
S100 Family of Calcium-Binding Proteins Pp. 609-616
Joseph Markowitz, Alexander D. MacKerell Jr. and David
J. Weber
[Abstract]
New Opportunities for Pregnane X Receptor (PXR) Targeting
in Drug Development. Lessons from Enantio- and Species-Specific
PXR Ligands Identified from A Discovery Library of Amino Acid
Analogues Pp. 617-625
Peter Wipf, Haibiao Gong, Jelena M. Janjic, Song Li, Billy
W. Day and Wen Xie
[Abstract]
DNA Intercalators in Cancer Therapy: Organic and Inorganic
Drugs and Their Spectroscopic Tools of Analysis Pp.
627-648
Nial J. Wheate, Craig R. Brodie, J. Grant Collins, Sharon
Kemp and Janice R. Aldrich-Wright
[Abstract]
Angiogenesis and Metastasis Inhibitors for the Treatment
of Malignant Melanoma Pp. 649-661
Riichiro Abe, Yasuyuki Fujita and Sho-ichi Yamagishi
[Abstract]
Abstracts
[Back to top]
Allosteric Enhancers for A1
Adenosine Receptor
Pier Giovanni Baraldi, Maria Antonietta Iaconinoto, Allan
R. Moorman, Maria Dora Carrion, Carlota Lopez Cara, Delia
Preti, Olga Cruz López, Francesca Fruttarolo, Mojgan
Aghazadeh Tabrizi and Romeo Romagnoli
Allosteric enhancers at the adenosine A1
receptor have received attention as anti-arrhythmic cardiac
agents, and, more recently, as anti-lipolytic agents. In addition,
allosteric modulators at the adenosine A1
receptor have therapeutic potential as analgesics and neuroprotective
agents. In particular, the compounds with improved potency
as enhancers and reduced antagonist properties are mentioned.
[Back to top]
Natural Peroxy Anticancer Agents
Valery M. Dembitsky, Tatyana A. Gloriozova and Vladimir
V. Poroikov
Present review describes research on novel natural anticancer
agents isolated from terrestrial and marine sources. More
than 120 cytotoxic anticancer compounds have shown confirmed
activity in vitro tumor cell lines bioassay and are
of current interest to Natural Cancer Institute for further
in vivo evaluation. Intensive searches for new classes
of pharmacologically potent agents produced by terrestrial
and marine organisms have resulted in the discovery of dozens
of compounds possessing high cytotoxic activities. However,
only a limited number of them have been tested in pre-clinical
and clinical trials. One of the reasons is a limited supply
of the active ingradients from the natural sources. However,
the pre-clinical and clinical development of many terrestrial
and/or marine-derived natural products into pharmaceuticals
is often hampered by a limited supply from the natural source.
Total synthesis is of vital importance in these situations,
allowing for the production of useful quantities of the target
compound for further biological evaluation. With computer
program PASS some additional biological activities are also
predicted, which point toward new possible applications of
these compounds. This review emphasizes the role of terrestrial
and marine peroxides as an important source of leads for drug
discovery.
[Back to top]
New Perspectives in the Management of Secondary Hyperparathyroidism
Francesco Locatelli, Monica Limardo and Giuseppe Pontoriero
The traditional treatment of secondary hyperparathyroidism,
which affects many patients with chronic kidney disease and
is associated with an increased risk of morbidity and mortality,
is not very effective. Recent approaches to its management
include the use of vitamin D analogues, non-calcium non-aluminium
containing phosphate binders, and calcimimetics.
[Back to top]
Back to the Future: COX-2 Inhibitors for Chemoprevention
and Cancer Therapy
Fazlul H. Sarkar, Shreelekha Adsule, Yiwei Li and Subhash
Padhye
For more than a century, inhibition of prostaglandin biosynthesis
via inhibition of the fatty acid cyclooxygenase (COX)
has been achieved by non-steroidal anti-inflammatory drugs
(NSAIDs), which targets both COX-1 and COX-2 and as such could
be responsible for causing gastrointestinal (GI) toxicity.
COX-2 is an inducible enzyme produced by many cell types in
response to multiple stimuli. Recently, COX-2 over-expression
has been found in several types of human cancers such as colon,
breast, prostate and pancreas and appears to control many
cellular processes. Because of its role in carcinogenesis,
apoptosis, and angiogenesis, it is an excellent target for
developing new drugs with selectivity for prevention and/or
treatment of human cancers. Development of selective COX-2
inhibitors has been successfully documented and as such showed
less toxicity to GI tract as compared to conventional NSAIDs.
However, the long term use of COX-2 selective inhibitors showed
cardiovascular toxicity, and thus their utilization for cancer
prevention and therapy is currently questionable, suggesting
that further development of novel COX-2 selective agents are
needed. Among many solid tumors, pancreatic cancer has the
worst prognosis, and inflammation has been identified as a
significant factor in the development of pancreatic malignancy.
Several cytokines, reactive oxygen species (ROS) and mediators
of inflammatory pathway such as activation of nuclear factor-kappaB
(NF-κB)
and COX-2 leads to an increase in cell proliferation, survival,
and inhibition of pro-apoptotic pathway, ultimately resulting
in tumor angiogenesis, invasion and metastasis. In this brief
review, we summarize the role of COX-2 and discuss some of
the experimental data linking inflammation with the development
of pancreatic cancer. In addition, we provide further evidence
regarding the state of our knowledge toward the development
of novel COX-2 targeting agents for the prevention and/or
treatment of human cancers especially pancreatic cancer.
[Back to top]
A Search for Inhibitors of S100B, a Member of the
S100 Family of Calcium-Binding Proteins
Joseph Markowitz, Alexander D. MacKerell Jr. and David
J. Weber
Typically, malignant melanoma has wild-type p53, and yet this
cancer proliferates. S100B, which binds p53 and is up-regulated
in melanoma, down-regulates wild-type p53 tumor suppressor
function. Inhibitors of the S100B-p53 interaction were identified
using computer aided drug design (CADD) combined with NMR
methodologies and represent potentially new chemotherapeutics
for melanoma.
[Back to top]
New Opportunities for Pregnane X Receptor (PXR) Targeting
in Drug Development. Lessons from Enantio- and Species-Specific
PXR Ligands Identified from A Discovery Library of Amino Acid
Analogues
Peter Wipf, Haibiao Gong, Jelena M. Janjic, Song Li, Billy
W. Day and Wen Xie
Nuclear hormone receptors (NHRs) are transcription factors
that bind to lipophilic signaling molecules (ligands), and
subsequently regulate the expression of target genes. Since
NHR ligands have potential as therapeutic agents, one of the
most active research areas in the NHR field is the synthesis
and identification of small molecule ligands for NHRs. Wipf
et al. have recently reported the creation of a discovery
library using a new method for the synthesis of homoallylic
amides, allylic amides and C-cyclopropylalkylamides.
This article is intended to review the use of this discovery
library to screen for activators for the pregnane X receptor
(PXR), a master xenobiotic receptor that regulates the expression
of Phase I and Phase II enzymes as well as drug transporters.
Our screening of the discovery library identified potent PXR
activators whose carbon scaffolds are distinct from the chemical
structures of known PXR agonists. Moreover, we found that
enantiomers of the same compound show a species-specific activation
of PXR. The development of the discovery library and the implications
of enantiospecificity of PXR ligand design represent the primary
focus of this account.
[Back to top]
DNA Intercalators in Cancer Therapy: Organic and Inorganic
Drugs and Their Spectroscopic Tools of Analysis
Nial J. Wheate, Craig R. Brodie, J. Grant Collins, Sharon
Kemp and Janice R. Aldrich-Wright
Since the discovery of the DNA intercalation process by Lerman
in 1961 thousands of organic, inorganic octahedral (particularly
ruthenium(II) and rhodium(III)) and square-planar (particularly
platinum(II)) compounds have been developed as potential anticancer
agents and diagnostic agents. The design and synthesis of
new drugs is focused on bis-intercalators which have two intercalating
groups linked via a variety of ligands, and synergistic
drugs, which combine the anticancer properties of intercalation
with other functionalities, such as covalent binding or boron-cages
(for radiation therapy). Advances in spectroscopic techniques
mean that the process of DNA intercalation can be examined
in far greater detail than ever before, yielding important
information on structure-activity relationships. In this review
we examine the history and development of DNA intercalators
as anticancer agents and advances in the analysis of DNA-drug
interactions.
[Back to top]
Angiogenesis and Metastasis Inhibitors for the Treatment
of Malignant Melanoma
Riichiro Abe, Yasuyuki Fujita and Sho-ichi Yamagishi
Malignant melanoma is one of the most highly invasive
and metastatic tumors. Melanoma is an increasingly common
malignancy as well, and its mortality rates have been rapidly
increasing above those of any other cancer in recent years.
Surgical resection and systemic chemotherapy are the main
therapeutic strategies for the treatment of malignant melanoma.
However, these approaches are insufficiently effective and
may be associated with significant adverse effects. Angiogenesis,
a process by which new vascular networks are formed from pre-existing
capillaries, is required for tumors to grow, invade and metastasize.
Tumor vessels are genetically stable, and less likely to accumulate
mutations that allow them to develop drug resistance in a
rapid manner. Therefore, targeting vasculatures that support
tumor growth, rather than cancer cells, is considered the
most promising approach to malignant melanoma therapy. Now,
novel anti-angiogenic agents with tolerable side effects is
actually desired for the treatment of patients with malignant
melanoma. In this paper, we review the current understanding
of anti-angiogenic therapy for malignant melanoma, especially
focusing on pigment epithelium-derived factor (PEDF), which
was recently identified as the most potent endogenous inhibitor
of angiogenesis in the mammalian eye. We also discuss here
the involvement of a receptor for advanced glycation end products
(RAGE) in angiogenesis, melanoma growth and metastasis, and
the therapeutic implications of the blockers of RAGE in this
devastating disorder.
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