Current Topics in Medicinal Chemistry, Volume 4, No. 2, 2004
Contents
Anticancer
Compounds
Guest
Editor: Antonio Espinosa
Actual Targets in Cytodifferentiation Cancer
Therapy Pp.175-202
Jose
A. Gomez-Vidal, Joaquin Campos, Juan A. Marchal, Houria Boulaiz, Miguel A.
Gallo, Esmeralda Carrillo, Antonio Espinosa and Antonia Aranega
3D QSAR Models of Interactions Between b-Tubulin and Microtubule Stabilizing
Antimitotic Agents (MSAA): A Survey on Taxanes and Epothilones Pp.203-217
Fabrizio
Manetti, Laura Maccari, Federico Corelli, and Maurizio Botta
Antitumor Potential of Aza-bioisosterism in
Anthracenedione-based Drugs Pp.219-230
Claudia
Sissi and Manlio Palumbo
Distamycin A as Stem of DNA Minor Groove
Alkylating Agents Pp.231-239
Pier
Giovanni Baraldi, Maria del Carmen Nunez, Antonio Espinosa and Romeo Romagnoli
Recent Studies on Natural Products as
Anticancer Agents Pp.241-265
Angel
G. Ravelo, Ana Estevez-Braun, Haydee Chavez-Orellana, Elisa Perez-Sacau, Dulce
Mesa-Siverio
Abstracts
[Back to top] Actual Targets in Cytodifferentiation Cancer
Therapy
Jose
A. Gomez-Vidal, Joaquin Campos, Juan A. Marchal, Houria Boulaiz, Miguel A. Gallo,
Esmeralda Carrillo, Antonio Espinosa and Antonia Aranega
Transformation of a normal cell
into a tumor cell results from six essential alterations in cell physiology.
There is a complex relationship that exists between growth, differentiation,
neoplastic transformation, and the expression of genes and tumor suppressor
genes. The knowledge of these mechanisms demonstrates that it is possible to
pharmacologically modulate the growth and differentiation of tumor cells. The
differentiation therapy focuses on demonstrating that cancer is a reversible
state with altered maturation in which the transformed phenotype may be
suppressed by cytostatic agents and by the pharmacological differentiation
towards benign forms with no proliferative potential. One of the mechanisms
determining the activity of target genes is the post-translational modification
of the Nterminal tails of core histones. Inappropriate repression of genes
required for cell differentiation has been linked to several forms of cancer.
Histone deacetylase inhibitors modulate transcription, and are endowed with
cytodifferentiating, antiproliferative and apoptogenic properties. Retinoids
modulate cell differentiation, proliferation, apoptosis and morphogenesis in
vertebrates, and have proved to be clinically useful. Their biological effects
are mediated by the activation of retinoic acid receptors, which are
ligand-dependent gene transcription factors. Checkpoints during cell cycle
allow the cell to respond to proliferation signals or decide between the
alternate pathways leading to cytokinesis, differentiation, quiescence, and
cell death. Abrogation of normal cell cycle controls in tumor cells contributes
to their inability to differentiate and the restoration of such controls in G1
can lead to the resumption of differentiation and terminal cell division.
Chemical inhibitors of cyclin-dependent kinases have been reported to stimulate
differentiation of tumor-cell lines.
[Back to top] 3D QSAR Models of Interactions Between b-Tubulin and Microtubule Stabilizing
Antimitotic Agents (MSAA): A Survey on Taxanes and Epothilones
Fabrizio
Manetti, Laura Maccari, Federico Corelli, and Maurizio Botta
In the last two decades,
paclitaxel (Taxol®, 1) has dominated the anticancer chemotherapy as one of the
most important antimitotic agents. Despite its clinical success, it presents
some limitations due to its low aqueous solubility or multidrug-resistance
(MDR) susceptibility. Among new compounds sharing paclitaxel's mechanism of action,
epothilones have emerged as very promising candidates and are currently under
clinical trials. While the electron crystallography (EC) structure of tubulin
with embedded paclitaxel is available, only hypotheses about epothilone binding
upon the protein may be advanced. This review illustrates our efforts in the
minireceptor modeling approach as the most recent advances in the field of
three-dimensional quantitative structure-activity relationship (3D QSAR)
studies involving taxanes, epothilones and the corresponding protein
environment.
[Back to top] Antitumor Potential of Aza-bioisosterism in
Anthracenedione-based Drugs
Claudia
Sissi and Manlio Palumbo
Aza-bioisosteres of anthracene-9,10-diones and of anthrapyrazoles comprise an innovative class of anticancer compounds. They are formally derived by introduction of one or more nitrogens into the carbocyclic ring system of the parent drugs. Bioisosteres exhibit extensive changes in the physico-chemical properties and in the interactions with the pharmacological targets, DNA and DNA-topoisomerase II, when compared to the carbocyclic analogues. A favourable spectrum of activity, reduced side effects and a unique tropism for solid tumors make the new derivatives a very interesting family of drugs. In particular, a 2-aza-anthracene-9,10-dione and a 9-aza-anthrapyrazole derivative are presently undergoing advanced clinical trials and appear to be promising in view of their approval as anticancer drugs.
[Back to top]
Distamycin
A as Stem of DNA Minor Groove Alkylating Agents
Pier
Giovanni Baraldi, Maria del Carmen Nunez, Antonio Espinosa and Romeo Romagnoli
Analogues of naturally occurring
antitumor agents, such as distamycin A, which bind in the minor groove of DNA,
represent a new class of anticancer compounds currently under investigation.
Distamycin A has driven researcher's attention not only for their biological
activity, but also for its non intercalative binding to the minor groove of
doublestranded B-DNA, where it forms strong reversible complex preferentially
at the nucleotide sequences consisting of 4-5 adjacent AT base pairs. The
pyrrole-amide skeleton of distamycin A has been also used as DNA sequence selective
vehicles for the delivery of alkylating functions to DNA targets, leading to a
sharp increase of its cytotoxicity, in comparison to that, very weak, of
distamycin itself. In the last few years, several hybrid compounds, in which
known antitumor derivatives or simple active moieties of known antitumor agents
have been tethered to distamycin frames, have been designed, synthesized and
tested. Several efforts have been made to modify DNA sequence selectivity and
stability of the distamycin and the structural modifications have been based on
replacement of pyrrole by other heterocycles and/or benzoheterocycles obtaining
a novel class of minor groove binding molecules called lexitropsins. The role
of the amidino moiety, by means of the substitution with various groups, which
includes ionizable, acid or basic, and non-ionizable groups, has been also
studied. The synthesis of a hybrid deriving among the combination of the
distamycin A and naturally occurring alkylating agent has been also reported.
Several classes of distamycin derivatives that have been reported in the
published literature have been described in this review article.
[Back to top] Recent Studies on Natural Products as
Anticancer Agents
Ángel
G. Ravelo, Ana Estévez-Braun, Haydee Chávez-Orellana, Elisa Pérez-Sacau, Dulce
Mesa-Siverio
Cancer will be the major cause of
death in the 21st century and natural products should provide novel
and more effective anticancer agents. This review deals with new natural molecules
liable to become anticancer drugs, as well as recent specific strategies for a
selective treatment of cancer. The introduction presents the current state of
the art on anticancer research. Beside, in the following subheadings we
summarize our research on cytotoxic natural quinone methide-triperpenes and
their analogues. We also discuss our results on the anti-tumour promoting
activity of natural naphthoquinones and their derivatives.