Current Pharmaceutical Design, Vol. 6, No. 18, 2000
From a Classic Approach in Cancer
Chemotherapy Towards Differentiation Therapy: Acyclic and Cyclic Seven-Membered
5-Fluorouracil O,N-Acetals. Pp. 1797-1810.
J. Campos, J.
F. Domínguez, M. A. Gallo and A. Espinosa
Antitumor Properties of Podophyllotoxin and
Related Compounds. Pp. 1811-1839.
M.Gordaliza,
M.A. Castro, J.M. Miguel del Corral and A. San Feliciano
Understanding and Exploiting Nature's
Chemical Arsenal: The Past, Present and Future of Calicheamicin Research. Pp. 1841-1879.
Jon S.
Thorson, Eric L. Sievers, Joachim Ahlert, Erica Shepard, Ross E. Whitwam,
Kenolisa C. Onwueme and Mark Ruppen
Mucins in the Diagnosis and Therapy of
Pancreatic Cancer. Pp. 1881-1896.
Jenny J.L. Ho
Fibroblast Growth Factors and Their
Inhibitors. Pp. 1897-1924.
F. Manetti,
F. Corelli and M. Botta
[Back to top] Structure-based Design of Compounds Inhibiting Grb2-SH2 Mediated Protein-protein Interactions in Signal Transduction Pathways.
Receptor protein tyrosine kinases are usually
activated upon binding their growth factors, or other suitable ligands, to
their extracellular domains. These activated receptors initiate cytoplasmic
signalling cascades which, when aberrant, can result in different disease
states, such as oncogenic transformation. Many receptor protein tyrosine
kinases use Src homology 2 domains (SH2) to couple growth factor activation
with intracellular signalling pathways to mediate cell control and other
biological events. The characterization of the components involved
in these signal transduction pathways has resulted in the identification of new
attractive targets for therapeutic intervention. Such is the case for the
protein-protein interactions involving the SH2 domain of growth factor receptor
bound protein 2 (Grb2). Agents that specifically disrupt Grb2-SH2 binding
interactions involved in aberrant signalling could potentially shut down these
oncogenic pathways and thus block human malignancies.
This paper reviews the structural characteristics of the Grb2-SH2 domain and the approaches which have been used to identify antagonists of the Grb2-SH2 domain. Examples have been selected from our own research to illustrate how the unique structural features of the ligand-bound Grb2-SH2 have been exploited to design potent and selective Grb2-SH2 antagonists.
[Back to top]
From a Classic Approach in Cancer Chemotherapy
Towards Differentiation Therapy: Acyclic and Cyclic Seven-Membered
5-Fluorouracil O,N-Acetals.
Novel derivatives of 5-fluorouracil (5-FU) possessing a broader spectrum of antitumor activity and fewer toxic side effects than 5-FU have been sought. Herein, we report three different types of 5-FU O,N-acetals: a) a novel class of 5-fluorouracil-containing acyclonucleosides. The antitumor activities of such compounds were assessed against HEp human cells showing that (RS)-1-{[3-(2-hydroxyethoxy)-1-cyclopentoxy]propyl}-5-fluorouracil 3c is 4-fold more active than 5-FU. (RS)-1-{[3-(2-hydroxyethoxy)-1-isopropoxy]propyl}-5-fluorouracil 3b has important potential advantages over 5-FU because of its lower toxicity and its ability to induce myogenic differentiation in rhabdomyosarcoma cells. Our results suggest that this drug may be useful for differentiation therapy in this type of tumor; b) within the cyclic prodrugs of 5-FU, a series of new ring-expanded isosteres (1,4-oxaheteroepanes) of Ftorafur were synthesized. The level of diastereoselectivity in the preparation of cis and trans 1-(3-chloromethyl)-1,4-dioxepan-5-yl)-5-fluorouracil, although modest, suggests a potentially general approach for controlling the stereochemistry of this unexplored class of reactions involving the preparation of 5-FU seven-membered O,N-acetals; c) new 5-FU acyclic analogs containing two 5-FU moieties at both ends of the molecules with a linker having two amide bonds have been designed and synthesized. These bis(5-FU-O,N-acetals) show interesting antineoplastic activities against the HT-29 cell line.
[Back to top]
Antitumor Properties of Podophyllotoxin and Related
Compounds.
The lignan family of natural products
includes compounds with important antineoplastic and antiviral properties such
as podophyllotoxin and two of their semisynthetic derivatives, etoposide and
teniposide. The latter are included in a wide variety of cancer chemotherapy
protocols. Due to these biological activities, lignans, and especially
cyclolignans, have been the objective of numerous studies focused to prepare
better and safer anticancer drugs.
The mechanism by which podophyllotoxin blocks
cell division is related to its inhibition of microtubule assembly in the
mitotic apparatus. However, etoposide and teniposide were shown not to be
inhibitors of microtubule assembly which suggested that their antitumor
properties were due to another mechanism of action, via their interaction with
DNA and inhibition of DNA topoisomerase II. Other podophyllotoxin derivatives
has also been reported which retained or even improved the cytotoxic activity,
but these were weak inhibitors of topoisomerase II in vitro; the data revealed that such analogs exhibit a different,
as yet unknown, mechanism of action.
The main deficiency of these compounds is
their cytotoxicity for normal cells and hence side effects derived from their
lack of selectivity against tumoral cells. In this regard it is necessary to
investigate and prepare new more potent and less toxic analogs, that is, with
better therapeutic indices. It is well accepted from structure-activity studies
in this field that the trans-lactones
are more potent as antineoplastics than the cis-lactones.
Not only the configuration of the D ring is an important factor for high
cytotoxic activity, but also a quasi-axial
arrangement of the E ring is necessary. On this basis, studies on lignans have
been addressed to modify the lactone moiety and prepare analogs with
heteroatoms at different positions of the cyclolignan skeleton.
Our group has been working during the last
few years on chemical transformations of podophyllotoxin and analogs and we
have prepared a large number of cyclolignan derivatives some of which display
potent antiviral, immunosuppressive and cytotoxic activities. We have reported
several new cytotoxic agents with nitrogen atoms at C-7 or C-9 or at both C-7
and C-9: imine derivatives, oxime derivatives, pyrazoline-, pyrazo- and
isoxazoline-fused cyclolignans. At present, we are preparing mainly new
compounds by modifications of the A and E cyclolignan-rings. They are being
tested on cultures of different tumoral cell lines (P-388 murine leukemia,
A-549 human lung carcinoma, HT-29 human colon carcinoma and MEL-28 human
melanoma) and some of them have shown an interesting and selective
cytotoxicity.
[Back to top] Understanding and Exploiting Nature's Chemical Arsenal: The Past, Present and Future of Calicheamicin Research.
The enediyne antitumor antibiotics are appreciated for their novel molecular architecture, their remarkable biological activity and their fascinating mode of action and many have spawned considerable interest as anticancer agents in the pharmaceutical industry. Of equal importance to these astonishing properties, the enediynes also offer a distinct opportunity to study the unparalleled biosyntheses of their unique molecular scaffolds and what promises to be unprecedented modes of self-resistance to highly reactive natural products. Elucidation of these aspects should unveil novel mechanistic enzymology, and may provide access to the rational biosynthetic modification of enediyne structure for new drug leads, the construction of enediyne overproducing strains and eventually lead to an enediyne combinatorial biosynthesis program. This article strives to compile and present the critical research discoveries relevant to the clinically most promising enediyne, calicheamicin, from a historical perspective. Recent progress, particularly in the areas of biosynthesis, self-resistance, bio-engineering analogs and clinical studies are also highlighted.
[Back to top] Mucins
in the Diagnosis and Therapy of Pancreatic Cancer.
Mucins are large glycoproteins that form a
protective layer along the lumens of the organs of the gastrointestinal and
reproductive tracts. Frequently in tumors of the pancreas there are changes in
the structure of mucin carbohydrates and/or levels of apomucin types.
Originally mucins were of interest clinically because diagnostic tests could be
based on their levels in circulation. More recently mucin directed monoclonal
antibodies have been used to target tumors with cytotoxic agents. There is now
a considerable literature on the development of mucin-based vaccines. Both
monoclonal antibodies and vaccines could be powerful tools to specifically
target tumor cells in distant metastases. Gene therapy based upon the MUC1 gene
promoter is being investigated to target therapeutic genes to MUC1 expressing
cells. The carbohydrates of mucins on the surface of tumor cells have been
reported to inhibit cells of the immune system. These carbohydrates also act as
ligands during the process of tumor cell metastasis. Another approach to
therapy is to block interactions between the ligands and their receptors.
[Back to top] Fibroblast Growth Factors and Their Inhibitors.
F. Manetti, F. Corelli and M. Botta
Fibroblast growth factors (FGFs) are members
of a family of polypeptides synthesized by a variety of cell types during the
processes of embryonic development and in adult tissues. FGFs have been
detected in normal and malignant cells and show a biological profile that
includes mitogenic and angiogenic activity with a consequent crucial role in
cell differentiation and development. To activate signal transduction pathways, FGFs use
a dual receptor system based on
tyrosine kinases and heparan sulfate (HS) proteoglycans. Based on these
considerations, a variety of inhibitors able to block the interactions between
FGFs and their receptors have been designed and investigated for their
biological properties related to antiangiogenesis and antitumor activity. In
this paper, in addition to an extensive description of the FGF family members,
we report several compounds acting as FGF inhibitors by direct interaction with
the growth factors. Suramin and other diverse polyanionic polysulfated and
polysulfonated compounds are described, with a particular focus on suradistas.
For this class of molecules, by means of molecular modeling procedures, a
binding model to FGF-2 has been proposed and the structure-activity
relationships of suradistas have been analyzed on the basis of the
computational model described.