Design of New Anti-Cancer
Agents Based on Topoisomerase Poisons Targeted to Specific DNA Sequences Pp-219-235
P.B. Arimondo and C. Hélène
Naphthalimides as Anticancer Agents: Synthesis and Biological Activity Pp-237-255
M.F. Braña and A. Ramos
Advances in the Chemistry
and Pharmacology of Ecteinascidins, A Promising New Class of Anticancer Agents Pp-257-276
Manzanares, C. Cuevas, R. García-Nieto, E. Marco and
F. Gago
Biospecific Interaction
Analysis (BIA) as a Tool for the Design and Development of Gene Transcription
Modifiers Pp-277-291
Roberto Gambari
Cytotoxic Activity of Styryl
Lactones and their Derivatives Pp-293-300
Hari Babu Mereyala and Maju Joe
Aminophosphonic Acids of
Potential Medical Importance Pp-301-312
Pawel Kafarski and Barbara Lejczak
Tumor Bone Diseases:
Molecular Mechanisms and Opportunities for Novel Treatments Pp-313-329
Mira Susa, Markus Glatt and Anna Teti
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Design of New Anti-Cancer
Agents Based on Topoisomerase Poisons Targeted to Specific DNA Sequences
P.B. Arimondo and C. Hélène
There
is considerable interest in the development of sequence-selective DNA drugs.
Chemical agents able to interfere with DNA topoisomerases - essential nuclear
enzymes- are widespread in nature, and some of them have outstanding
therapeutic efficacy in human cancer and infectious diseases. Several classes
of antineoplastic drugs, such as amsacrine, daunorubicin, etoposide (acting on
type II topoisomerases), camptothecin and indolocarbazole derivatives of the
antibiotic rebeccamycin (acting on type IB topoisomerases, have been shown to
stimulate DNA cleavage by topoisomerases leading to cell death. However, these
molecules exhibit little sequence preference. A convenient strategy to confer
sequence specificity consists in the attachment of these topoisomerase poisons
to sequence-specific DNA binding elements. Among sequence-specific DNA ligands,
oligonucleotides can bind with high specificity of recognition to the major
groove of double-helical DNA, resulting in triple helix formation. In this
context, derivatives of camptothecin, indolocarbazole, anthracycline and
acridine poisons have been covalently tethered to triple helix-forming
oligonucleotides. The use of triple-helical DNA structures offers an efficient
system to target topoisomerase I and II-mediated DNA cleavage to specific
sequences and to increase the drug efficacy at these sites. Chemical
optimization of the conjugates is essential to the efficacy of drug targeting.
Consequently, the rational design of this new class of anti-cancer agents,
conceived from topoisomerase poisons and triplex-forming oligonucleotides, may
be exploited to improve the efficacy and selectivity of the DNA damage induced
by topoisomerases.
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Naphthalimides as Anticancer
Agents: Synthesis and Biological Activity
M.F. Braña and A. Ramos
Naphthalimides
are a class of compounds with high antitumor activity upon a variety of murine
and human tumor cells. These compounds bind to DNA by intercalation of the
chromophore and two of them, mitonafide and amonafide, were used in clinical
trials. The therapeutic properties of these lead drugs were improved by
designing bisintercalating agents. One of these, elinafide, showed intense in
vitro and in vivo activity and is currently being used in clinical trials
against solid tumors. In this paper, the history of elinafide is described.
[Back to top]
Advances in the Chemistry
and Pharmacology of Ecteinascidins, A Promising New Class of Anticancer Agents
Manzanares, C. Cuevas, R. García-Nieto, E. Marco and
F. Gago
Ecteinascidins
are marine natural products consisting of two or three linked
tetrahydroisoquinoline subunits and an active carbinolamine functional group.
Their potent antiproliferative activity against a variety of tumor cells has
made them attractive candidates for development as anticancer agents. The lead
compound, ecteinascidin 743 (ET 743), is currently in phase II clinical trials
but the low amounts present in its natural source, the tunicate Ecteinascidia
turbinata, made it necessary to develop efficient synthetic procedures. Recent
improvements on the original synthesis are reviewed as well as new strategies
starting from readily available cyanosafracin B. ET 743 is known to bind to the
minor groove of DNA giving rise to a covalent adduct with the exocyclic amino
group at position 2 of a guanine in a fashion similar to saframycin
antibiotics. Some of the resulting complexes have been studied by a variety of
biochemical and spectroscopic methods and also by computer simulations. The
rules for sequence specificity have been well established (preferred targets
are RGC and YGG, where R and Y stand for purine and pyrimidine,
respectively), and it has been shown that binding of ET 743 to DNA is
accompanied by minor groove widening and DNA bending towards the major groove.
Although the precise target for antitumor action remains to be unambiguously
defined, a role in affecting the transcriptional regulation of some inducible
genes is rapidly emerging.
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to top]
Biospecific Interaction Analysis (BIA) as a
Tool for the Design and Development of Gene Transcription Modifiers
Roberto Gambari
The
applications of surface plasmon resonance (SPR) and biosensor technology for
biospecific interaction analysis (BIA) of molecular interactions between
transcription modifiers and target biomolecules is here described for the
identification of possible candidates for drug research and development in
antitumor and antiviral therapy. SPR-based BIA offers many advantages with
respect to most of the other available methodologies to study biomolecular
interactions. It should be underlined that (a) most commercially available
biosensors are fully automated instruments; (b) no labelling is required; (c) a
large variety of activated sensor chips are commercially available allowing the
immobilization of either proteins or target DNA or RNA; (d) the amount of both
ligand and analyte needed to obtain informative results is low; (e) the assay
is rapid and (f) the sensor chip could be re-used many times, leading to low
running costs, with the only limitation of verifying the stability of the
immobilized ligand. Approaches employing SPR-based BIA were described for the
development of (a) triple-helix forming oligonucleotides (TFO) and peptide
nucleic acids (PNAs), (b) DNA-binding drugs, (c) decoy molecules and (d) PNAs
able to perform strand invasion. All these biomolecules are of great interest
for the development of transcription modifiers. Since alteration of the
expression of transcription factors is involved in tumor cell growth and
metastasis, SPR-based BIA appears to be a methodology of great impact in the
design and development of anti-cancer agents.
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Cytotoxic Activity of Styryl
Lactones and their Derivatives
Hari Babu Mereyala and Maju Joe
Many
studies that have been conducted to establish the cytotoxic potency of styryl
lactones for several tumor cell lines is described. Extensive examination of
the activity of more than 50 cytotoxic styryl lactones isolated/synthesized
belonging to the genus goniothalamus representing future generation of
antitumor drugs is described for the first time at the molecular level.
Goniopypyrone (39) is the most cytotoxic compound followed by altholactone
(+)-1 (10-5 to 10-7
molar for IC50). Enantiomer (-)-1
and three stereocongeners 2-4 did not exhibit any significant increase in
cytotoxicity. Cytotoxicity of semisynthetically derived products 5-11 is
discussed recognising 11-nitro altho-lactone (+)-5 as a promising lead
compound.
Eight
membered styryl lactones 12a - 12e are substrates with important cytotoxicity
explained by the inhibition of the mammalian mitochondrial respiratory chain
complex I. Among C7-C8
functionalised styryl lactones gonio diol (25) is the most active being
selectively cytotoxic against A549 tumour cells. Goniofufurone (42) and several
of its derivatives including one-carbon homologues 43-50 were reported to be
inactive.
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Aminophosphonic Acids of Potential Medical Importance
Pawel Kafarski and Barbara Lejczak
Aminophosphonic
acids were almost unknown in 1959 but today they are the subjects of more than
6000 papers. Their negligible mammalian toxicity, and the fact that they very
efficiently mimic aminocarboxylic acids makes them extremely important
antimetabolites, which compete with their carboxylic counterparts for the
active sites of enzymes and other cell receptors. Although biological
importance of these compounds was recognized over 50 years ago they still represent
promising and somewhat undiscovered class of potential drugs.
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Tumor Bone Diseases:
Molecular Mechanisms and Opportunities for Novel Treatments
Mira Susa, Markus Glatt and Anna Teti
A
variety of cancers are associated with bone. Primary tumors can arise in bone,
common cancers, such as those of breast and prostate origin, metastasize to
bone, and multiple myeloma neoplastic disease affects bone profoundly. The
cellular and molecular mechanisms underlying these pathological processes are
increasingly being understood. The interaction of tumor cells with bone cells,
osteoblasts and osteoclasts, and with the bone local environment is a new
promising direction in research, which should help to develop new therapies. In
this article we will relate the newest developments in the molecular research
to the pathology of the tumor bone disease. Potential new targets for drugs,
aimed specifically at tumor bone diseases, will be highlighted. Furthermore, we
will describe the existing compounds that are either used in treatment or have
a potential as therapeutic agents, such as bisphosphonates, Src inhibitors, and
selective estrogen receptor modulators.