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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 4, May 2009
Contents
Tripentones: A Promising Series of Potent Anti-Cancer Agents
Pp. 369-380
C. Rochais, P. Dallemagne and
S. Rault
[Abstract] [Purchase
Article] [PMID: 19442038 PubMed - indexed for MEDLINE]
Novel Implications for Lysophospholipids,
Lysophosphatidic Acid and Sphingosine 1-Phosphate, as Drug
Targets in Cancer Pp. 381-391
O. Peyruchaud
[Abstract] [Purchase
Article] [PMID: 19442039 PubMed - indexed for MEDLINE]
The Effects of Cantharidin and Cantharidin
Derivates on Tumour Cells Pp. 392-396
D. Liu and Z. Chen
[Abstract] [Purchase
Article] [PMID: 19442040 PubMed - indexed for MEDLINE]
Cytotoxic and Anticancer Activities of
Isatin and Its Derivatives: A Comprehensive Review from 2000-2008
Pp. 397-414
K.L. Vine, L. Matesic, J.M. Locke, M. Ranson
and D. Skropeta
[Abstract] [Purchase
Article] [PMID: 19442041 PubMed - indexed for MEDLINE]
Recent Advances in the Development of
P-gp Inhibitors Pp. 415-436
C. Baumert and A. Hilgeroth
[Abstract] [Purchase
Article] [PMID: 19442042 PubMed - indexed for MEDLINE]
Discovery of 4-Aryl-4H-Chromenes
as Potent Apoptosis Inducers Using a Cell- and Caspase-Based
Anti-Cancer Screening Apoptosis Program (ASAP): SAR Studies
and the Identification of Novel Vascular Disrupting Agents
Pp. 437-456
S.X. Cai, J. Drewe and W. Kemnitzer
[Abstract] [Purchase
Article] [PMID: 19442043 PubMed - indexed for MEDLINE]
Anticancer Actions of Omega-3 Fatty Acids
– Current State and Future Perspectives Pp.
457-470
M. Wendel and A.R. Heller
[Abstract] [Purchase
Article] [PMID: 19442044 PubMed - indexed for MEDLINE]
Urea Derivatives as Anticancer Agents
Pp. 471-480
H.-Q. Li, P.-C Lv, T. Yan and
H.-L. Zhu
[Abstract]
[Purchase
Article] [PMID: 19442045 PubMed - indexed for MEDLINE]
Abstracts
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[Purchase
Article] [PMID: 19442038 PubMed - indexed for MEDLINE]
Tripentones: A Promising Series of Potent Anti-Cancer
Agents
C. Rochais, P. Dallemagne and
S. Rault
The 8H-thieno[2,3-b]pyrrolizinones,
some of which exert very potent cytotoxic activity against
tumor cell lines in vitro, are a promising novel
series of anti-cancer agents. These compounds belong to the
tripentone family and are based on 9H-pyrrolo[1,2-α]indol-
9-one derivatives and their heterocyclic isosteres. This paper
inventories the different synthetic strategies for tripentones
and reviews their biological effects and therapeutic potential.
[Back to top] [Purchase
Article] [PMID: 19442039 PubMed - indexed for MEDLINE]
Novel Implications for Lysophospholipids, Lysophosphatidic
Acid and Sphingosine 1-Phosphate, as Drug Targets in Cancer
O. Peyruchaud
Lysophosphatidic acid (LPA) and sphingosine 1-phosphate
(S1P) are naturally arising bioactive lipids. The roles of
LPA and S1P in angiogenesis, tumor growth and metastasis have
recently emerged. Blood platelets are an important source
of LPA and S1P in the organism. However, other types of cells
including cancer cells expressing autotaxin and sphingosine
kinases have the capacity to produce LPA and S1P, respectively.
During the past decade, studies revealed that LPA and S1P
interact with a large series of G-protein-coupled receptors,
at least seven for LPA (LPA1-5, GPR-87, P2Y5) and five for
S1P (S1P1-5). This may account for the wide variety of cell
types reacting to LPA and S1P stimulation and for the wide
range of cellular functions controlled by these lysophospholipids
such as proliferation, survival and motility. Genetic and
pharmacological approaches were developed to block the activities
of LPA or S1P in the context of cancer progression. This article
presents recent findings based on extensive cell culture experiments
and preliminary in vivo studies which demonstrate
that targeting the lysophospholipid tracks would be extremely
beneficial for patients suffering from cancer.
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[Purchase
Article] [PMID: 19442040 PubMed - indexed for MEDLINE]
The Effects of Cantharidin and Cantharidin Derivates
on Tumour Cells
D. Liu and Z. Chen
Natural product extracts are a rich source of small molecules
that display antitumor activity. Cantharidin, in the form
of the dried body of the Chinese blister beetles: Mylabris
phalerata or M. cichorii, displays antitumor activity
and induces apoptosis in many types of tumor cells. Cantharidin
has been used as an anticancer agent by the Chinese for the
treatment of hepatoma and oesophageal carcinoma for a long
time. Although cantharidin is a natural toxin that possesses
potent anti-tumor properties, its clinical application is
limited due to severe side-effects and highly toxic nature.
Therefore, some modified cantharidin analogues are synthesized
chemically in order to achieve a comparable antitumour property
to the mother compound but simultaneously produce a less toxic
effect on non-cancer cells. In recent years, based on the
structure of cantharidin, there has been intense interest
in developing potent and selective inhibitors of PP1 and PP2A
on tumour cells. Though numerous analogues of cantharidin
have been synthesized and researched with tumour cell lines,
there is little success on clinical application because of
the potential toxicity of cantharidin derivates. The focus
of this review is to describe how cantharidin and cantharidin
derivates participate in antitumour processes in tumour cells,
and discuss the molecular mechanisms of cantharidin and cantharidin
derivates on tumour cells.
[Back to top] [Purchase
Article] [PMID: 19442041 PubMed - indexed for MEDLINE]
Cytotoxic and Anticancer Activities of
Isatin and Its Derivatives: A Comprehensive Review from 2000-2008
K.L. Vine, L. Matesic, J.M. Locke, M. Ranson
and D. Skropeta
Isatin (1H-indole-2,3-dione) and its
derivatives demonstrate a diverse array of biological and
pharmacological activities including anticonvulsant, antibacterial,
antifungal, antiviral and anticancer properties. This broad
spectrum of biochemical targets has been facilitated by the
synthetic versatility of isatin, which has allowed the generation
of a large number of structurally diverse derivatives including
analogues derived from substitution of the aryl ring, and/or
derivatisation of the isatin nitrogen and C2/C3 carbonyl moieties.
The recent FDA approval of the oxindole sunitinib malate,
as a kinase inhibitor for the treatment of advanced renal
carcinoma and gastrointestinal stromal tumours, underscores
the increasing interest in isatins as a new class of antineoplastic
agents. In addition to potent kinase inhibition, the mechanism
of action of other isatin derivatives includes the inhibition
and/or modulation of proteases, translation initiation, neo-vascularisation
and tubulin polymerisation. It was therefore the objective
of this review to systematically evaluate the cytotoxic and
anticancer properties of various substituted isatins and collate
these findings to be used as a guide for future structure-activity
relationship and mode of action studies. This is the first
review to comprehensively discuss the in vitro and
in vivo anticancer activities of isatin and its substituted
derivatives.
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[Purchase
Article] [PMID: 19442042 PubMed - indexed for MEDLINE]
Recent Advances in the Development of P-gp Inhibitors
C. Baumert and A. Hilgeroth
During the last decades multidrug resistance (MDR) emerged
as main problem in the anti-cancer therapy with cytostatically
active agents. Classical as well as recently developed cytostatics
develop the phenomenon of loosing activity in former drug-sensitive
cells. Although MDR is a multifactorial process, the main
obstacle is the expression of multidrug-efflux pumps that
lowers the intracellular drug levels. P-glycoprotein (P-gp)
is the longest identified efflux pump. As the attempt to overcome
MDR by the use of inhibitors of the efflux pump activities
turned out as most promising effect, the development of P-gp
inhibitors has been a challenge for medicinal chemists. The
article reviews the advances in P-gp inhibitor development
by focussing on structure-activity relationships in the different
compound classes to document improvements. The success has
been the reduction of cytotoxic properties. The undesired
activities could be much lowered in the case of compound classes
that were derived from pharmacologically active drugs. Undesired
drug interactions and limited in vivo activities
are still a problem.
[Back to top] [Purchase
Article] [PMID: 19442043 PubMed - indexed for MEDLINE]
Discovery of 4-Aryl-4H-Chromenes
as Potent Apoptosis Inducers Using a Cell- and Caspase-Based
Anti-Cancer Screening Apoptosis Program (ASAP): SAR Studies
and the Identification of Novel Vascular Disrupting Agents
S.X. Cai, J. Drewe and W. Kemnitzer
Many cancer cells are known to have defects in the apoptosis
machinery. Therefore identification of compounds that can
activate or promote apoptosis in cancer cells is an attractive
approach for targeted therapies. By applying a novel cell-
and caspase-based Anti-cancer Screening Apoptosis Program
(ASAP) HTS assay, 4-aryl-4H-chromenes were identified
as potent apoptosis inducers. 4- Aryl-4H-chromenes
were found to induce nuclear fragmentation and PARP cleavage,
as well as to arrest cells at the G2/M stage followed
by apoptosis as determined by the flow cytometry analysis
assay in multiple human cell lines (e.g. Jurkat, T47D). These
compounds were found to be highly active in the growth inhibition
MTT assay, including for paclitaxel resistant, p-glycoprotein
overexpressed, MESSA/ DX5 tumor cells. Functionally, they
were found to be potent inhibitors of tubulin polymerization
and to effectively inhibit the binding of colchicine to tubulin.
In addition, several 4-aryl-4H-chromenes were also
found to be effective vascular disrupting agents (VDA). One
of the lead compounds, EPC2407, is currently in clinical trials
as a novel tumor vascular disrupting agent.
[Back to top] [Purchase
Article] [PMID: 19442044 PubMed - indexed for MEDLINE]
Anticancer Actions of Omega-3 Fatty Acids
– Current State and Future Perspectives
M. Wendel and A.R. Heller
Omega-3 fatty acids (ω3-FA) were shown to attenuate
growth and induce apoptosis in a variety of human cancer cell
lines derived from colonic, pancreatic, prostate, and breast
cancer. In addition, recent findings indicate that ω3-FA
act synergistically with chemotherapeutic
agents and may also be used to enhance tumour radiosensitivity.
The mechanisms underlying the anti-tumour effects of ω3-FA
are complex. Incorporation of ω3-FA in biological membranes
alters the profile of lipid mediators generated during inflammatory
reactions. Furthermore, ω3-FA act as ligands of nuclear
peroxisome proliferator- activated receptors that attenuate
transcription of NF-κB-dependent genes. Thereby, the
cyclooxygenase-2/prostaglandin E2- dependent production
of pro-angiogenic vascular endothelial growth factor and levels
of anti-apoptotic bcl-2 and bcl-XL are decreased.
Eicosanoid-independent pro-apoptotic pathways include enhanced
lipid peroxidation, modulation of mitochondrial calcium homeostasis
and enhanced production of reactive oxygen species as well
as activation of p53.
This review article will give a comprehensive overview over
the pleiotropic actions of ω3-FA and will discuss the
potential of ω3-FA and derivatives like conjugated eicosapentaenoic
acid as important nutritional adjuvant therapeutics in the
management of various human cancer diseases and the impact
of nutritional ω-3 FA on cancer prevention.
[Back to top] [Purchase
Article] [PMID: 19442045 PubMed - indexed for MEDLINE]
Urea Derivatives as Anticancer
Agents
H.-Q. Li, P.-C Lv, T. Yan and
H.-L. Zhu
Within the past ten years, a huge volume of
research on the synthesis, structure-activity relationships
(SAR), and anticancer activities of the urea derivatives was
reported. Many aromatic urea derivatives such as N-phenyl-N’-(2-chloroethyl)ureas
(CEUs) and benzoylureas (BUs) show good anticancer activity,
and these compounds have mainly been proved to be tubulin
ligands that inhibit the polymerization of tubulin. Heterocyclic
urea derivatives play an important role in anticancer agents
because of their good inhibitory activity against receptor
tyrosine kinases (RTKs), raf kinases, protein tyrosine kinases
(PTKs), and NADH oxidase, which play critical roles in many
aspects of tumorigenesis. Thiourea derivatives are also of
wide interest because of their diverse anticancer activity
against various leukemias and solid tumors. In this review,
the anticancer activity of the urea derivatives mentioned
above is summarized in detail. It is hoped that increasing
knowledge of the SAR and cellular processes underlying the
antitumor-activity of urea derivatives will be beneficial
to the rational design of new generation of urea anticancer
drugs.
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