Download Exporter la page en pdf

Team Publications
Organic Synthesis and Cell Biology
Year of publication 2015
Tatiana Cañeque, Filipe Gomes, Trang Thi Mai, Giovanni Maestri, Max Malacria, Raphaël
Rodriguez (2015 Aug 21)
Synthesis of marmycin A and investigation into its cellular activity.
Nature chemistry : 744-51 : DOI : 10.1038/nchem.2302
Summary
Anthracyclines such as doxorubicin are used extensively in the treatment of cancers.
Anthraquinone-related angucyclines also exhibit antiproliferative properties and have been
proposed to operate via similar mechanisms, including direct genome targeting. Here, we
report the chemical synthesis of marmycin A and the study of its cellular activity. The
aromatic core was constructed by means of a one-pot multistep reaction comprising a
regioselective Diels-Alder cycloaddition, and the complex sugar backbone was introduced
through a copper-catalysed Ullmann cross-coupling, followed by a challenging Friedel-Crafts
cyclization. Remarkably, fluorescence microscopy revealed that marmycin A does not target
the nucleus but instead accumulates in lysosomes, thereby promoting cell death
independently of genome targeting. Furthermore, a synthetic dimer of marmycin A and the
lysosome-targeting agent artesunate exhibited a synergistic activity against the invasive
MDA-MB-231 cancer cell line. These findings shed light on the elusive pathways through
which anthraquinone derivatives act in cells, pointing towards unanticipated biological and
therapeutic applications.
Angelica Mariani, Alexandra Bartoli, Mandeep Atwal, Ka C Lee, Caroline A Austin, Raphaël
Rodriguez (2015 May 7)
Differential Targeting of Human Topoisomerase II Isoforms with Small
Molecules.
Journal of medicinal chemistry : 4851-6 : DOI : 10.1021/acs.jmedchem.5b00473
Summary
The TOP2 poison etoposide has been implicated in the generation of secondary malignancies
during cancer treatment. Structural similarities between TOP2 isoforms challenge the
rational design of isoform-specific poisons to further delineate these processes. Herein, we
describe the synthesis and biological evaluation of a focused library of etoposide analogues,
with the identification of two novel small molecules exhibiting TOP2B-dependent toxicity. Our
findings pave the way toward studying isoform-specific cellular processes by means of small
molecule intervention.
Year of publication 2014
Raphaël Rodriguez, Kyle M Miller (2014 Oct 14)
INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 1
Team Publications
Organic Synthesis and Cell Biology
Unravelling the genomic targets of small molecules using high-throughput
sequencing.
Nature reviews. Genetics : 783-96 : DOI : 10.1038/nrg3796
Summary
Small molecules–including various approved and novel cancer therapeutics–can operate at
the genomic level by targeting the DNA and protein components of chromatin. Emerging
evidence suggests that functional interactions between small molecules and the genome are
non-stochastic and are influenced by a dynamic interplay between DNA sequences and
chromatin states. The establishment of genome-wide maps of small-molecule targets using
unbiased methodologies can help to characterize and exploit drug responses. In this Review,
we discuss how high-throughput sequencing strategies, such as ChIP-seq (chromatin
immunoprecipitation followed by sequencing) and Chem-seq (chemical affinity capture and
massively parallel DNA sequencing), are enabling the comprehensive identification of smallmolecule target sites throughout the genome, thereby providing insights into unanticipated
drug effects.
Delphine Larrieu, Raphaël Rodriguez, Sébastien Britton (2014 Sep 2)
[Chemical inhibition of NAT10 corrects defects of laminopathic cells].
Mé decine sciences : M/S : 745-7 : DOI : 10.1051/medsci/20143008010
Summary
INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 2