Pyrazole ribonucleoside analogues were prepared via a linear approach starting with the reaction of D-ribosylhydrazine with 1,3-dicarbonyl or acrylonitrile derivatives, thereby avoiding the regio- and stereoselectivity challenges typically encountered in N-glycosylation reactions. Three series of pyrazole nucleoside analogues, as along with selected corresponding pronucleotides, were prepared and their antiviral activity against Zika virus and Sars-Cov-2 is reported.

Various series of 4,6-disubstituted-2-thiopyridine derivatives were synthesized and evaluated as potential ecto-5'-nucleotidase (CD73) inhibitors. Altogether, about ninety compounds were prepared using a general synthetic pathway involving one or two steps (eventually one-pot) procedures. Variation of the nature of the substituents in positions 4 and 6 (methyl, trifluoromethyl or phenyl) of the thiopurine ring, as well as on the thiol function, was examined and led to marked differences both in term of reactivity and ability to interfere with the putative target protein. Using a functional assay on immune cells, few compounds belonging to series 4 were shown to be able to antagonize the inhibition of the T-cell proliferation at both 100 mu M and 10 mu M (completely for 4 ab and partially for 4 ai), that is as potent as AOPCP which entirely reversed the inhibitory impact of exogenous ATP on T cell proliferation until 62.5 mu M. In addition, we have shown that both compounds (4 ab and 4 ai) were also capable of moderately inhibiting the hA2A receptor with Ki in the mu molar range in HEK-293 cells. Thus, with the aim to reduce the molecular size and the lipophilicity of our initial scaffold, we finally observed by serendipity a modification of the potential target of our compounds.

We present a study of the seasonal evolution of Titan’s thermal field and distributions of haze, C2H2, C2H4, C2H6, CH3C2H, C3H8, C4H2, C6H6, HCN and HC3N from March 2015 (Ls = 66°) to September 2017 (Ls = 93°), i.e. from the last third of northern spring to early summer. We analyzed thermal emission of Titan’s atmosphere acquired by the Cassini Composite Infrared Spectrometer (CIRS) with limb and nadir geometry to retrieve the stratospheric and mesospheric temperature and mixing ratios pole-to-pole meridional cross sections from 5 mbar to 50 μbar (120-650 km).The southern stratopause varied in a complex way and showed a global temperature increase from 2015 to 2017 at high-southern latitudes. Stratospheric southern polar temperatures, which were observed to be as small as 120 K in early 2015 due to the polar night, showed a 30-K increase (at 0.5 mbar) from March 2015 to May 2017 due to adiabatic heating in the subsiding branch of the global overturning circulation. All photochemical compounds were enriched at the South Pole by this subsidence. Polar cross sections of these enhanced species, which are good tracers of the global dynamics, highlighted changes in the structure of the southern polar vortex. These high enhancements combined with the unusually low temperatures (

Introduction:The JAXA/Martian Moon eXploration (MMX) mission will be launched to the Martian system in 2026 with the objective of deciphering the origins of Phobos and Deimos [1]. One of the instruments onboard the MMX spacecraft will be MIRS, an imaging-infrared spectrometer covering a wavelength range from 0.9 µm to 3.6 µm [2]. In this work, we will present simulations of MIRS imaging of Phobos realized to prepare the future science exploitation of MIRS data and assess instrument performances. These simulations will also be useful during the operations of MIRS to anticipate the operations such as the Deimos flybys and Phobos landing.Figure 1: Example of surface reflectance at 1 µm (left) and temperature at 3 µm (right) landscapes obtained with OASIS simulation. Method:The generation of a spectral MIRS image is obtained with the use of a suit of three simulators. The observation mission scenarios are initially derived through AURORA [3], which provides all necessary orbital and instrument information, including the spacecraft position, pointing, etc. The second simulator, OASIS [4], is dedicated to the generation of all the geometric information (incidence, emission, phase, etc.) for each pixel/facet of the Phobos surface. AURORA provides the observation geometries fed into OASIS. The tool considers topographic variation on the surface through the use of the Phobos shape model. From the obtained illumination angles, a Hapke model is used to compute the bidirectional reflectance. The thermal component of the spectra is accounted for, through the use of a Standard Thermal Model. The current model does not account for multiple scattering and Mars reflected light on Phobos and Deimos.To avoid extremely long computational time, the geometric calculations are only performed at a single wavelength. The spatial and spectral terms of the solar and thermal irradiance are decoupled to allow extrapolation of a spectrum from the simulated landscape.After generating the reflectance and temperature maps (Fig. 1), the MIRAGES simulator [5] is run to model the MIRS instrument response, including light propagation through the mirrors, grating, and other optical elements, as well as accounting for the radiometric efficiency of these components, and introducing a geometric distortion. This allows to obtain 2D MIRS raw images. In the final stage, the images are processed further using a portion of the MIRS pipeline to obtain corrected and calibrated images. This includes distortion correction, ADU to I/F conversion, and spectral registration procedures. A thermal correction is subsequently applied to remove the contribution of the thermal tail. Results:The MIRS images were simulated for two scheduled observations of Phobos, designated as QSO-H (quasi-stationary orbit at high altitude) and QSO-M (quasi-stationary orbit at medium altitude). A typical rendered image for a QSO-H orbit is presented in Fig. 2.Figure 2: Example of a typical MIRS image for QSO-H orbit, obtained after the three simulators. In addition to the interest of having the capacity to simulate relatively rapidly MIRS images, we also investigated the detectability of several components of interest for the Phobos’ surface. In particular, we assessed the detectability of small patches of hydrated minerals and organics at the surface of Phobos by MIRS. For this purpose, we used as input, the experimental spectra obtained in our previous works for detectability studies in a Phobos regolith simulant [6,7]. We defined patches of different sizes from a diameter of 3.5 km to 12.9 m at the surface of Phobos. We found that the homogeneous patches are visible in the QSO-H orbit for a diameter of approximately 40 m but not visible when the diameter is reduced to ~13 m. This is in agreement with the expected spatial resolution in the QSO-H orbit which was estimated to be between 31 and 66 m/px. An example of a MIRS observation sequence is presented in Fig. 3. Whereas MIRS images 1 and 2 of the figure correspond to a “classic” area on Phobos, image 3 clearly shows a bright line at the center of the images. This bright line corresponds to MIRS scanning over a small patch of phyllosilicate in our simulated Phobos surface model.From these 2D images, it is possible to extract the 1D spectrum of both organic and classic Phobos regions. Typical obtained spectra are presented in Fig. 3 (bottom-left corner panel). The contrast between the two regions is evident when looking at the 2.7 µm region, where an absorption band is visible in the case of the phyllosilicates-rich patch compared to the classic Phobos surface.Figure 3: Example of 5 images of a MIRS observation sequence on a landscape obtained by OASIS. The passage on the hydrated mineral patch can be visually seen as a bright line through the spectral direction in the center of images 3 and 4. Bottom left corner: Example of two 1D spectra extracted for a MIRS image (panel 3), before thermal tail removal. The black solid line corresponds to the phyllosilicate patch MIRS rendered spectrum, and the red solid line corresponds to the ‘classic’ Phobos surface MIRS spectrum. The 2.7 µm band due to OH in hydrated minerals is visible in the black spectrum. Conclusion: Our simulations allow to explore the detectability of key components for Phobos and Deimos, with a particular focus on organics and hydrated minerals, for a typical QSO-H orbit. In further investigation, we plan to assess the detectability of inhomogeneous and/or mixed patches as well as addressing other MMX orbits and Deimos flybys. The simulations of Phobos and Deimos observations will be pivotable to prepare the MMX mission. Acknowledgments: The authors acknowledge the Centre National d’Etudes Spatiales (CNES) for the continuous support. References: [1] Kuramoto et al. (2021), EPS, 74, 12 [2] Barucci et al. (2021), EPS, 73, 211 [3] Sawyer et al. (2023), Acta Astronautica, 210 [4] Jorda et al. (2010), SPIE Symposium [5] Théret et al. (2023), LPSC [6] Wargnier et al. (2023), MNRAS, 524, 3 [7] Wargnier et al., submitted to Icarus (10.48550/arXiv.2405.02999)

Three oxygen-bearing molecules have been detected in Titan's atmosphere. Carbon monoxide (CO) is the most abundant one witha volume mixing ratio (VMR) of ~50 ppm (e.g. Serigano et al. 2016). Because of its very long chemical lifetime (several millions years) and as it does not condense in Titan's atmosphere, it is well homogenized by atmospheric dynamics. The second most abundant oxygen-bearing molecule is carbon dioxide (CO2) with a VMR of ~15 ppb. It shows a local minimum near 0.1 mbar (~ 250 km altitude) at almost all latitudes (Mathé et al. 2020). Such vertical VMR profile is currently not reproduced by photochemical models. The less abundant oxygen molecule detected in Titan's middle atmosphere is H2O (Cottini et al. 2012) with a VMR smaller than 0.5 ppb at 230 km with no evidence of latitudinal variations.There is currently no consensus regarding the source of oxygen compounds in Titan's atmosphere. The most recent and complete photochemical models, which couple oxygen, nitrogen and hydrocarbon ion and neutral chemistry, incorporate different external sources. An external flux of only OH can lead to the formation of all three oxygenated molecules in the model of Vuitton et al. (2019), while Dobrijevic et al. (2014) explored a possible internal (outgassing of primordial CO from surface) or external sources of O (from Enceladus plumes) and OH/H2O (from micrometeorites). Both type of models roughly reproduce the observed VMR of CO, CO2 and H2O.As studied by Loison et al. (2017), one way to constrain the source of oxygen in Titan's atmosphere is to model measurements of isotopic ratios in oxygenated molecules. Our objectives here are to determine the most accurate 12C/13C and 16O/18O isotopic ratios in CO2 using the entire CIRS dataset acquired between 2004 and 2017 and to investigate potential latitudinal and seasonal variations, which could be linked to potential fractionation processes. We have analyzed 41 limb observations acquired between 2004 and 2017 at all latitudes. Although our work is still in progress, we derive preliminary values of CO2/13CO2 = 50 ± 3 and CO2/C16O18O = 107 ± 6 combining all the 41 datasets. The inferred isotopic ratios are smaller in CO2 than in CO and other carbon-bearing species, suggesting that some fractionation processes occur. We will also discuss the search for latitudinal and seasonal variations. References : - Cottini et al. 2012. Icarus 220, 855.- Dobrijevic et al. 2014. Icarus 228, 324.- Loison et al. 2017. Icarus 291, 17.- Serigano et al. 2016. ApJ 821, L8.- Mathé et al. 2020. Icarus 344, 113547.- Vuitton et al. 2019. Icarus 324, 120.

In the Martian atmosphere, carbon dioxide (CO2) clouds have been revealed by numerous instruments around Mars from the beginning of the XXI century. These observed clouds can be distinguished by two kinds involving different formation processes: those formed during the winter in polar regions located in the troposphere, and those formed during the Martian year at low- and mid-northern latitudes located in the mesosphere (Määattänen et al, 2013). Microphysical processes of the formation of these clouds are still not fully understood. However, modeling studies revealed processes necessary for their formation: the requirement of waves that perturb the atmosphere leading to a temperature below the condensation of CO2 (transient planetary waves for tropospheric clouds (Kuroda et al., 20123), thermal tides (Gonzalez-Galindo et al., 2011) and gravity waves for mesospheric clouds (Spiga et al., 2012)). In the last decade, a state-of-the-art microphysical column (1D) model for CO2 clouds in a Martian atmosphere was developed at Laboratoire Atmosphères, Observations Spatiales (LATMOS) (Listowski et al., 2013, 2014). We use our full microphysical model of CO2 cloud formation to investigate the occurrence of these CO2 clouds by coupling it with the Global Climate Model (GCM) of the Laboratoire de Météorologie Dynamique (LMD) (Forget et al., 1999). We recently activated the radiative impact of CO2 clouds in the atmosphere. Last modeling results on Martian CO2 clouds properties and their impacts on the atmosphere will be presented and be compared to observational data.

Synthetic nucleoside mimics are re-emerging as crucial contenders for antiviral and anticancer medications. While, Ribavirin stands out for its unique antiviral properties, predominantly associated with its distinctive triazole heterocycle as a nucleobase, the exploration of alternative nitrogen-based aromatic heterocycles hold great promises for the discovery of novel bioactive nucleoside mimics. Although nucleoside derivatives synthesized from hydrazine-ribose units have been in development for many decades, they have been little evaluated biologically and even less for their antiviral properties. With the aim of taking a closer look at these under-explored derivatives and investigating their synthetic pathways, this review provides an overview of the molecular design, the chemical synthesis, and the biological activity, when available, of these nucleoside analogues. Overall, the entire body of work already done motivates further exploration of these analogues and encourages us of formulating structurally novel nucleoside drug candidates featuring innovative mode of action.

Abstract Martian CO2 ice clouds are intriguing features, representing a rare occurrence of atmospheric condensation of a major component. These clouds play a crucial role due to their radiative properties, interactions with surface, and coupling with microphysical cycles of aerosols. Observations have been limited, prompting modeling studies to understand their formation and dynamics. Here, we present the first high‐resolution 3D simulations of CO2 ice clouds using a Large‐Eddy Simulation (LES) model incorporating CO2 microphysics. We investigate cloud formation in idealized temperature perturbations in the polar night. A reference simulation with a −2K perturbation demonstrates that the formed CO2 ice cloud possesses a convective potential, leading to its ascent in the troposphere. We determine the timescales and orders of magnitude of various phenomena involved in the lifecycle of a CO2 ice cloud. Sensitivity tests show that convection can be inhibited or intensified by the thermodynamic and microphysical conditions of the simulated environment.

The nucleotidase ISN1 is a potential therapeutic target of the purine salvage pathway of the malaria parasite Plasmodium falciparum. We identified PfISN1 ligands by in silico screening of a small library of nucleos(t)ide analogues and by thermal shift assays. Starting from a racemic cyclopentyl carbocyclic phosphonate scaffold, we explored the diversity on the nucleobase moiety and also proposed a convenient synthetic pathway to access the pure enantiomers of our initial hit (compound (±)-2). 2,6-Disubstituted purine containing derivatives such as compounds 1, (±)-7e and β-L-(+)-2 showed the most potent inhibition of the parasite in vitro, with low micromolar IC50 values. These results are remarkable considering the anionic nature of nucleotide analogues, which are known to lack activity in cell culture experiments due to their scarce capacity to cross cell membranes. For the first time, we report the antimalarial activity of a carbocyclic methylphosphonate nucleoside with an L-like configuration.

Various series of 4,6-biaryl-2-thiopyridine derivatives were synthesized and evaluated as potential ecto-5 '-nucleotidase (CD73) inhibitors. Two synthetic routes were explored and the coupling of 4,6-disubstituted 3-cyano-2-chloro-pyridines with selected thiols allowed us to explore the structural diversity. Somehow divergent results were obtained in biological assays on CD73 inhibition using either the purified recombinant protein or cell-based assays, highlighting the difficulty to target protein-protein interface on proteins existing as soluble and membrane-bound forms. Among the 18 new derivatives obtained, three derivatives incorporating morpholino substituents on the 4,6-biaryl-2-thiopyridine core were shown to be able to reverse the adenosine-mediated immune suppression on human T cells. The higher blockade efficiency was observed for 2-((3-cyano-4,6-bis(4-morpholinophenyl)pyridin-2-yl)thio)-N-(isoxazol-3-yl)acetamide (with total reversion at 100 mu M) and methyl 2-((3-cyano-4,6-bis(4-morpholinophenyl)pyridin-2-yl)thio)acetate (with partial reversion at 10 mu M). Thus, this series of compounds illustrates a new chemotype of CD73 allosteric inhibitors.

<p>Molecular nitrogen (N<sub>2</sub>) and methane (CH<sub>4</sub>) are the two major gas of Titan’s atmosphere. Their dissociation in the upper atmosphere by photons and photo-electrons leads to a wealth of chemical reactions forming more complex molecules like nitriles and hydrocarbons, which subsequently combine to form Titan’s photochemical haze.</p> <p>Isotopic ratios measured in N<sub>2</sub> and CH<sub>4</sub> are of particular interest to constrain the origin and evolution of Titan’s atmosphere. While the same isotopic ratios measured in photochemical species bring constraints on fractionation processes occurring through their formation and/or loss.      </p> <p>We focus on the determination on the <sup>14</sup>N/<sup>15</sup>N and the <sup>12</sup>C/<sup>13</sup>C isotopic ratios in HCN and the <sup>12</sup>C/<sup>13</sup>C ratio in HC<sub>3</sub>N by analyzing their thermal emission acquired by the Cassini Composite Infrared Spectrometer (CIRS) from 2004 to 2017 (from the northern winter to the northern summer).  We used the entire CIRS dataset acquired with a limb-geometry viewing at the highest spectral resolution (0.5 cm<sup>-1</sup>). This allows us to search for potential variations of these isotopic ratios with latitude or with season, which could help to identify potential fractionation processes. Our analysis incorporates the temperature and minor species volume mixing ratio profiles inferred previously by Mathé et al. (2020) from the same limb dataset. We will present our results regarding the isotopic ratios in HCN for all latitudes, while we will present the <sup>12</sup>C/<sup>13</sup>C ratio in HC<sub>3</sub>N only at high latitudes, as this nitrile is not detected at mid- and low-latitudes.</p> <p>References: <br />- Mathé et al., 2020. Seasonal changes in the middle atmosphere of Titan from Cassini/CIRS observations: Temperature and trace species abundance profiles from 2004 to 2017. Icarus 344,  id. 113547.</p> <p> </p>

The ecto‐5′‐nucleotidase CD73 is involved in the production of immunosuppressive adenosine in the tumoral microenvironment and recently became a validated target in immuno‐oncology. To avoid formation of CD73‐produced adenosine, several series of potential inhibitors of the target enzyme based on a triazole scaffold were synthetized and evaluated on recombinant purified hCD73 and in cell‐based assays.

Recently, we reported the racemic synthesis of 3'-fluoro-5'-norcarbocyclic nucleoside phosphonates bearing adenine as the heterocyclic base. For this study, to evaluate the antiviral activity of each enantiomer, we synthesized both enantiomers, as well as their corresponding bis(POM) prodrugs. Anti-HIV-1 evaluation against the LAI strain and clinically NRTI-resistant HIV-1 strains are presented. The activities against these different strains show that the activities of bis(POM) prodrug (-)-9 are equivalent or even superior to those of (R)-PMPA.

Three series of nucleotide analogues were synthesized and evaluated as potential CD73 inhibitors. Nucleobase replacement consisted in connecting the appropriate aromatic or purine residues through a triazole moiety that is generated from 1,3-dipolar cycloaddition. The first series is related to 4-substituted-1,2,3-triazolo-beta-hydroxyphosphonate ribonucleosides. Additional analogues were also obtained, in which the phosphonate group was replaced by a bisphosphonate pattern (P-C-P-C, series 2) or the ribose moiety was removed leading to acyclic derivatives (series 3). The beta-hydroxyphosphonylphosphonate ribonucleosides (series 2) were found to be potent inhibitors of CD73 using both purified recombinant protein and cell-based assays. Two compounds (2a and 2b) that contained a bis(trifluommethyl)phenyl or a naphthyl substituents proved to be the most potent inhibitors, with IC50 values of 4.8 +/- 0.8 04 mu M and 0.86 +/- 0.2 mu M, compared to the standard AOPCP (IC50 value of 3.8 +/- 0.9 mu M), and were able to reverse the adenosine-mediated immune suppression on human T cells. This series of compounds illustrates a new type of CD73 inhibitors.

Carbocyclic nucleoside analogues are an essential class of antiviral agents and are commonly used in the treatment of viral diseases (hepatitis B, AIDS). Recently, we reported the racemic synthesis and the anti-human immunodeficiency virus activities (HIV) of 3′-fluoro-5′-norcarbocyclic nucleoside phosphonates bearing purines as heterocyclic base. Based on these results, the corresponding racemic norcarbocyclic nucleoside phosphonates bearing pyrimidine bases were synthesized. The prepared compounds were evaluated against HIV, but none of them showed marked antiviral activity compared to their purine counterparts.

DAST and Deoxofluor are usually used for nucleophilic fluorination of nucleosides via S(N)1 or S(N)2 mechanism. DAST and Deoxo-fluor could enhance anomerization of N-substituted thymidine and 2'-deoxyuridine in dichloromethane into the more stable and favored alpha-anomers due to in-situ liberation of HF. This is strongly supported by computational calculations based on the density functional theory, that were performed to rationalize energy stability and electronic properties of both anomers in order to provide further insights into the proposed mechanism.

The Cassini/Composite InfraRed Spectrometer (CIRS) instrument has been observing the middle atmosphere of Titan over almost half a Saturnian year. We used the CIRS dataset processed through the up-to-date calibration pipeline to characterize seasonal changes of temperature and abundance profiles in the middle atmosphere of Titan, from mid-northern winter to early northern summer all around the satellite. We used limb spectra from 590 to 1500 cm$^{-1}$ at 0.5-cm$^{-1}$ spectral resolution, which allows us to probe different altitudes. We averaged the limb spectra recorded during each flyby on a fixed altitude grid to increase the signal-to-noise ratio. These thermal infrared data were analyzed by means of a radiative transfer code coupled with an inversion algorithm, in order to retrieve vertical temperature and abundance profiles. These profiles cover an altitude range of approximately 100 to 600 km, at 10- or 40-km vertical resolution (depending on the observation). Strong changes in temperature and composition occur in both polar regions where a vortex is in place during the winter. At this season, we observe a global enrichment in photochemical compounds in the mesosphere and stratosphere and a hot stratopause located around 0.01 mbar, both linked to downwelling in a pole-to-pole circulation cell. After the northern spring equinox, between December 2009 and April 2010, a stronger enhancement of photochemical compounds occurred at the north pole above the 0.01-mbar region, likely due to combined photochemical and dynamical effects. During the southern autumn in 2015, above the South pole, we also observed a strong enrichment in photochemical compounds that contributed to the cooling of the stratosphere above 0.2 mbar. Close to the northern spring equinox, in December 2009, the thermal profile at 74{\deg}N exhibits an oscillation that we interpret in terms of an inertia-gravity wave.