| Current
Bioactive Compounds
ISSN: 1573-4072
Current Bioactive Compounds
Volume 5, Number 1, March 2009
Contents
Natural Product Inspired Small Molecular Scaffolds
in Anticancer Therapy
Guest Editor: Jetze J. Tepe
Editorial Pp. 1
Phenanthroindolizidines and Phenanthroquinolizidines:
Promising Alkaloids for Anti-Cancer TherapyPp. 2-19
Sherry R. Chemler
[Abstract] [Full
text article]
3-Substituted-3-hydroxy-2-oxindole, an Emerging New
Scaffold for Drug Discovery with Potential Anti-Cancer and
other Biological Activities Pp. 20-38
Satyamaheshwar Peddibhotla
[Abstract] [Full
text article]
2-Aminoimidazoles from Leucetta
Sponges: Synthesis and Biology of an Important Pharmacophore
Pp. 39-78
J.D. Sullivan, R.L. Giles and R.E.
Looper
[Abstract] [Full
text article]
Anticancer Agents: VTA or VDA Pp.
79-97
Paul R. Sebahar, J. Adam Willardsen and
Mark B. Anderson
[Abstract] [Full
text article]
Abstracts
[Back to top]
Editorial: Natural Product Inspired Small Molecular
Scaffolds in Anticancer Therapy
Natural products isolated from plant, animal or fermentation
have long been the main source for the chemotherapeutic intervention
of cancer. However, in the later part of the 20th
century, the advances of combinatorial chemistry have taken
centerstage in the drug discovery process and natural product
synthesis took a temporary backseat for these new chemical
processes. Combinatorial techniques have resulted into large
libraries in a very cost-efficient manner that can be screened
for their biological activities. However, only a surprising
low number of compounds found in such libraries have advanced
to an FDA approved drug. This relative low success rate is
primarily due to the lack of diveristy of new scaffolds with
respect to their structural complexity, stereochemistry and
chemical space. During the last decade, diversity oriented
synthesis of small molecule libraries has become increasingly
important in the search and development of new pharmaceutical
leads. New synthetic methods are allowing for efficient and
rapid production of highly diverse libraries of small yet
complex molecules that can be screened for biological relevance.
Screening of these libraries does not only lead to the identification
of new drug leads, but also to potential new therapeutic protein
targets and protein-drug interaction. These new leads can
subsequently be optimized, by combinatorial chemistry, to
generate new drug candidates.
In order to maximize the potential of new scaffold libraries,
the combination of natural product synthesis and diveristy-oriented
synthesis has resulted in a renewed focus on natural product
inspired design of small molecule scaffolds. In this approach,
common structural features found in natural product pharmacophores,
are incorporated in a new scaffold libraries and tested for
its biological relevance. In this context, the present issue
highlights some of the recent trends with emphasis on natural
product inspired scaffold syntheses.
Jetze J. Tepe
Department of Chemistry
College of Natural Sciences
Michigan State University
East Lansing, MI 48824
USA
Tel: 517-355-9715, Ext. 147
Fax: 517-353-1793
E-mail: tepe@chemistry.msu.edu
URL: http://www.chemistry.msu.edu/faculty/tepe/default.shtml
[Back to top]
Phenanthroindolizidines and Phenanthroquinolizidines: Promising
Alkaloids for Anti-Cancer Therapy
Sherry R. Chemler
[Full
text article]
The phenanthroindolizidine and phenanthroquinolizidine
alkaloids, typified by tylophorine and cryptopleurine, are
a family of plant-derived small molecules with significant
therapeutic potential. The plant extracts have been used in
herbal medicine and the isolated compounds have displayed
a range of promising therapeutic activity such as anti-ameobicidal,
anti-viral, anti-inflammatory and anti-cancer activity. Despite
their therapeutic protential, no compounds in this class have
fully passed clinical trials. Drawbacks include low in
vivo anti-cancer activity, central nervous system toxicity
and low natural availability. A number of biological effects
of these compounds, such as protein and nucleic acid synthesis
suppression, have been identified, but the specific biomolecular
targets have not yet been identified. Significant effort has
been expended in the synthesis and structure-activity-relationship
(SAR) studies of these compounds with the hope that a new
drug will emerge. This review will highlight important contributions
to the isolation, synthesis, SAR and mechanism of action of
the phenanthroindolizidine and pheanthroquinolizidine alkaloids.
[Back to top]
3-Substituted-3-hydroxy-2-oxindole, an Emerging New Scaffold
for Drug Discovery with Potential Anti-Cancer and other Biological
Activities
Satyamaheshwar Peddibhotla
[Full
text article]
Natural products and small molecules inspired by them
are enjoying a resurgence of interest because they intersect
biological space effectively and selectively. On account of
their unprecedented structural diversity and biological activities
oxindole natural products continue to attract the interest
of chemists and biologists alike. Quarternary or spirocyclic
3-alkyl(aryl)-3-hydroxy-2-oxindole scaffold is at the core
of several natural products with a wide spectrum of biological
activities. Convolutamydines, arundaphine, donaxaridine, maremycins,
paratunamide, celogentin K, TMC-95A-D, neuroprotectin B, flustraminol
A and B, 3-hydroxy welwitindolinones and pyrrolidinoindoline-type
alkaloid, CPC-1 are some examples of a growing list of bioactive
3-substituted-3-hydroxy-2-oxindole natural products. Simultaneous
with the extraordinary progress in the development of selective
synthetic methods, a number of drug discovery programs have
now started to recognize the importance of this ‘privileged’
scaffold, because of the potent anti-oxidant, anti-cancer,
anti-HIV, neuroprotective and other biological properties
and diverse modes of action of this class of natural products
and analogs inspired by them. There is strong impetus for
the continued synthesis of novel diversity libraries based
on the 3-substituted-3-hydroxy-2-oxindole core for the potential
treatment of proliferative and other diseases and a clear
understanding of underlying cellular pathways involved. In
fact, this process is well underway as exemplified by the
recent synthesis of novel spirocyclic tetrahydrofuran- and
isoxazolidine-2-oxindole libraries capable of achieving growth
inhibition of lung adenocarcinoma (A549) cells, hepatocellular
carcinoma (HepG2) cells and human breast cancer cell line,
MCF-7. This review covers the isolation, diverse structure,
activity, synthesis, and known medicinal chemistry of 3-substituted-3-hydroxy-2-oxindoles.
Bioactive natural products and small-molecules built around
a 3 substituted-3-hydroxy-2-oxindole core scaffold.
[Back to top]
2-Aminoimidazoles from Leucetta Sponges: Synthesis
and Biology of an Important Pharmacophore
J.D. Sullivan, R.L. Giles and R.E.
Looper
[Full
text article]
This review will focus on the ability of the 2-aminoimidazole
to occupy a unique subset of chemical space which makes it
an ideal pharmacophore for the development of small molecule
collections for discovery based research. These observations
rely both on the use of 2 aminoimidazoles as building blocks
in medicinal chemistry as well as the recent discovery of
alkaloids from sponges of the genus Leucetta which
exhibit a diverse range of biological activities around a
relatively limited structural core. The preparation of these
compounds will also be highlighted.
[Back to top]
Anticancer Agents: VTA or VDA
Paul R. Sebahar, J. Adam Willardsen and
Mark B. Anderson
[Full
text article]
The tumor vasculature is quite an attractive target for
anti-cancer/anti-tumor therapy because the blood vessels provide
the route for nutrient/waste and oxygen/carbon dioxide exchanges
as well as a convenient route for tumor metastatic spread.
The complex interplay of the tumor with the local blood vasculature
is intriguing. Targeting the vasculature in an effort to control
the tumor life cycle is therefore very complex yet enticing
as a treatment option. In reviewing the literature discussing
vascular targeting/disrupting agents, it is sometimes less
than clear as to what exactly defines or differentiates a
vascular targeting agent (VTA; antiangiogenic or stopping
tumors from producing new blood vessels) from a vascular disrupting
agent (VDA; disrupting the "established" tumor vasculature).
Although, there appears to be differences between these two
strategies of modifying the tumor vasculature including differences
in the administration schedules. The use of the VTA/VDA terms
in scientific reports is not always clear since some agents
may also exhibit activities attributed to a VTA and/or a VDA.
However these agents are defined, the important goal is to
severely cripple and/or "shut-down" the tumor's
ability to maintain viability and to subsequently become metastatic
and hence are important in the armamentarium of anti-tumor/anti-cancer
treatment strategies. This brief review of selected literature
reports attempts to summarize some of the chemical structural
elements associated with these types of agents and asks the
question "Are there common chemical structural features
emerging that may assist in a differentiating theme?"
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