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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 8, Number 2, February 2008
Contents
Recent Advances in Cancer Chemotherapy-Part I
Guest Editor: Diwan S. Rawat
Editorial Pp. 122
Enediyne Anticancer Antibiotic Lidamycin: Chemistry,
Biology and Pharmacology Pp. 123-131
R-g. Shao and Y-s. Zhen
[Abstract]
Acetylenic Anticancer Agents Pp. 132-170
A. Siddiq and V. Dembitsky
[Abstract]
Plant Polyphenolics as Anti-Invasive Cancer Agents
Pp. 171-185
M.E. Bracke, B.W.A. Vanhoecke, L. Derycke, S. Bolca, S.
Possemiers, A. Heyerick, C.V. Stevens, D. De Keukeleire, H.T.
Depypere, W. Verstraete, C.A. Williams, S.T. McKenna, S. Tomar,
D. Sharma, A.K. Prasad, A.L. DePass and V.S. Parmar
[Abstract]
Targeted Tumor Diagnosis and Therapy with Peptide
Hormones as Radiopharmaceuticals Pp. 186-199
I.U. Khan and A.G. Beck-Sickinger
[Abstract]
Biological and Pharmacological Roles of N6-Isopentenyladenosine:
An Emerging Anticancer Drug Pp. 200-204
M. Bifulco, A.M. Malfitano, M.C. Proto, A. Santoro, M.G.
Caruso and C. Laezza
[Abstract]
General Articles
Recent Advances in Classical and Non-Classical
Antifolates as Antitumor and Antiopportunistic Infection Agents:
Part II Pp. 205-231
A. Gangjee, H.D. Jain and S. Kurup
[Abstract]
Gene Directed Enzyme Prodrug Therapy for Ovarian
Cancer: Could GDEPT Become a Promising Treatment Against Ovarian
Cancer? Pp. 232-239
A. Nawa, T. Tanino, C.H. Luo, M. Iwaki, H. Kajiyama, K.
Shibata, E. Yamamoto, K. Ino, Y. Nishiyama and F. Kikkawa
[Abstract]
Abstracts
[Back to top]
Editorial:
Cancer has been one of the most deadly diseases characterized
by uncontrolled cell divisions and the ability of these cells
to spread either by invasion, or by metastasis. It
has overtaken the heart disease which is one of the commonest
causes of death in some developed countries. Cancer affects
people at all ages, but risk tends to increase with age. Worldwide
over 11 million people are diagnosed with cancer and 7 million
deaths are reported annually. It is estimated that there will
be 16 million new cases every year by 2020. In spite of improved
understanding of molecular biology of cancer and advances
in oncology, replacement of conventional therapies like chemotherapy
and radiation therapy still remains impossible. Natural product
has been a source of new drugs since ancient times and about
60% anti-cancer drugs available today, are either derived
from natural sources or their synthetic analogues. Some of
the notable plant based drugs that has entered in the clinical
trials are taxol, obtained from the bark of pacific yew trees-Taxus
brievifolia, camptothecin isolated from the Chinese ornamental
tree Camptpotheca acuminata. Camptothecin showed
great promises in the 1970’s, but its clinical use was
hampered due to its severe side effects. The structure activity
relationship studies conducted on camptothecin derivatives
resulted in the discovery of anti-cancer drugs such as topotecan
and irinotecan. Microorganisms have also been the source of
the key drugs for cancer chemotherapy and some of the microorganism
based anticancer drugs are bleomycins, dactinomycin, mytomycine,
anthracylinones, calchiamycin, dynamycine, daunomycin and
doxorubicin (adriamycin). All of these compounds were introduced
to the clinic before their mode of action had been determined.
The anti-cancer activity of most of these compounds is due
to their ability to cleave the DNA through different modes.
This especial issue entitled “Recent advances in cancer
chemotherapy” provides glimpses of recent development
on anti-cancer drugs that includes synthetic, semi-synthetic,
natural products and their clinical applications. The articles
are written by leading scientists in the field which clearly
shows that there are indeed fascinating and fundamentally
important problems to be addressed and that considerable advances
towards their understanding have been made. The present issue
deals with the anti-cancer agents of natural sources or their
synthetic or semi-synthetic derivatives. Enediyne class of
compounds has received much attention of the scientist in
recent years due to their potential use in the anti-cancer
drug discovery programme. Shao et al. describes the
recent progress, particularly in the area of biosynthesis,
immunoconjugates and clinical studies of lindamycin. The pharmacological
applications of lidamycin in cancer therapy and its potential
use as anti-cancer agents have also been discussed. Dembitsky
et al. presented a comprehensive literature collection
on the acetylenic anticancer natural products. The review
presents anti-cancer activity of more than 300 acetylenic
metabolites isolated from terrestrial and aquatic organisms.
Parmar et al. presented an excellent literature collection
on the natural polyphenolic compounds as antiinvasive agents.
Prof. Beck-Sickinger described the role of radiolabelled receptor
binding peptides as a new class of radiopharmaceuticals for
tumor scintigraphy and to treat cancers by using peptide receptor
radiation therapy (PRRT). Lastly, Bifulco et al.
discuss preliminary clinical observation that indicates a
possible use of N6-isopentenyladenosine as anticancer drug.
Finally, I would like to thank to all contributors and reviewers
who helped me to bring this issue in its present shape. In
particular, to the authors for generously contributing their
expertise in the preparation of this issue. I greatly appreciate
the honor given to me by Prof. Michelle Prudhomme, Editor-in-Chief,
Anti-Cancer Agents in Medicinal Chemistry, in entrusting me
as a Guest Editor of this special issue. Anti-Cancer Agents
in Medicinal Chemistry is a high-standard international journal
through which important discoveries in the area of anti-cancer
research becomes available to the scientific community. I
hope that readers will enjoy reading this issue and it will
stimulate interactive research with other specialist areas.
The mutual interaction among scientist of different disciplines
will be helpful for the development of more effective drugs,
diagnostics and therapies for the treatment of cancer.
Dr. Diwan S. Rawat
Department of Chemistry
University of Delhi, Delhi-110007
India
Tel: 91-11-27667465
Fax: 91-11-27667501
E-mail: dsrawat@chemistry.du.ac.in
[Back to top]
Enediyne Anticancer Antibiotic Lidamycin: Chemistry, Biology
and Pharmacology
R-g. Shao and Y-s. Zhen
The enediyne antibiotics, the potent anticancer agents that
contain diyne-ene functional groups, are appreciated for their
novel molecular architecture, their remarkable biological
activity and their fascinating mechanism of action. Their
anticancer activity is apparently due to their ability to
damage DNA through radical-mediated hydrogen abstraction.
The enediyne antibiotics show markedly cytotoxicities against
cancers in vitro and in vivo. Lidamycin
is a member of the enediyne anticancer antibiotic family.
This review examines lidamycin with particular emphasis on
the discovery, the biological properties and its structure-activity
relationships. In addition, the possible mechanisms of action
of lidamycin are described. Recent progress, particularly
in the areas of biosynthesis, and immunoconjugates are highlighted.
Finally, the pharmacological applications of lidamycin in
cancer therapy and its potential use as anticancer agents
are also discussed.
[Back to top]
Acetylenic Anticancer Agents
A. Siddiq and V. Dembitsky
This review is a comprehensive survey of acetylenic anticancer
agents obtained from living organisms. Acetylenic metabolites
belong to a class of molecules containing triple bond(s).
They are found in plants, fungi, microorganisms, and marine
invertebrates. Although acetylenes are common as components
of terrestrial plants, fungi, and bacteria, it is only within
the last 30 years that biologically active polyacetylenes
having unusual structural features have been reported from
plants, cyanobacteria, algae, invertebrates, and other sources.
Naturally occurring aquatic acetylenes are of particular interest
since many of them display important biological activities
and possess antitumor, antibacterial, antimicrobial, antifungal,
phototoxic, HIV inhibitory, and immunosuppressive properties.
There is no doubt that they are of great interest, especially
for the medicinal chemistry, and/or pharmaceutical industries.
This review presents structures and describes cytotoxic activities
of more than 300 acetylenic metabolites isolated from living
organisms.
[Back to top]
Plant Polyphenolics as Anti-Invasive Cancer Agents
M.E. Bracke, B.W.A. Vanhoecke, L. Derycke, S. Bolca, S.
Possemiers, A. Heyerick, C.V. Stevens, D. De Keukeleire, H.T.
Depypere, W. Verstraete, C.A. Williams, S.T. McKenna, S. Tomar,
D. Sharma, A.K. Prasad, A.L. DePass and V.S. Parmar
Because invasion is, either directly or via
metastasis formation, the main cause of death in cancer patients,
development of efficient anti-invasive agents is an important
research challenge. We have established a screening program
for potentially anti-invasive compounds. The assay is based
on organotypic confronting cultures between human invasive
cancer cells and a fragment of normal tissue in three dimensions.
Anti-invasive agents appeared to be heterogeneous with regard
to their chemical nature, but plant alkaloids, polyphenolics
and some of their synthetic congeners were well represented.
Even within this group, active compounds were quite diverse:
(+)-catechin, tangeretin, xanthohumol and other prenylated
chalcones, 3,7-dimethoxyflavone, a pyrazole derivative, an
isoxazolylcoumarin and a prenylated desoxybenzoin. The data
gathered in this system are now applied in two projects. Firstly,
structure-activity relationships are explored with computer
models using an artificial neural network approach, based
on quantitative structural descriptors. The aim of this study
is the prediction and design of optimally efficient anti-invasive
compounds. Secondly, the metabolism of orally ingested plant
polyphenolics by colonic bacteria is studied in a simulator
of the human intestinal microbial ecosystem (SHIME) and in
human intervention trials. This method should provide information
on the final bioavailability of the active compounds in the
human body, with regard to microbial metabolism, and the feasibility
of designing pre- or probiotics that increase the generation
of active principles for absorption in the gastro-intestinal
tract. The final and global aim of all these studies is to
predict, synthesize and apply in vivo molecules with
an optimal anti-invasive, and hence an anti-metastatic activity
against cancer.
[Back to top]
Targeted Tumor Diagnosis and Therapy with Peptide Hormones
as Radiopharmaceuticals
I.U. Khan and A.G. Beck-Sickinger
Regulatory, receptor-binding peptides could be considered
as future agents of choice for diagnostic imaging and therapy
of cancers because their receptors are overexpressed in various
human cancer cells. Peptides exhibit several advantages over
classical macromolecules or drugs, e.g., from the chemical
point of view: they are easy to synthesize and can withstand
harsh chemical conditions which are required for chelation
and radiolabeling. From the biological point of view, peptides
exhibit fast blood clearance and high target-to-background
ratios through receptor-mediated internalization. Furthermore,
they are effective carriers for the delivery of cytotoxic
drugs to target the affected tissues, thus avoiding normal
cells from non-specific toxicity of anticancer agents. Owing
to these features, radiolabeled receptor-binding peptides
have emerged as a new class of radiopharmaceuticals for tumor
scintigraphy and, more recently, to treat cancers by using
peptide receptor radiation therapy (PRRT). The challenge in
this scenario is to modify bioactive peptide hormones and
to synthesize new sequences with improved metabolic stability
without affecting the receptor binding properties after labeling
with a chelator for incorporation of a radiometal. At the
present time, however, the radiolabeled cholecystokinin-2
(CCK2)- and octreotide somatostatin-receptor selective analogs
are the only examples that are being used in clinical practice.
Other peptides such as neurotensin-, substance P-, gastrin-releasing
peptide-, glucagons-like peptide 1 and neuropeptide Y (NPY)
are under investigation to target breast, prostate, ovary,
pancreas and brain tumors, in which overexpression of these
peptide receptors has been reported. Among these peptides,
neuropeptide Y (NPY) seems to be a very promising candidate
because the change in its subtype receptor expression correlates
with neoplastic changes. Here, we summarize the variety of
experiences gained in the development of various peptide analogs,
chelator/radiolabeling techniques for applications in tumor
imaging and therapy.
[Back to top]
Biological and Pharmacological Roles of N6
Isopentenyladenosine: An Emerging Anticancer Drug
M. Bifulco, A.M. Malfitano, M.C. Proto, A. Santoro, M.G.
Caruso and C. Laezza
A common modification of eukaryotic and bacterial tRNAs
is isopentenylation of the adenosine at position 37, with
the formation of isopentenyladenosine. N6-Isopentenyladenosine
plays a major role in posttranscriptional processes, including
the function of mammalian selenocysteine tRNA. This molecule
seems to have metabolic effects that, for its relationships
with isoprenoid metabolism and its direct biological activities,
affects mammalian cell cytoskeleton, proliferation and apoptosis.
In addition, preliminary clinical observation seems to indicate
a possible use of N6-Isopentenyladenosine as anticancer drug.
[Back to top]
Recent Advances in Classical and Non-Classical Antifolates
as Antitumor and Antiopportunistic Infection Agents: Part
II
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) are newer antifolates
that 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). Recently, classical antifolates that do
not need to be polyglutamylated have also been developed and
include plevitrexed (6) and GW1843 (7).
Nolatrexed (8), trimethoprim {TMP, (11)}
and piritrexim {PTX, (12)} are nonclassical
antifolates for antitumor and parasitic chemotherapy that
passively diffuse into cells and hence do not have to depend
on FPGS or the reduced folate carrier (RFC). Structural requirements
for inhibition with antifolates have been studied extensively
and novel agents that exploit key interactions in the active
site of TS, DHFR, FPGS, and RFC have been proposed. 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 were discussed in Part I. The 6-6
bicyclic and tricyclic antifolates will be discussed here
in Part II.
[Back to top]
Gene Directed Enzyme Prodrug Therapy for Ovarian Cancer: Could
GDEPT Become a Promising Treatment Against Ovarian Cancer?
A. Nawa, T. Tanino, C.H. Luo, M. Iwaki, H. Kajiyama, K.
Shibata, E. Yamamoto, K. Ino, Y. Nishiyama and F. Kikkawa
Gene-directed enzyme prodrug therapy (GDEPT) involves
the treatment concept of having maximal efficacy and minimal
adverse effects. Several GDEPT strategies have been developed
combining cytosine deaminase and 5-fluorocytosine, cytochrome
P450 2B1 and cyclophosphamide, and carboxylesterase (CES)
and irinotecan in experimental models. The active forms of
these prodrugs, however, are not a frontline therapy for the
treatment of ovarian cancer. It would be beneficial to develop
a more effective prodrug-enzyme combination for the treatment
of this disease.
Paclitaxel (TaxolR; TAX)
is currently one of the most important anti-cancer drugs in
chemotherapy of ovarian cancer. One of TAX prodrugs, 2’-ethylcarbonate-linked
paclitaxel (TAX-2’-Et), was generated and examined regarding
its pharmacological aspects. The prodrug of TAX-2’-Et
converts into active form TAX by carboxylesterase (CES). TAX-2’-Et
did not exhibit polarized transport in the Caco-2 cells expressing
P-glycoprotein (P-gp) in the absence or presence of verapamil
which is a inhibitor of P-gp, suggesting that TAX-2’-Et
is not a target of P-gp like TAX and rhodamine123. Moreover,
SKOV3/TAX60 cells which are overexpressing P-gp did not also
exhibit any change in cellular uptake of TAX-2’-Et regardless
of the absence or presence of verapamil. Consequently, the
uptake of TAX-2’-Et into the TAX-resistant cells was
quantitatively similar to that internalized in the parental
SKOV3 cells which are P-gp-negative. In the CES-transfected
SKOV3 cells, the EC50 value
of TAX (10.6 nM) was approximately 4-fold higher than that
of TAX-2’-Et (2.5 nM). We herein provide evidence that
TAX-2’-Et could circumvent P-gp-associated cellular
efflux of TAX, suggesting that this combination therapy is
a potential GDEPT strategy for ovarian cancer in the future.
Finally, this review focuses on the development, application
and potential of various GDEPTs for treating ovarian cancer,
and the scope and progress of new GDEPTs are discussed.
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