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Anti-Cancer
Agents in Medicinal Chemistry
(Formerly 'Current Medicinal Chemistry - Anti-Cancer Agents')
ISSN: 1871-5206
Anti-Cancer Agents in Medicinal
Chemistry
Volume 9, Number 2, February 2009
Contents
Marine Macrolides, a Promising Source of Antitumor Compounds
Pp. 122-137
J.G. Napolitano, A.H. Daranas, M. Norte
and J.J. Fernández
[Abstract] [Purchase
Article] [PMID: 19199861 PubMed - indexed for MEDLINE]
Quercetin and Its Derivatives: Synthesis, Pharmacological
Uses with Special Emphasis on Anti-Tumor Properties and Prodrug
with Enhanced Bio-Availability Pp. 138-161
K.V. Hirpara, P. Aggarwal, A.J. Mukherjee, N.
Joshi and A.C. Burman
[Abstract] [Purchase
Article] [PMID: 19199862 PubMed - indexed for MEDLINE]
Importance and Limitations of Chemotherapy
Among the Available Treatments for Gastrointestinal Tumours
Pp. 162-184
J.J.G. Marin, M.R. Romero, A.G. Blazquez,
E. Herraez, E. Keck and O. Briz
[Abstract] [Purchase
Article] [PMID: 19199863 PubMed - indexed for MEDLINE]
Copper Complexes as Anticancer Agents
Pp. 185-211
C. Marzano, M. Pellei, F. Tisato and
C. Santini
[Abstract] [Purchase
Article] [PMID: 19199864 PubMed - indexed for MEDLINE]
Role of Tyrosine Phosphatase Inhibitors
in Cancer Treatment with Emphasis on SH2 Domain-Containing
Tyrosine Phosphatases (SHPs) Pp. 212-220
M. Irandoust, T.K. van den Berg, G.J.L.
Kaspers and J. Cloos
[Abstract] [Purchase
Article] [PMID: 19199865 PubMed - indexed for MEDLINE]
From Concept to Reality: The Long Road
to c-Met and RON Receptor Tyrosine Kinase Inhibitors for the
Treatment of Cancer Pp. 221-229
I. Dussault and S.F. Bellon
[Abstract] [Purchase
Article] [PMID: 19199866 PubMed - indexed for MEDLINE]
Molecular Modeling Applied to Anti-Cancer
Drug Development Pp. 230-238
M.C. Rosales-Hernandez, J. Bermúdez-Lugo,
J. Garcia, J. Trujillo-Ferrara and J. Correa-Basurto
[Abstract] [Purchase
Article] [PMID: 19199867 PubMed - indexed for MEDLINE]
2-Deoxy-D-Ribose, a Downstream Mediator
of Thymidine Phosphorylase, Regulates Tumor Angiogenesis and
Progression Pp. 239-245
Y. Nakajima, R. Madhyastha and M.
Maruyama
[Abstract]
[Purchase
Article] [PMID: 19199868 PubMed - indexed for MEDLINE]
Abstracts
[Back to top]
[Purchase
Article] [PMID: 19199861 PubMed - indexed for MEDLINE]
Marine Macrolides, a Promising Source
of Antitumor Compounds
J.G. Napolitano, A.H. Daranas, M. Norte
and J.J. Fernández
Marine organisms have attracted scientific community
as a rich source of natural products with unusual structural
features and remarkable biological activities. Marine macrolides
are a prominent class of natural products characterized by
a highly oxygenated polyene backbone containing a macrocyclic
lactone as a conformational constraint. Many marine macrolides
possess outstanding cell growth antiproliferative properties,
making them valuable molecular probes for the investigation
of biochemical pathways and promising lead compounds for the
development of new antitumor chemotherapeutic agents. In the
present review we intend to focus on marine macrolides with
potent cytotoxic activity that could be exploited in cancer
research and therapy, along with those macrolides currently
in clinical trials and/or preclinical development.
[Back to top] [Purchase
Article] [PMID: 19199862 PubMed - indexed for MEDLINE]
Quercetin and Its Derivatives: Synthesis, Pharmacological
Uses with Special Emphasis on Anti-Tumor Properties and Prodrug
with Enhanced Bio-Availability
K.V. Hirpara, P. Aggarwal, A.J. Mukherjee, N.
Joshi and A.C. Burman
Cancer is one of the leading causes of death in the world.
American Cancer Society reported 12 million new cases of malignancy
diagnosed worldwide in 2007, with 7.6 million people dying
from the disease. Plant-derived molecules have played an important
role in cancer chemotherapy. Many cytotoxic plant-derived
molecules such as vinblastine, vincristine, navelbine, etoposide,
teniposide, taxol, taxotere, topotecan and irinotecan have
been approved as anticancer drugs. Flavonoids, a plant-derived
molecule has shown to regulate proliferation and cell death
pathways leading to cancer. Some Flavonoids have already entered
in clinical trials, among them Quercetin is emerging as prospective
anticancer drug candidates and its prodrug QC12 has entered
in phase-I clinical studies. In this review authors have tried
to cover in brief but comprehensive way, the chemistry related
to synthesis and uses of “Quercetin &
its derivatives” with special emphasis on the anticancer
properties.
[Back to top]
[Purchase Article] [PMID: 19199863 PubMed - indexed for MEDLINE]
Importance and Limitations of Chemotherapy Among the Available
Treatments for Gastrointestinal Tumours
J.J.G. Marin, M.R. Romero, A.G. Blazquez,
E. Herraez, E. Keck and O. Briz
Gastrointestinal tumours constitute one of the worldwide
leading causes of death. One important limitation in the battle
against these types of cancer is their lack of sensitivity
to currently available chemotherapy and the development of
drug resistance during treatment. The mechanisms responsible
for this refractivity include a reduction in drug uptake,
enhanced drug export, intracellular inactivation of the effective
agent, alteration of the molecular target, an increase in
the activity of the target route to be inhibited or the appearance
or stimulation of alternative routes, enhanced repair of drug-induced
modification in the target molecules, and activation/inhibition
of intracellular signalling pathways, which leads to a negative
balance between apoptosis/survival of tumour cells. A better
understanding of these mechanisms is needed in order to develop
both accurate tests to predict the lack of response to chemotherapy
and novel approaches aimed to overcome the drug resistance
of gastrointestinal tumours. The complexity of this issue
is further increased owing to the existence of marked differences
among the types of primary malignant gastrointestinal tumours
and the diversity of tissues from which metastatic cells can
access the gut. Moreover, inter-individual variability plus
the fact that sensitivity/refractivity may change during the
evolution of the tumour further complicate the overall situation.
The present article reviews anti-cancer agents used either
alone or, more frequently, combined in regimens, as neoadjuvant
or postsurgical adjuvant chemotherapy within the context of
the available curative and palliative therapeutic options
used to treat the most common types of cancer of the gastrointestinal
tract and pancreas.
[Back to top] [Purchase
Article] [PMID: 19199864 PubMed - indexed for MEDLINE]
Copper Complexes as Anticancer Agents
C. Marzano, M. Pellei, F. Tisato and
C. Santini
Metal-based antitumor drugs play a relevant role in antiblastic
chemotherapy. Cisplatin is regarded as one of the most effective
drugs, even if severe toxicities and drug resistance phenomena
limit its clinical use. Therefore, in recent years there has
been a rapid expansion in research and development of novel
metal-based anticancer drugs to improve clinical effectiveness,
to reduce general toxicity and to broaden the spectrum of
activity.
The variety of metal ion functions in biology has stimulated
the development of new metallodrugs other than Pt drugs with
the aim to obtain compounds acting via alternative
mechanisms of action. Among non-Pt compounds, copper complexes
are potentially attractive as anticancer agents. Actually,
since many years a lot of researches have actively investigated
copper compounds based on the assumption proposal that endogenous
metals may be less toxic.
It has been established that the properties of copper-coordinated
compounds are largely determined by the nature of ligands
and donor atoms bound to the metal ion. In this review, the
most remarkable achievements in the design and development
of copper(I, II) complexes as antitumor agents are discussed.
Special emphasis has been focused on the identification of
structure-activity relationships for the different classes
of copper(I,II) complexes. This work was motivated by the
observation that no comprehensive surveys of copper complexes
as anticancer agents were available in the literature. Moreover,
up to now, despite the enormous efforts in synthesizing different
classes of copper complexes, very few data concerning the
molecular basis of the mechanisms underlying their antitumor
activity are available. This overview, collecting the most
significant strategies adopted in the last ten years to design
promising anticancer copper(I,II) compounds, would be a help
to the researchers working in this field.
[Back to top] [Purchase
Article] [PMID: 19199865 PubMed - indexed for MEDLINE]
Role of Tyrosine Phosphatase Inhibitors in Cancer Treatment
with Emphasis on SH2 Domain-Containing Tyrosine Phosphatases
(SHPs)
M. Irandoust, T.K. van den Berg, G.J.L.
Kaspers and J. Cloos
Protein tyrosine phosphorylation is one of the key mechanisms
involved in signal transduction pathways. This modification
is regulated by concerted action of protein tyrosine phosphatases
and protein tyrosine kinases. Deregulation of either of these
key regulators lead to abnormal cellular signaling, which
is largely associated with human pathologies including cancer.
Although the role of protein tyrosine kinases in cancer is
well established, less is known about the involvement of protein
tyrosine phosphatases in carcinogenesis and tumor progression.
Moreover, several inhibitors targeting protein tyrosine kinases
have demonstrated their value in cancer treatment, while interest
in protein tyrosine phosphatases as a target for treatment
has risen more recently. In this review we describe the progressive
efforts and challenges concerning the development of drugs
targeting phosphatases as promising novel cancer therapies.
We focus on two key regulatory SH2 domain-containing phosphatases,
SHP-1 and SHP-2 and one of their substrates, signal regulatory
protein alpha. Since SHPs have been linked to many different
malignancies, protein tyrosine phosphatases could offer a
great spectrum of new, targeted drugs.
[Back to top] [Purchase
Article] [PMID: 19199866 PubMed - indexed for MEDLINE]
From Concept to Reality: The Long Road to c-Met and RON Receptor
Tyrosine Kinase Inhibitors for the Treatment of Cancer
I. Dussault and S.F. Bellon
c-Met and RON are receptor tyrosine kinases (RTK) that
are closely related, both from a homology as well as from
a functional stand point. Both receptors can induce cell migration,
invasion, proliferation and survival in response to their
respective ligand. Moreover, both possess oncogenic activity
in vitro, in animal models in vivo and are
often deregulated in human cancers. c-Met attracted a lot
of interest shortly after its discovery in the mid-1980s because
of its unusual role in cell motility. Moreover, a causal role
for c-Met activating mutations in human cancer propelled an
intensive drug discovery effort throughout the research and
pharmaceutical communities to find inhibitors of c-Met. While
c-Met is now a well-accepted target for an anti-cancer drug,
less is known about the role of RON in cancer. Interestingly,
despite their many common attributes, c-Met and RON are activated
by different mechanisms in cancer cells. Because of the homology
between the two RTKs, some small molecule kinase inhibitors
of c-Met have inhibitory activity on RON, opening the door
to exploring the role of both receptors in human cancers.
In this review we will discuss the relevance of both c-Met
and RON deregulation in human cancers and the progress so
far in identifying small molecule kinase inhibitors that can
block the activity of these targets in vitro and
lead to anti-tumor effects in animal models.
[Back to top] [Purchase
Article] [PMID: 19199867 PubMed - indexed for MEDLINE]
Molecular Modeling Applied to Anti-Cancer Drug Development
M.C. Rosales-Hernandez, J. Bermúdez-Lugo,
J. Garcia, J. Trujillo-Ferrara and J. Correa-Basurto
In the past, anti-cancer drugs were identified and developed
without focusing on a particular macromolecular target. Currently,
the fields of molecular biochemistry, molecular biology, genetics
and pharmacology, among other disciplines, have grown considerably
in their ability to identify biological targets. These disciplines
are now searching for specific targets to treat cancer. These
targets exist in different cellular compartments (membrane,
cytoplasm, nucleus) as proteins, glycoproteins, nucleic acids,
etc. Computational tools have recently been used to explore
such targets and to corroborate previously obtained experimental
data. These methods have also been used to design new drugs
with the aim of decreasing illness and the economic resources
needed to discover drug candidates. Some of these computational
methods include quantum mechanics (ab initio and density
functional theories) and molecular mechanics (docking,
mo-lecular dynamics, and protein folding). Docking and
molecular dynamics are the most commonly used computational
tools for elucidating cancer targets. Using these tools, one
can identify the recognition processes between ligands and
targets at the atomic level. In addition, one can identify
the affinity and conformational changes of these molecular
complexes. In conclusion, we propose that the use of such
tools is necessary in order to identify new anti-cancer drugs.
[Back to top]
[Purchase Article] [PMID: 19199868 PubMed - indexed for MEDLINE]
2-Deoxy-D-Ribose, a Downstream Mediator of Thymidine Phosphorylase,
Regulates Tumor Angiogenesis and Progression
Y. Nakajima, R. Madhyastha and M.
Maruyama
Angiogenesis plays an important role in tumor metastasis
and progression, and thus inhibiting angiogenesis is a promising
strategy for treatment of cancer. However, tumor-associated
angiogenesis is influenced by various angiogenic factors in
the tumor microenvironment. Thymidine phosphorylase (TP, EC
2. 4. 2. 4), an enzyme involved in the reversible conversion
of thymidine to thymine, is an important mediator of angiogenesis,
tumorigenicity, metastasis and invasion. The angiogenic effect
of TP requires the enzymatic activity of TP. TP activity is
expressed at higher levels in a wide variety of solid tumors
than in adjacent non-neoplastic tissue. The tumor microenvironment
(hypoxia, acidosis) regulates the expression of TP, and TP
expression in tumor tissue shows significant correlation with
microvessel density and poor prognosis. 2-Deoxy-D-ribose (D-dRib),
one of the degradation products of thymidine generated by
TP activity, promotes angiogenesis and the chemotactic activity
of endothelial cells and also confers resistance to hypoxia-induced
apoptosis in some cancer cell lines. These findings suggest
that D-dRib is a downstream mediator of TP function. 2-Deoxy-L-ribose,
a stereoisomer of D-dRib, can inhibit D-dRib’s anti-apoptotic
effects and suppress metastasis and invasion of TP-expressing
tumors in mice. Although the mechanism of action of D-dRib
is still unknown, the physiological activities of D-dRib have
recently been reported by several groups. We review the role
of D-dRib in tumor progression and discuss inhibition of D-dRib
as a promising approach for chemotherapy of various tumors.
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