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Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 13, Number 8, 2006
Contents
Antiangiogenesis Drug Design: Multiple Pathways Targeting
Tumor Vasculature Pp. 849-862
Haizhen Zhong and J. Phillip Bowen
[Abstract]
Destroying RNA as a Therapeutic Approach Pp. 863-881
Alaeddin Tafech, Tyler Bassett, Dan Sparanese and Chow
H. Lee
[Abstract]
Cell Life Versus Cell Longevity: The Mysteries Surrounding
the NAD+ Precursor Nicotinamide Pp.
883-895
Faqi Li, Zhao Zhong Chong and Kenneth Maiese
[Abstract]
Luminescent Quantum Dots: A Very Attractive and Promising
Tool in Biomedicine Pp. 897-909
Jifang Weng and Jicun Ren
[Abstract]
The HIV Entry Inhibitors Revisited Pp. 911-934
J. Thomas Leonard and Kunal Roy
[Abstract]
Epigenetic Control Using Natural Products and Synthetic
Molecules Pp. 935-958
Takayoshi Suzuki and Naoki Miyata
[Abstract]
Application of Radioisotopes in Inflammation Pp.
959-965
A.R. Jalilian, M. Bineshmarvasti and S. Sardari
[Abstract]
Inhibition of Fatty Acid Synthase by Polyphenols Pp.
967-977
Wei-Xi Tian
[Abstract]
Abstracts
[Back to top]
Antiangiogenesis Drug Design: Multiple
Pathways Targeting Tumor Vasculature
Haizhen Zhong and J. Phillip Bowen
The initiation, growth, and development of new blood vessels
through angiogenesis are essential for tumor growth.
Tumor masses require access to blood vessels for a sufficient
supply of oxygen and nutrients to maintain growth and metastasis.
Inhibiting tumor blood vessel formation as proposed by Judah
Folkman in the early 1970s, therefore, offers promising therapeutic
approaches for treating tumor afflicted patients. The blood
vessel growth in normal tissues is regulated though a delicate
and complex balance between the collective action of proangiogenic
factors (e.g., vascular endothelial growth factor, VEGF) and
the collective action of angiogenic inhibitors (e.g., thrombospondin-1).
In pathological angiogenesis, the angiogenic switch
is shifted toward the proangiogenic factors, and if the imbalance
continues, irregular tumor vessel growth is the result. Despite
intense research, the mechanism of the angiogenic switch
is not fully understood. Many factors, however, have been
shown to be involved in regulating the equilibrium between
angiogenic stimulants and inhibitors. VEGFR tyrosine kinase,
methionine aminopeptidase-2 (MetAP-2), p53, tubulin, cyclooxygenase-2
(COX-2), and matrix metalloproteinases (MMPs) all directly
and/or indirectly influence the angiogenic switch.
This review will describe some of the advances in inhibitor
design and the mechanisms of action for the aforementioned
factors (targets) involved in angiogenesis regulation. Our
discussion reveals that a diaryl group separated by various
connecting modules is one of the most common features for
antiangiogenesis drug design. This idea has been a working
pharmacophore hypothesis for our own antiangiogenic drug design
endeavors over the years. The recent advances of combination
therapy (angiogenesis inhibitors with other chemotherapy/radiation)
are also discussed.
[Back to top]
Destroying RNA as a Therapeutic Approach
Alaeddin Tafech, Tyler Bassett, Dan Sparanese and Chow
H. Lee
The ability to target RNA, mRNA and viral RNA in particular,
for degradation is a powerful approach in molecular biology
and pharmacology. Such approaches can be used in the study
of gene function as in functional genomics, in the identification
of disease-associated genes, and for the treatment of human
diseases. This review provides a comprehensive up-to-date
look at all the current available technologies used for the
destruction of RNA, with a focus on their therapeutic potential.
This includes approaches that utilize the activity of protein
ribonucleases such as antisense oligonucleotide, small interfering
RNA, RNase P-associated external guide sequence, onconase
and bovine seminal RNase. Sequence-specific approaches that
do not utilize activity of protein ribonucleases, such as
ribozyme and DNazyme, are also reviewed and discussed. This
review should provide a useful starting framework for researchers
interested in using the RNA-destruction methodologies on the
bench and in the clinic, and serves as a stimulus for further
development of novel and more potent RNA degradation technologies.
This is particularly critical, given the anticipation of discoveries
of new cellular RNA degradation machineries and human diseases
that are associated with dysfunctional RNA molecules.
[Back to top]
Cell Life Versus Cell Longevity: The Mysteries
Surrounding the NAD+ Precursor Nicotinamide
Faqi Li, Zhao Zhong Chong and Kenneth Maiese
Nicotinamide, the amide form of niacin (vitamin B3),
is the precursor for the coenzyme β-nicotinamide
adenine dinucleotide (NAD+) and plays a significant
role during the enhancement of cell survival as well as cell
longevity. Yet, these abilities of nicotinamide appear to
be diametrically opposed. Here we describe the development
of nicotinamide as a novel agent that is critical for modulating
cellular metabolism, plasticity, longevity, and inflammatory
microglial function as well as for influencing cellular life
span. The capacity of nicotinamide to govern not only intrinsic
cellular integrity, but also extrinsic cellular inflammation
rests with the modulation of a host of cellular targets that
involve mitochondrial membrane potential, poly(ADP-ribose)
polymerase, protein kinase B (Akt), Forkhead transcription
factors, Bad, caspases, and microglial activation. Further
knowledge acquired in regards to the ability of nicotinamide
to foster cellular survival and regulate cellular lifespan
should significantly promote the development of therapies
against a host of disorders, such as aging, Alzheimer's disease,
diabetes, cerebral ischemia, Parkinson's disease, and cancer.
[Back to top]
Luminescent Quantum Dots: A Very Attractive and Promising
Tool in Biomedicine
Jifang Weng and Jicun Ren
Luminescent semiconductor nanocrystals, also known as quantum
dots (QDs), are generally composed of II-VI and III-V elements.
Due to their quantum confinement of charge carriers in tiny
spaces, QDs show some unique and fascinating optical properties,
and are characterized as sharp and symmetrical emission spectra,
high quantum yields, broad absorption spectra, good chemical
and photo-stability and size dependent emission wavelength
tunability. Recently, QDs have been successfully used as new
fluorescent tags in many biological and biomedical fields,
and will become a new promising tool in biomedical studies,
clinical diagnostics, drug delivery and photodynamic therapy.
In this review, firstly, the methodology of QDs preparation
was introduced, which included organic synthesis, aqueous
synthesis and microwave assisted aqueous synthesis. Secondly,
some procedures for the QDs bio-conjugation with biomarkers
were described. And then, some key applications of QDs were
summarized, which mainly covered biomedical imaging, immunoassay,
DNA hybridization, and photodynamic therapy. Finally, future
prospects were discussed.
[Back to top]
The HIV Entry Inhibitors Revisited
J. Thomas Leonard and Kunal Roy
The new generation of antiviral drugs intended to counter
HIV-1 entry into susceptible cells is emerging swiftly. The
antiviral agents that inhibit HIV entry to the target cells
(denoted as HIV entry inhibitors) are already in different
phases of clinical trials. Operating early in the viral life
cycle, they prevent viral entry, and have a novel, highly
specific mechanism of action with a low toxicity profile.
Entry inhibitors have different toxicity and resistance profiles
than the existing reverse transcriptase and protease inhibitors.
Some of these compounds demonstrated in vitro synergism
with other classes of antivirals, thus offering the rationale
for their combination in therapies for HIV-infected individuals.
It is worth focusing on recent developments in HIV entry inhibitors,
as most of the current drug regimens suffer from the events
of developing resistance against existing combination therapies.
Recent advances in the understanding of the cellular and molecular
mechanisms of HIV-1 entry provide the basis for novel therapeutic
strategies that prevent viral penetration of the target cell-membrane,
while reducing detrimental virus and treatment effects on
cells and prolonging virion exposure to immune defenses. A
number of potential sites for therapeutic intervention become
accessible during the narrow window between virus attachment
and the subsequent fusion of viral envelope with the cell
membrane. The HIV-1 coreceptors are particularly attractive
from the perspective of identifying new antiviral compounds,
since they are seven-transmembrane motif G protein-coupled
receptors (GPCRs), a family of proteins that is a well-validated
target for drug development. Among the many chemokine receptors
that can mediate HIV-1 entry in vitro, only CCR5
and CXCR4 are of frontline pharmacological importance. In
particular, CCR5 is essential for viral transmission and replication
during the early and clinically latent phase of disease. Several
small-molecule antagonists of CCR5 and CXCR4 that block chemokine
binding and HIV-1 entry have been identified in recent years.
Considerable advances have been made in the last years in
the design of derivatives acting as inhibitors of HIV entry.
The molecular mechanism involved in viral entry, the structural
and functional aspects of entry inhibitors are reviewed here.
We have also summarized the recent insights into how small-molecule
antagonists interact with CCR5 and CXCR4, focusing on drug
development programs that are well documented in the scientific
literature. An overview of the entry inhibitors that are in
preclinical or early clinical development, and the Quantitative
Structure-Activity Relationships (QSAR) studies reported for
the coreceptor antagonists are also be presented.
[Back to top]
Epigenetic Control Using Natural Products and Synthetic
Molecules
Takayoshi Suzuki and Naoki Miyata
The term “epigenetics” is defined as “heritable
changes in gene expression that occur without changes in DNA
sequence”. Recently, it has been revealed that DNA methylation
and histone modifications such as acetylation, methylation
and phosphorylation are epigenetic mechanisms according to
this definition. In other words, these posttranslational modifications
are important factors in determining when and where a gene
will be expressed. To date, several enzymes that catalyze
DNA or histone modifications have been identified, such as
DNA methyltransferases and histone deacetylases. Inhibitors
and activators of enzymes controlling epigenetic modifications
are considered useful not only as tools for the elucidation
of cellular and biological phenomena, but also as therapeutic
agents, since disruption of the balance of epigenetic networks
is known to cause some disease states such as cancer. In this
review, we present natural products and synthetic molecules
that inhibit or activate enzymes catalyzing DNA methylation
or histone modifications, and discuss the potential of epigenetic
therapy.
[Back to top]
Application of Radioisotopes in Inflammation
A.R. Jalilian, M. Bineshmarvasti and S. Sardari
Since the discovery of artificially produced radioisotopes
in the 1930’s, an estimated 10-12 million nuclear medicine
diagnostic and therapeutic procedures are currently performed
each year only in the United States. Gamma emission imaging
has been successfully applied to almost every organ of the
body (brain, bone, heart, kidney, lung, neuroreceptors) as
well as sites of inflammation, atherosclerosis, and thrombosis.
FDG-PET has been used in some of the inflammatory diseases
as well. On the other hand, both alpha. and
beta-emitting isotopes have been evaluated for brachytherapy
of rheumatoid diseases, each with different radiobiological
effectiveness. The current status of radionuclides for imaging,
therapy and research studies of inflammatory processes is
reviewed here and a look into the future directions is described
at the conclusion.
[Back to top]
Inhibition of Fatty Acid Synthase by Polyphenols
Wei-Xi Tian
Recently, animal fatty acid synthase (FAS) is reported as
a potential therapeutic target for obesity and cancer. Considerable
interest has been developed in identifying novel inhibitors
of the enzyme. It is found that tea polyphenols inhibit FAS
in both reversible and irreversible manners. Epigallocatechin
gallate (EGCG) and epicatechin gallate (ECG) inhibit FAS with
IC50 values of 52 μM
and 42 μM
mainly by reacting on the β-ketoacyl
reductase (KR) domain of FAS. The inhibitory ability of catechin
gallate (CG) is 15 and 12 folds higher than that of EGCG and
ECG. Its major reacting site on FAS is not KR. All of these
irreversibly inactivate FAS on the KR domain with similar
rates. Mulliken population analysis suggests that the positive
charge is distributed on the carbon atom of galloyl ester,
and this carbon becomes more susceptible for a nucleophilic
attack.
12 flavonoids inhibit FAS with IC50 values ranging
from 2 to 112 μM.
SAR analysis shows that the flavonoids containing two hydroxyl
groups in B ring and 5, 7-hydroxyl groups in A ring with C-2,
3 double bond are the most potent inhibitors. The inhibition
kinetics shows that they inhibit FAS competitively with acetyl
CoA and most likely react mainly on acyl transferase domain.
Further studies show that C ring of flavonoids is not necessary
for the inhibition. Resveratrol, phlorizin and NDGA contain
two phenyl rings connected by 2 to 4 atom chains instead of
C ring. Their IC50 values range from 5 μM to 40μM. From these
results, a common model for polyphenol inhibitor of FAS is
conceived.
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