Laboratoire Francis Perrin

A divergent cascade cycloisomerization/[3 + 2] vs. [2 + 2 + 1]-cycloaddition via gold or silver catalysis has been reported in 1,1,1,3,3,3-hexafluoroisopropan-2-ol (HFIP). The reaction was independently optimized for both metals leading to two hexacyclic derivatives comprising a bicyclo[3.2.1]octane unit and respectively a benzoxazinone or a N-oxo-indolinone pattern. The unique influence of HFIP was demonstrated via 19F and 31P NMR analyses. This process, involving the formation of C-C, C-O, and C-N bonds and of three stereogenic centers led to privileged scaffolds in a context of the search for increased molecular diversity of drug-candidate libraries. The versatility of this methodology was demonstrated by the synthesis of 25 different hexacyclic scaffolds (yields up to 98%). Gram-scale synthesis as well as post-functionalization reactions illustrated the versatility and interest of these catalytic transformations. DFT calculations were performed to rationalize the proposed mechanism of this cascade reaction.

Developmental and Epileptic Encephalopathies (DEEs) represent a clinically and genetically heterogeneous group of rare and severe epilepsies. DEEs commonly begin early in infancy with frequent seizures of various types associated with intellectual disability and leading to a neurodevelopmental delay or regression. Disease-causing genomic variants have been identified in numerous genes and are implicated in over 100 types of DEEs. In this context, genes encoding voltage-gated ion channels (VGCs) play a significant role, and part of the large phenotypic variability observed in DEE patients carrying VGC mutations could be explained by the presence of genetic modifier alleles that can compensate for these mutations. This review will focus on the current knowledge of the compensatory effect of DEE-associated voltage-gated ion channels and their therapeutic implications in DEE. We will enter into detailed considerations regarding the sodium channels SCN1A, SCN2A, and SCN8A; the potassium channels KCNA1, KCNQ2, and KCNT1; and the calcium channels CACNA1A and CACNA1G.

Aims. To date, infrared interferometry at best achieved contrast ratios of a few times 10−4 on bright targets. GRAVITY, with its dual-field mode, is now capable of high contrast observations, enabling the direct observation of exoplanets. We demonstrate the technique on HR 8799, a young planetary system composed of four known giant exoplanets. Methods. We used the GRAVITY fringe tracker to lock the fringes on the central star, and integrated off-axis on the HR 8799 e planet situated at 390 mas from the star. Data reduction included post-processing to remove the flux leaking from the central star and to extract the coherent flux of the planet. The inferred K band spectrum of the planet has a spectral resolution of 500. We also derive the astrometric position of the planet relative to the star with a precision on the order of 100 μas. Results. The GRAVITY astrometric measurement disfavors perfectly coplanar stable orbital solutions. A small adjustment of a few degrees to the orbital inclination of HR 8799 e can resolve the tension, implying that the orbits are close to, but not strictly coplanar. The spectrum, with a signal-to-noise ratio of ≈5 per spectral channel, is compatible with a late-type L brown dwarf. Using Exo-REM synthetic spectra, we derive a temperature of 1150 ± 50 K and a surface gravity of 104.3 ± 0.3 cm s2. This corresponds to a radius of 1.17−0.11+0.13 RJup and a mass of 10−4+7 MJup, which is an independent confirmation of mass estimates from evolutionary models. Our results demonstrate the power of interferometry for the direct detection and spectroscopic study of exoplanets at close angular separations from their stars.

Germ-cell tumors are relatively rare neoplasms that affect mostly young adults.The poor prognosis of these tumors has significantly improved after the advent of platinum compound, and most patients with metastatic germ cell tumors can be currently cured with combined modality treatment that comprises surgery, chemotherapy or radiotherapy.With the improved long-term prognosis, acute and chronic side effects of treatment represent an important issue.In the present study, we evaluated serum neopterin and plasma citrulline, a biomarker of gut damage in germ-cell tumor patients before and during 3 to 4 cycles of standard platinum-based chemotherapy.We report here the pilot results in the first 15 patients.Baseline serum neopterin concentrations were increased in a substantial proportion of patients, while plasma citrulline was mostly within the normal range.A significant negative correlation was observed between baseline serum neopterin and hemoglobin concentrations while positive concentration was noted between peripheral blood leukocyte count and neopterin.Changes in the investigated parameters were noted during the course of therapy.The study is ongoing.

The fluorescence properties of the 8-hydroxy-2'-deoxyguanosine (8-oxo-dG) in aqueous solution at pH 6.5 are studied by steady-state spectroscopy and femtosecond fluorescence up-conversion and compared with those of 2'-deoxyguanine (dG) and 2'-deoxyguanine monophosphate (dGMP). The steady-state fluorescence spectrum of 8-oxo-dG is composed of a broad band that peaks at 356 nm and extends over the entire visible spectral region, and its fluorescence quantum yield is twice that of dG/dGMP. After excitation at 267 nm, the initial fluorescence anisotropy at all wavelengths is lower than 0.1, giving evidence of an ultrafast internal conversion (<100 fs) between the two lowest excited ππ* states (Lb and La). The fluorescence decays of 8-oxo-dG are biexponential with an average lifetime of 0.7 ± 0.1 ps, which is about two times longer than that of dGMP. In contrast with dGMP, only a moderate dynamical shift (∼1400 vs 10,000 cm(-1)) of the fluorescence spectra of 8-oxo-dG is observed on the time scale of a few picoseconds without modification of the spectral shape. PCM/TD-DFT calculations, employing either the PBE0 or the M052X functionals, provide absorption spectra in good agreement with the experimental one and show that the deactivation path is similar to that proposed for dGMP, with a fast motion toward an energy plateau, where the purine ring keeps an almost planar geometry, followed by decay to S0, via out-of-the plane motion of amino substituent.

While ferrous heme (Fe(II)) within hemoproteins binds dioxygen efficiently, it has not yet been possible to observe the analog complex with ferric heme (Fe(III)). We present the first observation and characterization of the latter complex in a cooled ion trap. The bond formation enthalpy of ferric heme-O2 has been derived from the Van't Hoff equation by means of temperature dependent measurements. The binding energy of the [heme Fe(III)-O2](+) ionic complex is rather strong as compared to that of [heme Fe(III)-N2](+), showing the formation of an incipient Fe-O bond, which is confirmed by the electronic absorption spectra of the two complexes. This first observation of the [heme Fe(III)-O2](+) complex lays the basis for the precise description of its electronic states.

Intra-residue interactions play an important role in proteins by influencing local folding of the backbone. Taking advantage of the capability of gas phase experiments to provide relevant information on the intrinsic H-bonding pattern of isolated peptide chains, the intra-residue interactions of serine and cysteine residues, i.e., OH/SH···OC(i) C6 and NH(i···)O/S C5 interactions in Ser/Cys residues, are probed by laser spectroscopy of isolated peptides. The strength of these local side chain-main chain interactions, elegantly documented from their IR spectral features for well-defined conformations of the main chain, demonstrates that a subtle competition exists between the two types of intra-residue bond: the C6 H-bond is the major interaction with Ser, in contrast to Cys where C5 interaction takes over. The restricted number of conformers observed in the gas phase experiment with Ser compared to Cys (where both extended and folded forms are observed) also suggests a significant mediation role of these intra-residue interactions on the competition between the several main chain folding patterns.

The present combined theoretical and experimental investigation concerns the single photoionization of gas-phase acetyl cyanide and the fragmentation pathways of the resulting cation. Acetyl cyanide (AC) is inspired from both the chemistry of cyanoacetylene and the Strecker reaction which are thought to be at the origin of medium sized prebiotic molecules in the interstellar medium. AC can be formed by reaction from cyanoacetylene and water but also from acetaldehyde and HCN or the corresponding radicals. In view of the interpretation of vacuum ultraviolet (VUV) experimental data obtained using synchrotron radiation, we explored the ground potential energy surface (PES) of acetyl cyanide and of its cation using standard and recently implemented explicitly correlated methodologies. Our PES covers the regions of tautomerism (between keto and enol forms) and of the lowest fragmentation channels. This allowed us to deduce accurate thermochemical data for this astrobiologically relevant molecule. Unimolecular decomposition of the AC cation turns out to be very complex. The implications for the evolution of prebiotic molecules under VUV irradiation are discussed.