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Anti-Cancer
Agents in Medicinal Chemistry
(Formerly 'Current Medicinal Chemistry - Anti-Cancer Agents')
ISSN: 1871-5206
Upcoming Articles
Recent Advances in Validating MDM2 as a Cancer Target
Elizabeth R. Rayburn, Scharri J. Ezell and
Ruiwen Zhang
[Abstract]
Synthesis, Molecular Targets, and Antitumor Activities
of Substituted Tetrahydro-1-Oxopyrano[4,3-b][1]Benzopyrans
and Nanogels for Drug Delivery
Elisabeth M. Perchellet, Jean-Pierre H. Perchellet,
Chanran K. Ganta, Deryl L. Troyer, Aibin Shi and
Duy H. Hua
[Abstract]
Titanium and Vanadium Complexes as Anticancer Agents
Irena Kostova
[Abstract]
Copper Complexes as Anticancer Agents
Cristina Marzano, Maura Pellei, Francesco Tisato and
Carlo Santini
[Abstract]
Importance and Limitations of Chemotherapy Among the
Available Treatments for Gastrointestinal Tumours
Jose J.G. Marin, Marta R. Romero, Alba G. Blazquez, Elisa
Herraez, Emma Keck and Oscar Briz
[Abstract]
Synthesis of Quinazolines as Tyrosine Kinase Inhibitors
Sanjay K. Srivastava, Vivek Kumar, Shiv K. Agarwal,
Rama Mukherjee and Anand C. Burman
[Abstract]
Role of Tyrosine Phosphatase Inhibitors in Cancer
Treatment with Emphasis on SH2 Domain-Containing Tyrosine
Phosphatases (SHPs)
Mahban Irandoust, Timo K. van den Berg, Gertjan
J.L. Kaspers and Jacqueline Cloos
[Abstract]
2-Deoxy-D-Ribose, a Downstream Mediator of Thymidine
Phosphorylase, Regulates Tumor Angiogenesis and Progression
Yuichi Nakajima, Radha Madhyastha and Masugi
Maruyama
[Abstract]
From Concept to Reality: The Long Road to c-Met and
RON Receptor Tyrosine Kinase Inhibitors for the Treatment
of Cancer
Isabelle Dussault and Steven F. Bellon
[Abstract]
Molecular Modeling Applied to Anti-Cancer Drug Development
M.C. Rosales-Hernandez, J. Bermúdez-Lugo, Jazmin
Garcia, J. Trujillo-Ferrara and J. Correa-Basurto,
[Abstract]
Tyrosine Kinase Inhibitors for the Treatment of Chronic
Myeloid Leukemia
Manlio Tolomeo, Francesco Dieli, Nicola Gebbia and
Daniele Simoni
[Abstract]
Abstracts
[Back to top]
Recent Advances in Validating MDM2 as a Cancer Target
Elizabeth R. Rayburn, Scharri J. Ezell and Ruiwen
Zhang
The MDM2 oncogene is overexpressed in various human cancers.
Its expression correlates with the phenotypes of high-grade,
late-stage, and more resistant tumors. The auto-regulatory
loop between MDM2 and the tumor suppressor p53 has long been
considered the epitome of a rational target for cancer therapy.
As such, many novel agents have been generated to interfere
with the interaction of the two proteins, which results in
the activation of p53. Among these agents are several small
molecule inhibitors synthesized based upon the crystal structures
of the MDM2-p53 complex. With use of high-throughput screening,
several specific and effective agents for inhibition of the
protein-protein interaction were discovered. Recent investigations,
however, have demonstrated that many proteins regulate the
MDM2-p53 interaction, and that MDM2 may have p53-independent
oncogenic functions. In order for novel MDM2 inhibitors to
be translated to the clinic, it is necessary to obtain a better
understanding of the regulation of MDM2 and of the MDM2-p53
interaction. In particular, the implications of various interactions
between certain regulator(s) and MDM2/p53 under different
circumstances need to be elucidated to determine which pathway(s)
represent the best targets for therapy. Targeting both MDM2
itself and regulators of MDM2 and the MDM2-p53 interaction,
or use of MDM2 inhibitors in combination with conventional
treatments, may improve prospects for tumor eradication.
[Back to top]
Synthesis, Molecular Targets, and Antitumor Activities
of Substituted Tetrahydro-1-Oxopyrano[4,3-b][1]Benzopyrans
and Nanogels for Drug Delivery
Elisabeth M. Perchellet, Jean-Pierre H. Perchellet,
Chanran K. Ganta , Deryl L. Troyer, Aibin Shiand Duy H. Hua
A class of substituted 1H,7H-5a,6,8,9-tetrahydro-1-oxopyrano[4,3-b][1]benzopyrans
(tricyclic pyrones; TPs) was synthesized from a one-pot condensation
reaction of 6-substituted 4-hydroxy-2-pyrones and cyclohexenecarboxaldehydes.
The reaction involves a 6π-electrocyclic ring closing
process, and stereo- and regioselectivities were examined.
C3-Pyridyl-containing TPs may represent a novel synthetic
class of microtubule de-stabilizing anti-cancer drugs that
inhibit macromolecule synthesis, tubulin polymerization, and
the proliferation of a spectrum of wild-type and multi-drug
resistant tumor cell lines in vitro. A linear skeleton
with a N-containing aromatic ring attached at C3
of the top A-ring, a central pyran B-ring and a six-membered
bottom C-ring with no alkylation at C7 are required for the
antitumor activities of the lead compounds, a 3-pyridyl benzopyran
(code name H10) and its 2-pyridyl regioisomer
(code name H19). In addition to interacting
with the colchicine-binding site to inhibit tubulin polymerization
and increase the mitotic index, these TP analogs also block
the cellular transport of nucleosides to inhibit DNA synthesis
more effectively than other antimitotic agents. The anticancer
potential of TPs in vivo is suggested by the fact
that i.p. injections of H10 decrease the
growth of solid tumors in mice inoculated with lung or ovarian
carcinomas. A drug-delivery system involving nanogels was
studied. We incorporated the anticancer compound, 6-hydroxymethyl-1,4-anthracenedione
(code name AQ10) into PEG-PEI nanogel, and
found that AQ10-encapsulated nanogel PEG-PEI
is significantly more effective in altering the growth of
Pan 02 (pancreatic cancer) cells compared to AQ10
or nanogel PEG-PEI alone. Since AQ10 is insoluble
in water, PEG-PEI encapsulation represents a way to solubilize
and deliver this as well as other poorly soluble compounds.
[Back to top]
Titanium and Vanadium Complexes as Anticancer
Agents
Irena Kostova
A series of complexes containing titanium and vanadium
as a metal centers have shown to possess a wide spectrum of
antitumor properties. These series belong to the non-platinum
metal antitumor agents that appear to offer a different alternative
for cancer chemotherapy which do not follow mechanism of action
of the platinum complexes. The antitumor activity of both
titanocene and vanadocene complexes has been established against
various animal and xenografted human tumors. The exact mechanism
of action for these compounds has not been determined, the
target is unknown and even the exact chemical nature of the
formulated solutions is still unknown. It has been proposed
that these species interact with DNA, inhibiting the cell
cycle. However, the antitumor mechanism of the titanocenes
is most likely a complex pathway, probably involving a number
of different biological molecules related to the transport
and delivery of Ti species into cancer cells, and, after hydrolysis,
subsequent interaction with nucleic acids and/or proteins
and/or other potential coordinating constituents present in
the intracellular environment. The tendency to hydrolyze seems
to be one of the hypotheses for the tumor-inhibiting potency
of the titanocene dihalides. Vanadium compounds exert preventive
effects against chemical carcinogenesis on animals, by modifying,
mainly, various xenobiotic enzymes, inhibiting, thus, carcinogen-derived
active metabolites. The anticarcinogenic effects of vanadium,
in combination to its low toxicity, established also, by its
administration in humans, suggest vanadium as a candidate
antineoplastic agent against human cancer. New complexes being
more potent and less toxic favor this perspective. The use
of these species as chemotherapeutic agents remains relatively
unexplored and waits for future investigation. Research proceeded
during the recent decades, enriched our knowledge on the chemical
and biochemical properties, as well as the mechanisms of systemic,
cellular and molecular antitumor effects of titanium and vanadium
compounds.
[Back to top]
Copper Complexes as Anticancer Agents
Cristina Marzano, Maura Pellei, Francesco Tisato and
Carlo 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]
Importance and Limitations of Chemotherapy Among
the Available Treatments for Gastrointestinal Tumours
Jose J.G. Marin, Marta R. Romero, Alba G. Blazquez, Elisa
Herraez, Emma Keck and Oscar 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]
Synthesis of Quinazolines as Tyrosine Kinase Inhibitors
Sanjay K. Srivastava, Vivek Kumar, Shiv K. Agarwal,
Rama Mukherjee and Anand C. Burman
In the present review, the discovery and development
of quinazoline as tyrosine kinase inhibitors has been described.
The synthesis of most potent quinazoline inhibitors of EGFR,
VEGFR and PDGRF has been discussed. Structure activity relationship
for quinazoline as tyrosine kinase inhibitors has been established.
It was found that C-4, C-6 and C-7 positions in quinazoline
are appropriate sites for designing new tyrosine kinase inhibitors.
This review should help the medicinal chemist in designing
more effective tyrosine kinase inhibitors.
[Back to top]
Role of Tyrosine Phosphatase Inhibitors in Cancer Treatment
with Emphasis on SH2 Domain-Containing Tyrosine Phosphatases
(SHPs)
Mahban Irandoust, Timo K. van den Berg, Gertjan
J.L. Kaspers and Jacqueline 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]
2-Deoxy-D-Ribose, a Downstream Mediator of Thymidine
Phosphorylase, Regulates Tumor Angiogenesis and Progression
Yuichi Nakajima, Radha Madhyastha and
Masugi 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.
[Back to top]
From Concept to Reality: The Long Road to c-Met and
RON Receptor Tyrosine Kinase Inhibitors for the Treatment
of Cancer
Isabelle Dussault and Steven 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]
Molecular Modeling Applied to Anti-Cancer Drug Development
M.C. Rosales-Hernandez, J. Bermúdez-Lugo, Jazmin
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,
molecular 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]
Tyrosine Kinase Inhibitors for the Treatment of Chronic
Myeloid Leukemia
Manlio Tolomeo, Francesco Dieli, Nicola Gebbia and
Daniele Simoni
Imatinib mesylate (Gleevec) is a drug unique for the
treatment of certain forms of cancer. It works by targeting,
and turning off, specific tyrosine kinase proteins that cause
the uncontrolled cell growth and the inhibition of apoptosis
in cancer cells. Imatinib was designed on the basis of the
structure of the ATP binding site of the Abl protein kinase
with the aim to stabilize the inactive form of Bcr-Abl, an
oncoprotein involved in malignant transformation in chronic
myelogenous leukemia (CML). However, imatinib can also target
other tyrosine kinase proteins different from Bcr-Abl such
as Kit, that is the suspected cause of gastrointestinal stromal
tumor (GIST). Despite successful clinical results observed
in the last years, the long-term effects of imatinib and its
ability to completely eradicate CML are still unknown. Moreover,
similar to many other anti-cancer drugs, clinical resistance
to imatinib has emerged. In this review we will discuss the
in vitro and in vivo results obtained with
the novel tyrosine kinase inhibitors developed to overcome
imatinib resistance in Bcr-Abl expressing hematologiocal disorders. |
