Institut Curie / CNRS UMR 176 Conception, Synthesis and Targeting

Institut Curie / CNRS UMR 176
Conception, Synthesis and
Targeting of Biomolecules
Unit director: Jean-Claude Florent, PhD
The central activity of this chemistry unit is to
develop and use small molecule ligands to control
the biological activities of important target proteins.
and nucleic acids. Organic and Organometallic
synthesis is being used to design new bioactive
compounds, as well as natural-product analogues,
new chemicals to cross-link proteins and new
probes of biological function. Currently, the Institut
Curie–CNRS's proprietary library is comprised of
9 000 small chemical compounds arrayed in 96-well
plates.
The main research themes of the unit include:
Antivascular compounds (such as tubulin-binding
ligands).
Kinase inhibitors
G-quadruplex targeting agents
DNA fluorescent dyes
Photodynamic therapy of tumors with new
porphyrines.
Antitumour drug-targeting compounds for
antibody-directed enzyme prodrug therapy
Shiga toxin as a vector for agent delivery
(molecules, siRNA, immunogenic petides)
Methodology development in organic and
organometallic chemistry.
Protein–protein interaction inhibitors
Jean-Claude Florent, PhD
Medicinal Chemistry, Chemical biology, Drug
Targeting
Institut Curie / CNRS UMR 176
26 rue d'Ulm
75248 Paris
Tel : +33 1 56 24 66 58
Fax : +33 1 56 24 66 31
Email : [email protected]
KEYWORDS :
Antivascular agents, kinase inhibitors, drug targeting, chemical probes for biology, anti-cell
migrating agents, libraries of small molecules, methyl-transferase inhibitors, tubulin agents,
CK2 inhibitors, Phosphatase inhibitors
The main activity of my “Medicinal Chemistry, Bioorganic
Chemistry, Targeting" group is the pharmacomodulation and
synthesis of small molecules for the study of living organisms.
The synthesized molecules find multiple applications as
probes for proteomics/genomics and/or as agents for
therapeutic purposes.
We have a strong research activity on antitumour drug
targeting, particularly through the use of Shiga toxin-drug
conjugates (antitumour) or Shiga-peptide conjugates (for
antitumour immunology). Our laboratory is also involved in
another important field,, i.e. targeted therapy. Thus, we
particularly
develop
flavonoid
compounds
as
aminopeptidases inhibitors, potentially anti-angiogenic and
anti-metastastic. We have also synthesized tubulin ligands for
their potential antivascular activity, in particular analogues of
Combretastatin A4, and have conceived serine threonine
kinases, inhibitors of CK2 and PIM1.
We have organized the Curie-CNRS “chimiothèque”, a
collection of small molecules, comprising the products
synthesized at UMR 176, to which we continue adding small
molecules. Some of the hits found by our biologists partners
are being optimized as inhibitors of protein-protein
interactions involved in cell migration and metastasis (Llamiline/Syndecan3) and we develop a hit inhibitor of the
serine-threonine phosphatase I (PP1). Furthermore, within a
Curie network in connection with a team of biologists from our
Institute, we synthesize chemical probes to study molecular
biology and mechanisms relating to the retrograde route
taken by the Shiga toxin to the Golgi apparatus. This chemical
biology programme has allowed us to synthesize chemical
probes applied for the study of the Shiga toxin endocytosis
involving cell fluorescence microscopy on living cells or on
Geant Unilamelar vesicles as cell models membrane. We
have undertaken a programme on the proteomic analysis of
the cell surface proteins, which could follow this retrograde
route of endocytosis.
Figure 1 : Shiga toxin B subunit as a vector for antitumour drugs
The Shiga toxin B subunit (STxB) is used for intracellular
retrograde delivery of drug.
Recent/Key Publications
A. El Alaoui et al. (2008) Synthesis and properties of a
mitochondrial peripheral benzodiazepine receptor conjugate.
ChemMedChem. 3, 1687-1695.
R. Prudent et al. (2008) Expanding the chemical diversity of
CK2 inhibitors. Mol Cell Biochem, 316, 71-85.
W. Römer et al. (2007) Shiga toxin induces tubular
membrane invaginations for its uptake into cells. Nature 450,
670-675.
A. El Alaoui et al. (2007) Shiga toxin-mediated retrograde
delivery of a topoisomerase I inhibitor prodrug. Angewandte
Chemie 119, 6469-6472.
M. Arthuis, R. Pontikis, J.-C. Florent. (2009) Stereoselective
Synthesis of Novel Highly Substituted Isochromanone and
Isoquinolinone-Containing Exocyclic Tetrasubstituted. Alkenes
J. Org. Chem. 74, 2234-2237.
Patents available for licensing : 5
Philippe Belmont, PhD
Organometallic chemistry, heterocycles and
biological targets
Institut Curie / CNRS UMR 176
26 rue d'Ulm
75248 Paris Cedex 05
Tel : +33 1 56 24 68 24
Fax : +33 1 56 24 66 31
Email : [email protected]
KEYWORDS :
Heterocyclic chemistry, cycloisomerization and tandem reactions, silver-catalyzed and goldcatalyzed transformations, protein-kinase inhibitors, anti-proliferative and antipaludic
properties.
Our research group deals with an original access to novel
heterocyclic structures by organometallic and organic
chemistry. Then, their biological targets and anticancer
properties are investigated.
Our first project allowed us to access the acridine scaffold, a
known bioactive heterocycle, through a benzene ring
formation (benzannulation, Fig. 1), thanks to an ene-yne
cycloisomerization reaction catalyzed with rhodium(I) salts
([Rh] cat.). We then looked for a more general method, and
although the cationic gold complex Au(PPh3)SbF6 proved to
be the most active specie for this transformation, silver salts
such as AgSbF6 (needed for the anion metathesis in the gold
chemistry) led us to develop an original cycloisomerization
reaction for the access to polyaromatic derivatives:
naphthalenes, acridines and quinolines (Fig.1).
O
OTBS
Y
R
Y = N or CH
OTBS
or
[Ag] cat.
Y
O
N
R2
R2
Furoquinoline
Pyranoquinoline
Figure 2: Tandem acetalization/heterocyclization reaction.
Finally, we have synthesized tetrahydrocyclopenta[c]acridinone
structures in only 3 steps from a commercially available
quinoline. The key chemical step is a Pauson-Khand reaction
leading to an active compound on cyclin-dependent kinases at
submicromolar concentration (Fig. 3, kinase inhibition).
O
Key step :
Pauson
Khand
reaction
Cl
Commercially
available
quinoline
R2
N
R3
O
tetrahydrocyclopenta[c]acridinones
Heterocycle (in orange)
Kinase ATP binding pocket (in green)
R
Y = CH : Naphthalenes
Y = N : Acridines, quinolines
N
R2
N
[Rh] cat.
or
[Au] cat.
R1 OR3
OR3
O or
M = [Ag], [Au] cat.
N
H
BENZANNULATION
R1
Base (K2CO3)
or
R1
Figure 3: Kinase inhibition.
AMINOBENZANNULATION
R1
O
R1
n
R
N
R2
Recent/Key Publications
n
Y
Y
Starting material
N
H
R2
R
n =1, Y = N : Acridines, quinolines
n = 0, Y = NR : Carbazoles
n = 0, Y = O : Dibenzofurans
Figure 1: Benzannulation and aminobenzannulation reactions.
With the same starting material, thanks to the use of a
secondary amine, the enamine intermediate triggers the
cycloisomerization reaction onto the alkynyl group
(aminobenzannulation) to obtain bioactive heterocycles
such as acridines, quinolines, carbazoles and also
dibenzofurans (Fig. 1).
Also, our work is directed towards the access to furoquinoline
and pyranoquinoline cores, structurally related to known
bioactive alkaloids. First of all, the reaction was developed via
a base-catalyzed tandem cycloisomerization reaction and
thereafter a more general method was developed by
organometallic catalysis with gold and various silver salts.
More importantly, depending on the silver salt used (Ag2O
versus AgOTf) a regioselective 5-exo-dig versus 6-endo-dig
cyclization was observed, leading respectively to
furoquinolines and pyranoquinolines (Fig. 2).
P. Belmont et al. (2009). Silver and Gold Catalysis for
Cycloisomerization Reactions. Eur. J. Org. Chem., 6075-6089.
M. Tiano et al. (2008). Rapid access to amino-substituted
quinoline, (di)benzofuran and carbazole heterocycles through
an aminobenzannulation reaction. J. Org. Chem., 73, 41014109.
T. Godet et al. (2007). Silver versus Gold Catalysis in
Tandem Reactions of Carbonyl Functions onto Alkynes: a
Versatile Access to Furoquinoline and Pyranoquinoline Cores.
Chem. Eur. J., 13, 5632-5641.
P. Belmont et al. (2007). Acridine and Acridone Derivatives,
Anticancer Properties and Synthetic Methods: Where Are We
Now? Anti-Cancer Agents Med. Chem., 7, 139-169.
P. Belmont et al. (2005). An Efficient and Simple
Aminobenzannulation Reaction: Pyrrolidine as a Trigger for the
Synthesis of 1-Amino-Acridines. Org. Lett., 7, 1793-1795.
Marie-Paule Teulade-Fichou, PhD
Heterocyclic Chemistry and Design of
Biomolecules Interactions Inhibitors
Institut Curie / CNRS UMR 176
Centre Universitaire
91405 Orsay Cedex
Tel : +33 1 69 86 30 86
Fax : +33 1 69 07 53 81
Email : [email protected]
KEYWORDS :
Heterocyclic chemistry, cancer therapeutic agents, quadruplex nucleic acids ligands,
telomere targeting agents, DNA fluorescent dyes, retinoblastoma, photosensitising
molecules, compound library screening, hit identification and optimisation
Our group works on the design of compounds that target
various proteins, enzymes and nucleic acids of interest for
cancer therapy. Our research is carried out in close
collaboration with biochemists, biologists and clinicians.
The group has a broad expertise in organic synthesis and bioorganic chemistry with a strong background in molecular
recognition of biological targets.
mouse model grafted with an anatomopathological sample of
human retinoblastoma.
The Institut Curie-CNRS compound library
To date our diverse chemical libraries is composed of more
than 8500 compounds. Our collection has been screened
against a number of therapeutically interesting targets which led
to the identification of promising novel chemical hits. Some of
DNA structural probes
these are currently being optimised, and in particular some
We are designing probes with the property to bind to protein-protein interaction modulating agents.
secondary structures of DNA in strategic regions of the
genomic DNA. For example we are actively working at
developing distinct families of G-quadruplex DNA binding
molecules and Mismatched DNA ligands which could offer
new perspectives in anticancer drug discovery (Fig. 1). In
addition, we have recently developed a novel family of redemitting dyes for use in optical tracking of DNA in cells by
multiphoton microscopy.
Figure 2: The structure of glyco-conjugated porphyrin-based
photosensitisers
Recent/Key Publications
Figure 1 : Structure of a quinacridine ligand and of its complex with
G-quadruplex DNA determined by NMR.
Purine libraries
We are constructing a library of novel and diverse purinebased compounds to be used to develop inhibitors of
molecular targets in Alzheimer's disease, Huntington's
disease (e.g. GSK-3, CDK5, CK1) and cancer (Tyrosine
kinases). The receptor tyrosine kinase c-Kit for example is
known to be involved in hematopoiesis and to be
overexpressed in various cancerous pathologies. In
collaboration with an industrial partner, we are developing
specific inhibitors of c-Kit and its mutated form.
Piazza A. et al. (2010) Genetic instability triggered by Gquadruplex interacting Phen-DC compounds in Saccharomyces
cerevisiae Nucleic Acid.Res. published on line March 19th
Brevet, D. et al. (2009) Mannose-targeted mesoporous silica
nanoparticles for photodynamic therapy. Chem. Commun.
1475-1477.
Granzhan A; et al. (2009) Macrocyclic DNA-Mismatch-Binding
Ligands:
Structural
Determinants
of
Selectivity.
Chem.Eur.J.,15,1314
Yang P. et al. (2009) Engineering Bisquinolinium-Thiazole
orange conjugates for fluorescent sensing of G-quadruplex
DNA Angew. Chem. Int .Ed. 48, 2188-2191.
Keriel A. et al. (2009) Protection against Retrovirus
Pathogenesis by SR Protein Inhibitors PLoS One 2009, 2, 4,
e4533.
Besselièvre F. et al. (2009) Copper-Catalyzed Direct
Alkynylation of Azoles. Angew. Chem. Int. Ed. Engl. 48, 9553-
9556.
Photosensitising molecules for retinoblastoma
The current treatment for retinoblastoma, the most frequent
eye tumour in children, exposes the patient to the long-term Patent available for licensing : 1
consequences of chemotherapy. The development of
alternative treatment using non-mutagenic photosensitizers
(i.e. compounds that damage cell components upon
photoactivation) is of particular interest for treating this tumour
type. The photosensitizers developed in our laboratory are
glycoconjugated tetrapyrrole macrocycles (Fig. 2). We are in
the process of evaluating the in vivo efficacy of these
glycoconjugated photosensitisers in an immunodeficient