| 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 7, September 2009
Contents
Enzymes as Useful Tools and Potential Targets
in Cancer Chemotherapy
Guest Editors: P. Ruzza and L. Quintieri
Editorial Pp. 716
Tyrosinase Activated Melanoma Prodrugs Pp.
717-727
Samaila Jawaid, Tariq H. Khan, Helen M.I.
Osborn and Nana Aba O. Williams
[Abstract] [Purchase
Article]
Proteases as Anti-Cancer Targets - Molecular and Biological
Basis for Development of Inhibitor-Like Drugs Against Cancer
Pp. 728-762
A. Bialas and P. Kafarski
[Abstract] [Purchase
Article]
Glutathione Transferases as Targets for Cancer Therapy
Pp. 763-777
Paolo Ruzza, Antonio Rosato, Carlo Riccardo Rossi, Maura
Floreani and Luigi Quintieri
[Abstract] [Purchase
Article]
ATP Non-Competitive Ser/Thr Kinase Inhibitors as Potential
Anticancer Agents Pp. 778-786
Giorgio Cozza, Andrea Bortolato, Ernesto Menta, Ennio
Cavalletti, Silvano Spinelli and Stefano Moro
[Abstract] [Purchase
Article] [PMID:
19799530 PubMed - indexed for MEDLINE]
WT1 Peptide Vaccine as a Paradigm for “Cancer Antigen-Derived
Peptide”-Based
Immunotherapy for Malignancies: Successful Induction of Anti-Cancer
Effect by Vaccination with a Single Kind of WT1 Peptide
Pp. 787-797
Yoshihiro Oka, Akihiro Tsuboi, Fumihiro Fujiki, Zheyu
Li, Hiroko Nakajima, Naoki Hosen, Toshiaki Shirakata, Sumiyuki
Nishida, Yusuke Oji, Ichiro Kawase and Haruo Sugiyama
[Abstract] [Purchase
Article]
The Nitric Oxide Prodrug JS-K and Its Structural Analogues
as Cancer Therapeutic Agents Pp. 798-803
Anna E. Maciag, Joseph E. Saavedra and Harinath
Chakrapani
[Abstract] [Purchase
Article]
Acronycine Derivatives: A Promising Series of Anti-Cancer
Agents Pp. 804-815
Q.C. Nguyen, T.T. Nguyen, R. Yougnia, T. Gaslonde, H.
Dufat, S. Michel and F. Tillequin
[Abstract] [Purchase
Article]
Targeting the Tumor Stroma with Peroxisome Proliferator
Activated Receptor (PPAR) Agonists Pp. 816-821
Annika Bundscherer, Albrecht Reichle, Christian Hafner,
Stefanie Meyer and Thomas Vogt
[Abstract] [Purchase
Article]
Abstracts
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Editorial
Cancer is the second leading cause of death in developed
societies, and epidemiologists predict that in a few years
it will overcome cardiovascular diseases to become the leading
cause of mortality. Although the death rate of many forms
of cancer seems to decrease, nevertheless most human tumours
remain essentially incurable once they have spread, even though
the chemotherapy era has been starting over 50 years ago.
Luckily, our understanding of the physiology of both normal
and neoplastic cells has largely increased in recent years,
raising the hope that we can comprehend the molecular abnormalities
that distinguish a cancer cell from its normal counterpart.
This knowledge will foster the development of targeted molecular
approaches that will kill tumour cells while leaving normal
tissues untouched, thus increasing the "therapeutic index"
of current cytotoxic agents or allowing the design of new
specific anticancer drugs.
In designing such sophisticated cancer treatments, it is necessary
to consider the processes that govern normal cellular physiology.
Thus, the goal of this Issue is to explore enzymes of particular
importance to human cancer. Studies on enzymes in cancer date
back to 1924 when Warburg and co-workers reported that cancer
tissues exhibit a greater rate of aerobic glycolysis. Subsequently,
many authors have studied tissue enzymes in the attempt to
extrapolate theories regarding malignant growth and describing
enzymes patterns in neoplastic tissues.
Purpose of this Issue is to consider tumour-associated enzymes
as targets for chemotherapeutic agents acting as enzyme inhibitors
or as enzyme-activated prodrugs. These latter would realize
the Ehrlich’s concept of a “magic bullet”
for the treatment of cancer, being the “magic bullets”
compounds with low toxicity to normal tissues and high efficacy
against neoplastic cells. This idea, originally associated
with antimicrobial agents, unfortunately misses its target
with conventional anticancer drugs.
While it is impossible to present a fully comprehensive overview
in a fast-moving field that encompasses most aspects of cellular
physiology, the contributions in this Issue were selected
to reflect different and somehow new areas of cancer research,
providing a panoramic view of four different classes of enzymes
controlling critical cellular events, which are commonly subverted
in human cancers.
In relation to each of these enzymes, several molecules are
discussed regarding organ- or tumor-selective action. In addition,
it is concluded that the development of enzyme inhibitors
as well as prodrugs has been relatively successful even though
all compounds lack a complete selectivity. Therefore, further
work is required to explore the differences between normal
and cancer cells and to develop optimal enzyme ligands.
Undoubtedly, the contributions in this Issue reflect the state-of-the-art
in one of the most exciting areas of cancer chemotherapy,
but also in cell biology, biochemistry, and molecular genetics.
Nonetheless, either enzyme-activated prodrugs or enzyme inhibitors
are no longer a topic restricted to sophisticated scientific
discussions, since they are already regarded as a leading
hope for the future of cancer therapy by clinical oncologists
around the world.
In this exciting era in which scientific advances and medical
practice are rapidly converging, the aim of this volume is
to inform and inspire both scientists and physicians toward
a common area of interest.
P. Ruzza
Co-Guest Editor
Anti-Cancer Agents in Medicinal Chemistry
Institute of Biomolecular Chemistry of CNR, Padova Unit
Via F. Marzolo 1, I-35131 Padova
Italy
E-mail: paolo.ruzza@unipd.it
L. Quintieri
Co-Guest Editor
Anti-Cancer Agents in Medicinal Chemistry
Dept. of Pharmacology and Anesthesiology, University of Padova
Largo E. Meneghetti 2, I-35131
Italy
E-mail: luigi.quintieri@unipd.it
[Back to top]
[Purchase
Article]
Tyrosinase Activated Melanoma Prodrugs
Samaila Jawaid, Tariq H. Khan, Helen M.I. Osborn and
Nana Aba O. Williams
Metastatic malignant melanoma remains a highly aggressive
form of skin cancer for which no reliable methods for treatment
exist. Given the increasing incidence of this cancer, considerable
attention has focused on the development of new and improved
methods for tackling this disease. Within this article, methods
for treating melanoma are reviewed and discussed with particular
attention focusing on prodrugs that are activated by the tyrosinase
enzyme. This enzyme is up-regulated and is of elevated activity
within malignant melanomas compared with healthy melanocytes,
providing an ideal in-situ tool for the activation of melanoma
prodrugs. By way of background to the prodrug strategies discussed
within this review, the causes of melanoma, the enzymology
of tyrosinase, and the chemistry of the biosynthetic pathways
associated with melanogenesis are presented. Aspects of the
design, mode of action, and biological profiles of key prodrugs
that are activated by tyrosinase, and that show potential
for the treatment of melanoma, are then presented and compared.
[Back to top] [Purchase
Article]
Proteases as Anti-Cancer Targets - Molecular and Biological
Basis for Development of Inhibitor-Like Drugs Against Cancer
A. Bialas and P. Kafarski
The systematic improvement of methods used for unraveling
physiological and pathological role of proteases, as well
as for elucidation of relevant hydrolase structures contributes
to the progress in the area of new inhibitor-like drugs development.
Many of protease inhibitors have entered clinics and are now
successfully applied for the treatment of various systemic
disorders caused by deregulation of physiological processes
governed by proteolytic enzymes, including cardiovascular,
neurodegenerative and inflammatory diseases. A clinical approach
based on targeting of proteases involved in pathomechanism
of given diseases also stimulates the interest as anti-cancer
strategy alternative, or supplementary, to surgical intervention
and radiotherapy. In this survey we present some current achievements
on the field of development of protease inhibitors designed
as potential anti-cancer drugs and/or tools for studying molecular
basis of processes associated with the cancer development
and spread. Our intention is to show the results of this research
in context of the structure-activity relationship (SAR) studies,
which explain inhibitor requirements of the target proteases.
We also provide the examples of attempts being made to eliminate
drawbacks of the earlier-developed inhibitors (e.g. such as
low selectivity or poor pharmacological profile arising from
their peptide-like character). Moreover, modern approach to
protease targets recognition by means of so-called activity-based
protein profiling as well as new ‘fail-off’ methodology
of in vivo inhibitor screening, which provide structures
potent both in vitro and under physiological conditions
are also described. At last, an example proving usefulness
of high throughput screening as method for selection of the
non-peptidic leads for protease inhibitors can be found in
this article.
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Article]
Glutathione Transferases as Targets for Cancer Therapy
Paolo Ruzza, Antonio Rosato, Carlo Riccardo Rossi, Maura
Floreani and Luigi Quintieri
Besides catalyzing the inactivation of various electrophile-producing
anticancer agents via conjugation to the tripeptide glutathione,
some cytosolic proteins belonging to the glutathione transferase
(formerly glutatione-S-transferase; GST) superfamily
are emerging as negative modulators of stress/drug-induced
cell apoptosis through the interaction with specific signaling
kinases. In addition, several data link the overexpression
of some GSTs, in particular GSTP1-1, to both natural and acquired
resistance to various structurally unrelated anticancer drugs.
Tumor overexpression of these proteins has provided a rationale
for the search of GST inhibitors and GST-activated cytotoxic
prodrugs. In the present review we discuss the current structural
and pharmacological knowledge of both types of GST-targeting
compounds.
[Back to top] [Purchase
Article] [PMID:
19799530 PubMed - indexed for MEDLINE]
ATP Non-Competitive Ser/Thr Kinase Inhibitors as Potential
Anticancer Agents
Giorgio Cozza, Andrea Bortolato, Ernesto Menta, Ennio
Cavalletti, Silvano Spinelli and Stefano Moro
Protein kinases are one of the largest known families of enzyme
characterized by having a well conserved ATP binding pocket.
Most of the synthetic kinase inhibitors are ATP-competitive,
but display some potential problems, like selectivity, discrepancy
between the in vitro and in vivo inhibition
assays and an high risk of developing mutation inside the
ATP-binding pocket. Recently some new inhibitors with a non-competitive
mechanism of action were reported, with intresting results
both in vitro and in vivo.
[Back to top] [Purchase
Article]
WT1 Peptide Vaccine as a Paradigm for “Cancer Antigen-Derived
Peptide”-Based
Immunotherapy for Malignancies: Successful Induction of Anti-Cancer
Effect by Vaccination with a Single Kind of WT1 Peptide
Yoshihiro Oka, Akihiro Tsuboi, Fumihiro Fujiki, Zheyu
Li, Hiroko Nakajima, Naoki Hosen, Toshiaki Shirakata, Sumiyuki
Nishida, Yusuke Oji, Ichiro Kawase and Haruo Sugiyama
Wilms’ tumor gene (WT1) possesses oncogenic
functions and is expressed in various kinds of malignancies,
which suggests that the gene’s product, the WT1 protein,
should be one of the most promising cancer antigens. In fact,
the WT1 protein was shown to be highly immunogenic in cancer
patients. WT1 peptides that could induce WT1-specific CTLs
(WT1 CTL peptides) were identified, and vaccination of cancer
patients with these WT1 CTL peptides induced immunological
responses, which were assessed by ex vivo immuno-monitoring,
such as the tetramer assay, and in vivo immuno-monitoring,
such as the peptide-specific delayed type hypersensitivity
reaction. The induced immunological responses then led to
clinical responses such as solid tumor shrinkage, a decrease
in leukemia cells, and reduction of M-protein (multiple myeloma).
Long-term stabilization of disease with good quality of life,
which might be characteristic of cancer vaccine therapy, was
also reported. It is noteworthy that injection of a “single”
kind of WT1 peptide elicited an immunological response strong
enough to induce a clinical response, indicating that the
WT1 peptide vaccine has therapeutic potential. The number
of reports of the successful treatment of cancer patients
(not only adult but also childhood malignancies) with WT1
vaccination is increasing. Strategies for further improvement
in the efficacy of therapy, including combined use of chemotherapy
drugs, molecular-target-based drugs, or WT1 helper peptides,
are being proposed. WT1 peptide vaccination in an “adjuvant
setting” should be considered a promising treatment
to protect against progression or relapse of malignancies
in cases with minimal residual disease.
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Article]
The Nitric Oxide Prodrug JS-K and Its Structural Analogues
as Cancer Therapeutic Agents
Anna E. Maciag, Joseph E. Saavedra and Harinath
Chakrapani
Nitric oxide (NO) prodrugs of the diazeniumdiolate class are
routinely used as reliable sources of nitric oxide in chemical
and biological laboratory settings. O2-(2,4-dinitrophenyl)
diazeniumdiolates, which are derivatized forms of ionic diazeniumdiolates,
have been found to show potent anti-proliferative activity
in a variety of cancer cells, presumably through the effects
of NO. One important member of this class of diazeniumdiolates,
O2-(2,4-dinitrophenyl)
1-[(4 ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate
(JS-K), has shown promise as a novel cancer therapeutic agent
in a number of animal models. This review describes the developments
in chemical and biochemical characterization and structure-activity
relationship of JS-K and its analogues. In addition, some
molecular mechanistic insights into the observed anti-proliferative
activity of JS-K are discussed. Finally, a structural motif
is presented for O2-(aryl)
diazeniumdiolate nitric oxide prodrugs that show potency comparable
with that of JS-K.
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Article]
Acronycine Derivatives: A Promising Series of Anti-Cancer
Agents
Q.C. Nguyen, T.T. Nguyen, R. Yougnia, T. Gaslonde, H.
Dufat, S. Michel and F. Tillequin
The pyranoacridone acronycine (1) exhibits
antitumor properties against a large panel of solid tumor
models, but its moderate potency and low water solubility
severely hampered the subsequent clinical trials. Development
of synthetic analogues followed the isolation from several
Sarcomelicope species of acronycine epoxide (17),
which led to a hypothesis of bioactivation of acronycine by
transformation of the 1,2-double bond into the corresponding
oxirane. 1,2-Diacyloxy-1,2-dihydroacronycine derivatives exhibited
antitumor properties, with a broadened spectrum of activity
and an increased potency. The demonstration that acronycine
interacted with DNA led to the development of benzo[α],
[b], and [c]acronycine analogs. 1,2-Dihydroxy-1,2-dihydrobenzo[b]acronycine
esters and diesters were active in human orthotopic models
of cancers xenografted in nude mice. The activity of these
compounds, exemplified by cis-1,2-diacetoxy-1,2-dihydrobenzo[b]acronycine
(49), developed in phase I clinical trials
under the code S23906-1, was correlated with their ability
to give covalent adducts with DNA, involving reaction between
the N-2 amino group of guanines in the minor groove and the
ester group at the benzylic position of the drug. The influence
of the kinetics of DNA alkylation on the cytotoxic and antitumor
properties showed a strong correlation between antiproliferative
activity and DNA alkylation kinetics, with the most cytotoxic
compounds, appearing as the slowest DNA alkylators. Hybrid
compounds associating the acridone or benzo[b]acridone
chromophore of acronycine derivatives and the epoxyfuran alkylating
unit present in psorospermin also displayed potent antiproliferative
activities, alkylating DNA guanine units at position N-7
in the major groove, as natural xanthones belonging to the
psorospermin series.
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Article]
Targeting the Tumor Stroma with Peroxisome Proliferator Activated
Receptor (PPAR) Agonists
Annika Bundscherer, Albrecht Reichle, Christian Hafner,
Stefanie Meyer and Thomas Vogt
Tumor cells depend on and are able to modulate the tumor stroma
establishing a permissive and supportive environment of their
own. Targeting the tumor stroma has evolved as a novel concept
that has attracted attention of cancer researchers aiming
at the treatment of metastatic cancer. The novel paradigm
is that modulating the stroma will possibly not cure the cancer,
but will make it a manageable disease for long periods of
time by prohibiting the cancer from growing beyond a certain
mass. Accordingly, in the last years, a multitude of stroma-targeting
agents were developed comprising either classic small molecule
drugs (e.g. sorafenib, an inhibitor of multiple tyrosine kinases)
or recombinant antibodies (e.g. anti-VEGF) for targeting of
tumor angiogenesis. Apart from these specifically targeted
drugs, some well established drugs, primarily designed for
non-oncologic diseases, have revealed antitumor activity on
the basis of nuclear receptor modulation unfolding pleiotropic
biological effects including stroma modulation. Peroxisome
Proliferator Activated Receptor (PPAR) agonists, particularly
thiazolidinedione derivatives such as pioglitazone and ciglitazone,
are promising examples as they exert both a direct antitumoral
and a broad spectrum of anti-stromal, antiangiogenic and immuno-modulating
activities. This review will focus on the stroma-mediated
anticancer activities of PPAR agonists.
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