| 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 2, March 2007
Contents
Acridine and Acridone Derivatives, Anticancer
Properties and Synthetic Methods: Where Are We Now?
Pp. 139-169
P. Belmont, J. Bosson, T. Godet and M. Tiano
[Abstract]
In Silico Design of Protein Kinase Inhibitors:
Successes and Failures Pp. 171-188
G.G. Dubinina, O.O. Chupryna, M.O. Platonov, P.O. Borisko,
G.V. Ostrovska, A.O. Tolmachov and A.A. Shtil
[Abstract]
Recent Progress in Discovery and Development of Antimitotic
Agents Pp. 189-208
A. Kiselyov, K.V. Balakin, S.E. Tkachenko, N. Savchuk
and A.V. Ivachtchenko
[Abstract]
Meta-Analysis of Anticancer Drug Structures –
Significance of Their Polar Allylic Moieties Pp.
209-222
N.S. Radin
[Abstract]
Vascular Endothelial Growth Factor (VEGF) Inhibition
- A Critical Review Pp. 223-245
I.S. Moreira, P.A. Fernandes and M.J. Ramos
[Abstract]
Antitumor Carbazoles Pp. 247-267
C. Asche and M. Demeunynck
[Abstract]
Abstracts
[Back to top]
Acridine and Acridone Derivatives, Anticancer
Properties and Synthetic Methods: Where Are We Now?
P. Belmont, J. Bosson, T. Godet and M. Tiano
Acridine derivatives are interesting chemotherapeutic
agents that were first used as antibacterial and antiparasite
agents. In this review we wish to concentrate our attention
on the anticancer properties of acridines used in clinics
since the 1970’s. Based on recent results, an outlook
on antitumour acridine chemotherapy will be proposed. The
biological activity of acridines is mainly attributed to the
planarity of these aromatic structures, which can intercalate
within the double-stranded DNA structure, thus interfering
with the cellular machinery. Recent understanding of the mode
of action of acridines leads to continuous and exciting research
in this heterocyclic family. Indeed, biological targets such
as topoisomerases I and II, telomerase/telomere and protein
kinases emerge and allow the design of novel acridine-based
patterns. This review further pinpoints the latest progress
in the development of anticancer agents based on naturally
occurring and synthetic acridines (e.g. acridones,
pyridoacridines); for this matter in vitro/in vivo
studies and clinical trial results will be discussed. The
DNA-affinic property of acridine is also useful to vectorise
drugs into cell nuclei and some applications in hypoxia-selective
treatment, platinum or N-mustard derived conjugates
will be reported. Some other properties including inhibition
of multidrug resistance or potential impact on Alzheimer disease
will be treated. It is noteworthy that the position and the
nature of the substituent on the heterocyclic core are determinants
for the biological property and selectivity observed. So,
we wish also to disclose a summary of recent synthetic methodologies
developed for acridine synthesis.
[Back to top]
In Silico Design of Protein Kinase Inhibitors:
Successes and Failures
G.G. Dubinina, O.O. Chupryna, M.O. Platonov, P.O. Borisko,
G.V. Ostrovska, A.O. Tolmachov and A.A. Shtil
Protein kinases are among the most exploited targets in modern
drug discovery due to key roles these enzymes play in human
diseases including cancer. The in silico approach,
an important part of rational design of protein kinase inhibitors,
is founded on vast information about 3D structures of these
enzymes. This review summarizes general structural features
of the kinase inhibitors and the studies applied toward a
large scale chemical database for virtual screening. Analyzed
are the ways of validating the modern docking tools and their
combinations with different scoring functions. In particular,
we discuss the kinase flexibility as a reason for failures
of the docking procedure. Finally, evidence is provided for
the main patterns of kinase-inhibitor interactions and creation
of the hinge-region-directed 2D filters.
[Back to top]
Recent Progress in Discovery and Development of Antimitotic
Agents
A. Kiselyov, K.V. Balakin, S.E. Tkachenko, N. Savchuk
and A.V. Ivachtchenko
This review highlights structural diversity of antimitotic
agents. In particular, we emphasized current antimitotic therapies
based on modulation of microtubule dynamics. With several
successful anticancer drugs on the market and numerous compounds
in clinical developments, tubulin-binding agents remain among
the most important categories of anticancer agents. Compounds
targeting mitotic kinases and kinesins are also discussed.
[Back to top]
Meta-Analysis of Anticancer Drug Structures –
Significance of Their Polar Allylic Moieties
N.S. Radin
This meta-analysis examines a wide range of small molecule
anticancer drugs to search for a structure common to all.
Although they encompass a very wide range of structures, nearly
all reveal the presence of an allylic O, N, or S atom. In
some, the allylic oxygen is a carbonyl group, or an alcohol
group, which can be substituted (ester, lactone, glycoside,
ether) or replaced by an amino or imino nitrogen Some antineoplastic
drugs do not exhibit this moiety but are converted in
vivo to allylic derivatives. An allylic hydroxyl is also
present in most sphingolipids, ubiquitous body components
that control proliferative and anti-proliferative
cell functions. Ceramide, the precursor of all the allylic
sphingolipids, seems to be a general inducer of apoptosis
in cancer cells. Further examination of sphingolipids and
anticancer drugs shows the frequent occurrence of [i] double
bonds conjugated to the allylic bond, (ii) two or more allylic
moieties in each molecule, (iii) lipophilic features, especially
linear chains, and (iv) attachment of an O, N, or S atom to
a carbon atom of the allylic double bond, e.g., –CH2–C(OMe)=CH–CH(OH)–CH2–.
Suggested mechanisms of action: (a) allylic ketone drugs undergo
a Michael condensation with tumor thiols or other reactive
groups; (b) allylic OH drugs undergo oxidation to an allylic
ketone, generating reactive oxygen; (c) some interfere with
mitochondrial ubiquinone, blocking ATP production; (d) some
act as a ceramide mimic (inhibitor or agonist) in ceramide-controlled
kinases, phosphatases, and proteases; (e) many antineoplastic
drugs stimulate ceramide-forming processes.
[Back to top]
Vascular Endothelial Growth Factor (VEGF) Inhibition
- A Critical Review
I.S. Moreira, P.A. Fernandes and M.J. Ramos
Angiogenesis, or formation of new blood capillaries from preexisting
vessels, plays both beneficial and damaging roles in the organism.
It is a result of a complex balance of positive and negative
regulators, and vascular endothelial growth factor (VEGF)
is one of the most important pro-angiogenic factors involved
in tumor angiogenesis. VEGF increases vascular permeability,
which might facilitate tumor dissemination via the
circulation causing a greater delivery of oxygen and nutrients;
it recruits circulating endothelial precursor cells, and acts
as a survival factor for immature tumor blood vessels. The
endotheliotropic activities of VEGF are mediated through the
VEGF-specific tyrosine–kinase receptors: VEGFR-1, VEGFR-2
and VEGFR-3. VEGF and its receptors play a central role in
tumor angiogenesis, and therefore the blockade of this pathway
is a promising therapeutic strategy for inhibiting angiogenesis
and tumor growth. A number of different strategies to inhibit
VEGF signal transduction are in development and they include
the development of humanized neutralizing anti-VEGF monoclonal
antibodies, receptor antagonists, soluble receptors, antagonistic
VEGF mutants, and inhibitors of VEGF receptor function. These
agents can be divided in two broad classes, namely agents
designed to target the VEGF activity and agents designed to
target the surface receptor function.
The main purpose of this review is to summarize all the available
information regarding the importance of the pro-angiogenic
factor VEGF in cancer therapy. After an overview of the VEGF
family and their respective receptors, we shall focus our
attention on the different VEGF-inhibitors existent nowadays.
Agents based upon anti-VEGF therapy have provided solid proofs
about their success, and therefore we believe that a critical
review is of the utmost importance to help researchers in
their future work.
[Back to top]
Antitumor Carbazoles
C. Asche and M. Demeunynck
Natural and synthetic carbazoles, either in a pure
substituted or in an annellated substituted form, represent
an important and heterogeneous class of anticancer agents,
which has grown considerably over the last two decades. Many
carbazole derivatives have been tested for cyctotoxic activity,
some of them have entered clinical trials, but only very few
have been approved for the treatment of cancer so far, since
the clinical application of many carbazoles has encountered
problems like severe side effects or multidrug resistance.
Due to their polycyclic, planar and aromatic structure carbazoles
are predestined for intercalation into DNA and therefore DNA
remains one of the main targets for cytotoxic carbazoles.
For many carbazoles cytotoxicity can be related to DNA-dependent
enzyme inhibition such as topoisomerase I/II and telomerase.
But also other targets such as cyclin-dependent kinases and
estrogen receptors have emerged.
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