UMR9187 / U1196 – Chimie, modélisation et imagerie pour la biologie

Publications de l’unité

Année de publication : 2018

Hee-Sheung Lee, Mar Carmena, Mikhail Liskovykh, Emma Peat, Jung-Hyun Kim, Mitsuo Oshimura, Hiroshi Masumoto, Marie-Paule Teulade-Fichou, Yves Pommier, William C Earnshaw, Vladimir Larionov, Natalay Kouprina (2018 Sep 1)

Systematic Analysis of Compounds Specifically Targeting Telomeres and Telomerase for Clinical Implications in Cancer Therapy.

Cancer research : Online : DOI : 10.1158/0008-5472.CAN-18-0894 En savoir plus
Résumé

The targeting of telomerase and telomere maintenance mechanisms represents a promising therapeutic approach for various types of cancer. In this work, we designed a new protocol to screen for and rank the efficacy of compounds specifically targeting telomeres and telomerase. This approach used two isogenic cell lines containing a circular human artificial chromosome (HAC, lacking telomeres) and a linear HAC (containing telomeres) marked with the EGFP transgene: compounds that target telomerase or telomeres should preferentially induce loss of the linear HAC but not the circular HAC. Our assay allowed quantification of chromosome loss by routine flow cytometry. We applied this dual-HAC assay to rank a set of known and newly developed compounds, including G-quadruplex (G4) ligands. Among the latter group, two compounds -Cu-ttpy and Pt-ttpy- induced a high rate of linear HAC loss with no significant effect on the mitotic stability of a circular HAC. Analysis of the mitotic phenotypes induced by these drugs revealed an elevated rate of chromatin bridges in late mitosis and cytokinesis as well as UFB (Ultrafine Bridges). Chromosome loss after Pt-ttpy or Cu-ttpy treatment correlated with the induction of telomere-associated DNA damage. Overall, this platform enables identification and ranking of compounds that greatly increase chromosome mis-segregation rates as a result of telomere dysfunction and may expedite the development of new therapeutic strategies for cancer treatment.

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Filippo Doria, Valentina Pirota, Michele Petenzi, Marie-Paule Teulade-Fichou, Daniela Verga, Mauro Freccero (2018 Aug 30)

Oxadiazole/Pyridine-Based Ligands: A Structural Tuning for Enhancing G-Quadruplex Binding.

Molecules (Basel, Switzerland) : 23 : 2162 : DOI : 10.3390/molecules23092162 En savoir plus
Résumé

Non-macrocyclic heteroaryls represent a valuable class of ligands for nucleic acid recognition. In this regard, non-macrocyclic pyridyl polyoxazoles and polyoxadiazoles were recently identified as selective G-quadruplex stabilizing compounds with high cytotoxicity and promising anticancer activity. Herein, we describe the synthesis of a new family of heteroaryls containing oxadiazole and pyridine moieties targeting DNA G-quadruplexes. To perform a structure⁻activity analysis identifying determinants of activity and selectivity, we followed a convergent synthetic pathway to modulate the nature and number of the heterocycles (1,3-oxazole vs. 1,2,4-oxadiazole and pyridine vs. benzene). Each ligand was evaluated towards secondary nucleic acid structures, which have been chosen as a prototype to mimic cancer-associated G-quadruplex structures (e.g., the human telomeric sequence, c-myc and c-kit promoters). Interestingly, heptapyridyl-oxadiazole compounds showed preferential binding towards the telomeric sequence (22AG) in competitive conditions vs. duplex DNA. In addition, G4-FID assays suggest a different binding mode from the classical stacking on the external G-quartet. Additionally, CD titrations in the presence of the two most promising compounds for affinity, TOxAzaPy and TOxAzaPhen, display a structural transition of 22AG in K-rich buffer. This investigation suggests that the pyridyl-oxadiazole motif is a promising recognition element for G-quadruplexes, combining seven heteroaryls in a single binding unit.

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Xiao Xie, Oksana Reznichenko, Ludovic Chaput, Pascal Martin, Marie-Paule Teulade-Fichou, Anton Granzhan (2018 Aug 27)

Topology-Selective Fluorescent « Light-Up » Probes for G-Quadruplex DNA Based on Photoinduced Electron Transfer.

Chemistry (Weinheim an der Bergstrasse, Germany) : 24 : 12638-12651 : DOI : 10.1002/chem.201801701 En savoir plus
Résumé

Six novel probes were prepared by covalent attachment of a G4-DNA ligand (PDC) to various coumarin or pyrene fluorophores. In the absence of DNA, the fluorescence of all probes is quenched due to intramolecular photoinduced electron transfer (PET) evidenced by photophysical and electrochemical studies, molecular modeling and DFT calculations. All probes demonstrate similarly high thermal stabilization of various G4-DNA substrates belonging to different folding topologies, as assessed by fluorescence melting experiments; however, their fluorimetric response is strongly heterogeneous with respect to structures of the probes and G4-DNA targets. Thus, the probes containing the 7-diethylaminocoumarin fluorophore demonstrate significant fluorescence enhancement in the presence of G4-DNA, with the strongest « light-up » response (20- to 180-fold) observed for antiparallel G4 structures as well as for hybrid G4 structures, formed by the variants of human telomeric sequence and capable of a conformation change to the antiparallel isoform. These results shed light on the influence of the linker and electronic properties of fluorophores on the efficiency of G4-DNA « light-up » probes operating via PET.

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Donia Essaid, Ali Tfayli, Philippe Maillard, Christophe Sandt, Véronique Rosilio, Arlette Baillet-Guffroy, Athena Kasselouri (2018 Jul 21)

Retinoblastoma membrane models and their interactions with porphyrin photosensitisers: An infrared microspectroscopy study.

Chemistry and physics of lipids : 215 : 34-45 : DOI : 10.1016/j.chemphyslip.2018.07.003 En savoir plus
Résumé

Fourier Transform Infrared (FTIR) microspectroscopy was used to highlight the interactions between two photosensitisers (PS) of different geometries, TPPmOH4 and a glycoconjugated analogous, TPPDegMan, and lipid bilayers modelling retinoblastoma cell membranes. Retinoblastoma is a rare disease occurring in young infants, for whom conservative treatments may present harmful side-effects. Photodynamic therapy (PDT) is expected to induce less side-effects, as the photosensitiser is only activated when the tumour is illuminated.

Since efficiency of the treatment relies on photosensitiser penetration in cancer cells, bilayers with three lipid compositions – pure SOPC, SOPC/SOPE/SOPS/Chol (56:23:11:10) and SOPC/SOPE/SOPS/Chol/CL (42:32:9:8:6) – were used as plasma and mitochondria model membranes. FTIR spectra showed that the interaction of the PSs with the lipid bilayers impacted the lipid organization of the latter, causing significant spectral variations. Both studied photosensitisers inserted at the level of lipid hydrophobic chains, increasing chain fluidity and disorder. This was confirmed by surface pressure measurements. Photosensitisers – TPPmOH4 more than TPPDegMan – also interacted with the polar region of the bilayer, forming hydrogen bonds with phosphate groups that induced major shifts of phosphate absorption bands. This difference in PS interaction with moieties in the polar region was more pronounced with the models with complex lipid composition.

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