| Anti-Cancer
Agents in Medicinal Chemistry
(Formerly 'Current Medicinal Chemistry - Anti-Cancer Agents')
ISSN: 1871-5206
Anti-Cancer Agents in Medicinal
Chemistry
Volume 7, Number 5, September 2007
Contents
Recent Advances Involving Palladium (II) Complexes
for the Cancer Therapy Pp. 484-491
A.C.F. Caires
[Abstract]
Oncologists’ Current Opinion on the Treatment
of Colon Carcinoma Pp. 492-503
M. Majer, W. Akerley and S.K. Kuwada
[Abstract]
Targeting Aberrant TGF-β
Signaling in Pre-Clinical Models of Cancer Pp. 504-514
A.A. Mourskaia, J.J. Northey and P.M. Siegel
[Abstract]
PARP Inhibitor Development for Systemic Cancer Targeting
Pp. 515-523
T. Zaremba and N.J. Curtin
[Abstract]
Recent Advances in Classical and Non-Classical Antifolates
as Antitumor and Antiopportunistic Infection Agents: Part
I Pp. 524-542
A. Gangjee, H.D. Jain and S. Kurup
[Abstract]
Development and Application of Peptide-Based Radiopharmaceuticals
Pp. 543-551
I. Dijkgraaf, O.C. Boerman, W.J.G. Oyen, F.H.M. Corstens
and M. Gotthardt
[Abstract]
Tumor Targeting with RGD Peptide Ligands-Design of
New Molecular Conjugates for Imaging and Therapy of Cancers
Pp. 552-558
E. Garanger, D. Boturyn and P. Dumy
[Abstract]
Polyphenolic Coumpounds in Chemoprevention of Colon
Cancer – Targets and Signaling Pathways Pp.
559-575
E. Rudolf, H. Andelová and M. Cervinka
[Abstract]
Histone Deacetylase Inhibitors in Cancer Therapy:
Latest Developments, Trends and Medicinal Chemistry Perspective
Pp. 576-592
K.V. Balakin, Y.A. Ivanenkov, A.S. Kiselyov and S.E. Tkachenko
[Abstract]
Abstracts
[Back to top]
Recent Advances Involving Palladium (II) Complexes
for the Cancer Therapy
A.C.F. Caires
This review deals with the most important results published
on the structures, reactivity and biomedical applications
of palladium(II) complexes in the cancer therapy in the last
five years. Biological mechanisms of palladium(II) complexes,
especially of palladacycle compounds were boarded. Among the
most recent advances in the studies involving correlations
between chemical structures of palladacycle compounds and
biological activities we mention i) the synthesis of metallic
isomer complexes containing ligands derivatives of pyridine
and imines in trans position having high antitumoral
activities, ii) the development of cationic complexes with
biological activity, iii) the discovery of preferential nucleotides
for the intercalation of metallic complexes in the double
helix of DNA of cancerous cells, configuring irreparable lesions
in the macromolecule and iv) the interaction of metallic complexes
with other biological molecules, like proteins and peptides,
through terminal amine groups, carboxylate groups, imidazolic
group of histidine and mostly with the thiol group of methionine.
Some of these interactions are related to drug nefrotoxicity
effect, which understanding is of fundamental importance.
v) Novel ortho-cyclopalladated compounds synthesized
from p-isopropylbenzaldehyde thiosemicarbazone have been described
with specific cytotoxic properties in tumor cells sensitive
to cis-diamminedichloroplatinum(II). The lysosomal
cysteine proteinases cathepsins B and L have been implicated
in a variety of pathological conditions, especially in diseases
involving tissue-remodeling states, such as tumor metastasis.
Our research group is studying inhibition of Cathepsin B by
new palladacycle compounds derived from N, N-dimethyl-1-phenethylamine
and having biphosphine ligands. New palladacycle compounds
derived from N,N-dimethyl-1-phenethylamine and the ligand
bis(diphenylphosphine)ferrocene were presented as effective
antitumoral agents.
[Back to top]
Oncologists’ Current Opinion on the Treatment
of Colon Carcinoma
M. Majer, W. Akerley and S.K. Kuwada
Colorectal cancer is a major global health problem with more
than a million new cases diagnosed worldwide in 2005. In the
United States, this malignancy is the third most common with
145,000 new cases and the second most lethal with 56,000 deaths
in 2005. Unfortunately, preclinical diagnostic screening in
the U.S. population is less than 30-40 percent.
The last decade has ushered in exciting new advances for medical
oncologists caring for patients with colorectal cancer. The
older cytotoxic chemotherapy drug 5-fluorouracil underwent
new formulation, and two new drugs, oxaliplatine and irinotecan,
were investigated as adjunctive therapies. Finally, targeted
therapies, including monoclonal antibodies against vascular
endothelial growth factor (bevacizumab) and the epidermal
growth factor receptor (cetuximab), are now standard treatment
for metastatic colorectal carcinoma. Systemic adjuvant chemotherapy
can be lifesaving in patients with locally advanced colorectal
carcinomas, which represent 60-70 percent of cases. For patients
with metastatic colorectal cancer, the survival rate has doubled.
With more effective drugs in the therapeutic armamentarium,
new controversies have arisen. Questions regarding the best
schedules for classical cytotoxic chemotherapy were largely
answered by contemporary clinical trials. The potential of
molecular genetic markers for prognosis or prediction of drug-specific
toxicity and efficacy have been explored, but their utility
for clinical practice is still being investigated.
We will review the rapidly changing, state-of-the-art combination
chemotherapy for adjuvant and metastatic disease. We will
discuss in detail the c-ERBB family of tyrosine kinases as
therapeutic targets in colorectal cancer.
[Back to top]
Targeting Aberrant TGF-β
Signaling in Pre-Clinical Models of Cancer
A.A. Mourskaia, J.J. Northey and P.M. Siegel
The TGF-β
signaling pathway is central to the control of diverse biological
processes including cellular proliferation, cell survival,
apoptosis, extracellular matrix deposition/remodeling, migration,
invasion and immune regulation/inflammation. Given the pleiotropic
effects of this cytokine, it comes as no surprise that numerous
pathological conditions are associated with alterations in
the TGF-β
pathway, including chronic fibrosis, airway remodeling (asthma),
cardiovascular disease and cancer. Thus, there are increasing
efforts to develop reagents and therapeutic strategies to
impair TGF-β
signaling. Here we review several classes of inhibitors, including
knock-down strategies aimed at signaling components of the
TGF-β
pathway, TGF-β
neutralizing antibodies, TGF-β
receptor extracellular domains that function as ligand traps
and small molecule kinase inhibitors. Strategies with potential
for application as anti-cancer therapeutics that have been
evaluated in pre-clinical animal models will be discussed.
TGF-β
action is complex, shifting from a tumor suppressor to a promoter
of tumor cell invasion and metastasis in several types of
cancer. This raises important issues regarding not only the
status of the TGF-β
pathway in the individual patient but also the precise stage
during disease progression that such inhibitors should be
employed. Potential consequences of targeting the TGF-β
pathway will also be considered.
[Back to top]
PARP Inhibitor Development for Systemic Cancer Targeting
T. Zaremba and N.J. Curtin
Poly(ADP-ribose) polymerase 1 (PARP-1) is a DNA-binding enzyme
that is activated by DNA breaks, converting them into an intracellular
signal via poly(ADP-ribosyl)ation of nuclear proteins.
Negatively charged polymers of ADP-ribose (PAR) attached to
PARP-1 itself and histones lead to chromatin relaxation, facilitating
the access of base excision/single strand break repair proteins
and activating these repair enzymes. PARP inhibitors have
been developed to investigate the role of PARP-1 in cell biology
and to overcome DNA repair-mediated resistance of cancer cells
to cytotoxic therapy. Since the early benzamide inhibitors
of the 1980s PARP inhibitors, developed through structure-activity
relationships and crystal structure-based drug design, that
are 1,000x more potent have been identified. These novel PARP
inhibitors have been shown to enhance the antitumour activity
of temozolomide (a DNA-methylating agent), to-poisomerase
poisons and ionising radiation in advanced pre-clinical studies
and are now under clinical evaluation. PARP inhibitors can
also selectively kill cells and tumours with homozygous defects
in the hereditary breast cancer genes, BRCA1 and BRCA2.
[Back to top]
Recent Advances in Classical and Non-Classical Antifolates
as Antitumor and Antiopportunistic Infection Agents: Part
I
A. Gangjee, H.D. Jain and S. Kurup
Antifolates that inhibit the key enzymes thymidylate synthase
(TS) and dihydrofolate reductase (DHFR) have found clinical
utility as antitumor and antiopportunistic agents. Methotrexate
{MTX, (1)} and 5-fluorouracil (5-FU) were
among the first clinically useful DHFR and TS inhibitors,
respectively. The development of resistance to 5-FU, its occasional
unpredictable activity and toxicity resulted in the search
of novel antifolates. Pemetrexed (4) and
raltitrexed (5) specifically inhibit TS,
and are clinically useful as antitumor agents. A major mechanism
of tumor resistance to clinically useful antifolates is based
on their need for polyglutamylation via the enzyme
folylpoly-γ-glutamate
synthetase (FPGS). Novel antifolates have been developed that
do not need to be polyglutamylated and include plevitrexed
(6) and GW1843 (7). Nonclassical
antifolates for antitumor and parasitic chemotherapy, such
as nolatrexed (8), trimethoprim {TMP, (11)}
and piritrexim {PTX, (12)}, can passively
diffuse into cells and hence do not have to depend on FPGS
or the reduced folate carrier (RFC). Variations in the structures
of antifolates have helped delineate the structural influence
on the interaction with TS, DHFR, FPGS, and RFC utilization.
The differences in the active site of human and pathogen DHFR
have also been exploited. The literature contains excellent
reviews on the design and synthesis of antifolates prior to
1996. This two-part review discusses the design, synthesis
and structural requirements for TS and DHFR inhibition and
their relevance to antitumor and parasitic chemotherapy, since
1996. Monocyclic and 6-5 fused bicyclic antifolates will be
discussed in Part I, while 6-6 bicyclic and tricyclic antifolates
will be discussed in Part II.
[Back to top]
Development and Application of Peptide-Based Radiopharmaceuticals
I. Dijkgraaf, O.C. Boerman, W.J.G. Oyen, F.H.M. Corstens
and M. Gotthardt
During the past decade, radiolabeled receptor-binding peptides
have emerged as an important class of radiopharmaceuticals
for tumor diagnosis and therapy. The specific receptor binding
property of the ligand can be exploited by labeling the ligand
with a radionuclide and using the radiolabeled ligand as a
vehicle to guide the radioactivity to the tissues expressing
a particular receptor. The concept of using radiolabeled receptor
binding peptides to target receptor-expressing tissues in
vivo has stimulated a large body of research in nuclear
medicine. Receptor binding peptides labeled with gamma emitters
(123I, 111In,
99mTc) can visualize receptor-expressing
tissues, a technique referred to as peptide-receptor radionuclide
imaging (PRRI). In addition, labeled with beta emitters (131I,
90Y, 188Re,
177Lu) these peptides have
the potential to irradiate receptor-expressing tissues, an
approach referred to as peptide-receptor radionuclide therapy
(PRRT). The first and most succesful imaging agent to date
is the somatostatin analog octreotide. It is used for somatostatin
receptor scintigraphy and PRRT of neuroendocrine tumors. Other
peptides such as Minigastrin, GLP-1, CCK, bombesin, substance
P, neurotensin, and RGD peptides are currently under development
or undergoing clinical trials.
In this review, an overview of the criteria of peptide ligand
development, the selection of radioisotopes, labeling methods,
and chemical aspects of radiopeptide synthesis is given. In
addition, the current state of clinical use of radiopeptides
for diagnosis and therapy of tumors is discussed.
[Back to top]
Tumor Targeting with RGD Peptide Ligands-Design of
New Molecular Conjugates for Imaging and Therapy of Cancers
E. Garanger, D. Boturyn and P. Dumy
Development of molecular devices endowed with tumor-targeting
functions and carrying cytotoxic components should enable
the specific delivery of chemotherapeutics to malignant tissues,
thus increasing their local efficacy while limiting their
peripheral toxicity. Such molecular vectors can pave the way
for the development of new classes of therapeutics, fighting
against protagonists of neoplastic development. In line with
this concept, peptide ligands containing the Arginine-Glycine-Aspartate
(RGD) triad, which display a strong affinity and selectivity
to the αVβ3
integrin, have been developed to target the tumor-associated
cells expressing the αVβ3
receptors. Among the validated ligands, the leader compound
is the cyclic pentapeptide c[-RGDf(NMe)V-]
(Cilengitide) developed by kessler et al. (J.
Med. Chem., 1999, 42, 3033-3040).
This compound has entered phase II clinical trials as an anti-angiogenic
agent. Further studies have been directed to develop molecular
conjugates of the parent c[-RGDfK-] with conventional chemotherapeutics
or with labels for non-invasive imaging technologies. More
recently, multimeric RGD containing compounds have been exploited
to improve the targeting potential as well as cell-membrane
breaching, through receptor-mediated endocytosis. The latter
have been constructed on various scaffolds (polylysines or
polyglutamates, liposomes, nanoparticles…). Our group
has developed a chemical system combining all these properties
where multivalent RGD targeting functions are associated with
functional molecules through a cyclopeptide template. The
latter represents a relevant non-viral vector for tumor targeting,
imaging and therapy. This review describes the considerations
for the design of the diverse RGD ligands developed so far
and reports an overview of the main applications of these
structures in cancer research.
[Back to top]
Polyphenolic Coumpounds in Chemoprevention of Colon
Cancer – Targets and Signaling Pathways
E. Rudolf, H. Andelová and M. Cervinka
Colorectal cancer is one of the leading causes of premature
death in people worldwide. Due to the fact that malignant
conversion of normal colonic cells requires several steps
and often proceeds over considerable time periods, primary
prevention of this process should include several approaches,
with optimization of nutrition and diet being among most important.
During past decades, several groups of chemicals (both naturally
occurring as well as synthetic) have been studied in terms
of their potential chemopreventive role in colorectal cancer
development. Naturally occurring plant polyphenols have recently
come into scientific focus because of their presence in various
popular natural products (wine grapes, teas, berries, peanuts)
and, more importantly, due to their reported antiproliferative
and cytostatic abilities in various in vitro and
in vivo models. This review seeks to summarize the
currently known targets and mechanisms whereby polyphenolic
compounds interfere with colonic cancer cells while evaluating
their chemopreventive potential in vivo.
[Back to top]
Histone Deacetylase Inhibitors in Cancer Therapy:
Latest Developments, Trends and Medicinal Chemistry Perspective
K.V. Balakin, Y.A. Ivanenkov, A.S. Kiselyov and S.E. Tkachenko
Regulation of gene expression is mediated by several mechanisms
such as DNA methylation, ATP-dependent chromatin remodeling,
and post-translational modifications of histones. The latter
mechanism includes dynamic acetylation and deacetylation of
ε-amino
groups of lysine residues present in the tail of the core
histones. Enzymes responsible for the reversible acetylation/deacetylation
processes are histone acetyltransferases (HATs) and histone
deacetylases (HDACs), respectively. There are three mammalian
HDAC families, namely HDACs I, II and III based on their sequence
homology. Inhibitors of HDACs induce hyperacetylation of histones
that modulate chromatin structure and gene expression resulting
in growth arrest, cell differentiation, and apoptosis of tumor
cells. In addition, HDAC inhibitors enhance efficacy of anticancer
agents that target DNA. Several formidable challenges associated
with their development include non-specific toxicity and poor
PK properties, including cell permeability. In this review,
we comment on the current progress in design, discovery, in
vitro/ex vivo activity and clinical potential of the
synthetic modulators of HDACs.
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