Le renseignement économique militaire en France à partir de 1916

Durant la Première Guerre mondiale, afin de permettre l’application d’un programme de guerre économique progressivement défini à partir de 1915, de nouveaux instruments de guerre doivent être envisagés. Créée pour les besoins de la défense nationale et légitimée dans le cadre du régime d’exception, la pratique du renseignement économique militaire contribue ainsi à l’élaboration des mesures de blocus économique des puissances centrales par les alliés. Elle se transforme, à partir de 1916, en outil permettant aux partisans de l’offensive économique d’orienter la conduite de la guerre économique en ce sens.Military-economic intelligence from 1916: strategic imperatives and war economics. During the First World War, in order to permit the application of a programme of economic warfare that became progressively more sharply defined from 1915 onwards; new tools of war had to be thought up. Military-economic intelligence was created to meet the needs of national defence, and given legitimacy by the wartime context of ‘exceptional measures’. Its conduct and implementation contributed to the formulation of the blockade measures that the Allies set in place around the Central Powers. And from 1916 onwards, military-economic intelligence came to be transformed into an instrument that enabled partisans of the economic offensive to channel the conduct of economic warfare in this direction

À l’origine de la création de l’armée tchécoslovaque en France : le général Milan Rastislav Štefánik

 « Ne détruire aucune pièce de ce dossier qui devra par la suite être classé aux célébrités. Le commandant Štefánik est le même que le général Štefánik, qui a été le premier ministre de la Guerre de la République tchécoslovaque. » Cette note manuscrite attachée à la première page du dossier personnel du général Milan Rastislav Štefánikannonce la complexité de la gestion d’un officier au parcours atypique. Né en Slovaquie en 1880, naturalisé français en 1912 et autorisé à conserver les deux na..

Preparation and evaluation of a set of bis(methoxycarbonylmethylthio) heteroquinones as CDC25B phosphatase inhibitors

A set of new heteroquinone derivatives bearing two methoxycarbonylmethylthio groups on the benzoquinone ring were synthesized and evaluated for CDC25B phosphatase inhibitory activity. All compounds inhibited the enzyme with IC50 values in the micromolar range regardless of the size and heteroatoms constituting the heterocycle fused to the quinone ring. Moreover, these quinonoid-based compounds showed moderate antiproliferative activity toward two cancer cell lines (HeLa and MiaPaca-2). These results provide additional data for CDC25 inhibition by quinone-type derivatives and highlight the importance of substituents on the quinonic moiety

TROIS-AZOLYLMÉTHYLENEINDOLIN-2-ONES, 3-IMIDAZOLYLINDOLES ET ANALOGUES STRUCTURAUX A POTENTIALITÉS ANTITUMORALES

NANTES-BU Médecine pharmacie (441092101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Les phosphates CDC25 constituent-elles des cibles importantes en cancérologie (Des inhibiteurs de l'activité enzymatique vers les inhibiteurs de l'interaction entre CDC25 et leurs substrats CDK-Cycline)

Les phosphatases CDC25 sont des éléments-clé de la régulation du cycle cellulairechez les eucaryotes; elles activent par une double déphosphorylation les complexes CDK/cyclines permettant ainsi la progression dans les différentes phases du cycle. Leur sur-expression, observée dans des cancers très fréquents, est corrélée à une forte agressivité des tumeurs et un mauvais pronostic ce qui en fait des cibles d intérêt en cancérologie. Deux nouvelles séries d inhibiteurs ont été développées à partir d une thiazolopyrimidinone (TZP), capable d inhiber l activité des CDC25, et préalablement identifiée par l équipe. La première série a été obtenue par dimérisation de deux noyaux thiazolonesconduisant à des inhibiteurs avec des CI50 de l ordre du micromolaire sur CDC25B plus actifs que les mono-thiazolones, ces composés étant sélectifs vs PTP1B et VHR. De plus, ces dimères semblent interagir avec le site actif et la poche de liaison des inhibiteurs. Une deuxième série d analogues de thiazolidin-4-one a été obtenue par simplification de la structure TZP. Une réaction à quatre composants, utilisant l énergie micro-onde, a été développée pour préparer rapidement des inhibiteurs de CDC25B avec des CI50 de l ordre du micromolaire. Enfin, une approche originale pour inhiber CDC25 en ciblant l interaction CDC25/CDK-Cycline a débutée. Un crible in silico/in vitro sera réalisé afin d identifier de petites molécules inhibitrices de cette interaction. Des études préliminaires pour la mise en place d outils permettant l évaluation de l affinité de ces molécules pour le site de reconnaissance de CDK2 ont été engagées.CDC25 phosphatases are key regulators of the cell cycle and its checkpoints. Hence, they are required to dephosphorylate and thus activate the Cdk/Cyclin complexes triggering progression through the different phases. Over-expression of CDC25 has been demonstrated in a large number of human tumors and is often associated with aggressiveness and poor clinical prognosis. CDC25 phosphatases may therefore represent attractive targets for anti-cancer therapy. Starting from a thiazolopyrimidinone (TZP) structure, previously reported as CDC25 inhibitor in our laboratory, two series of new compounds have been developed. Dimerisation of the thiazolone scaffold led to bis-thiazolone derivatives with inhibitory activities in the micromolar range greater than that observed for the mono-thiazolones. Moreover, most of these compounds were selective CDC25 inhibitors. A second scaffold was designed by opening of the pyrimidine ring of the TZP, leading to thiazolidine-4-one derivatives that inhibit CDC25B activities with values of IC50 in the micromolar range. A four-component reaction, using micro-wave irradiation, was developed to rapidly prepare these compounds. Finally, an approach aiming at inhibiting the interactions between phosphatase CDC25 and its substrate CDK2 was engaged. Several virtual chemical libraries will be screened in silico, and the small molecules candidates selected will be assessed for their binding affinity using an in vitro assay, that we sought to develop.PARIS5-Bibliotheque electronique (751069902) / SudocPARIS-BIUM-Bib. électronique (751069903) / SudocSudocFranceF

Synthesis of Triazole-Linked SAM-Adenosine Conjugates: Functionalization of Adenosine at N-1 or N-6 Position without Protecting Groups

More than 150 RNA chemical modifications have been identified to date. Among them, methylation of adenosine at the N-6 position (m6A) is crucial for RNA metabolism, stability and other important biological events. In particular, this is the most abundant mark found in mRNA in mammalian cells. The presence of a methyl group at the N-1 position of adenosine (m1A) is mostly found in ncRNA and mRNA and is mainly responsible for stability and translation fidelity. These modifications are installed by m6A and m1A RNA methyltransferases (RNA MTases), respectively. In human, deregulation of m6A RNA MTases activity is associated with many diseases including cancer. To date, the molecular mechanism involved in the methyl transfer, in particular substrate recognition, remains unclear. We report the synthesis of new SAM-adenosine conjugates containing a triazole linker branched at the N-1 or N-6 position of adenosine. Our methodology does not require protecting groups for the functionalization of adenosine at these two positions. The molecules described here were designed as potential bisubstrate analogues for m6A and m1A RNA MTases that could be further employed for structural studies. This is the first report of compounds mimicking the transition state of the methylation reaction catalyzed by m1A RNA MTases

Synthesis of carbapenems containing peptidoglycanmimetics and inhibition of the cross-linking activity of a transpeptidase of the L,D specificity

International audienceThe carbapenem class of β‐lactams has been optimized against Gram‐negative bacteria producing extended‐spectrum β‐lactamases by introducing substituents at position C2. Carbapenems are currently investigated for the treatment of tuberculosis as these drugs are potent covalent inhibitors of l,d‐transpeptidases involved in mycobacterial cell wall assembly. The optimization of carbapenems for inactivation of these unusual targets is sought herein by exploiting the nucleophilicity of the C8 hydroxyl group to introduce chemical diversity. As β‐lactams are structure analogs of peptidoglycan precursors, the substituents were chosen to increase similarity between the drug and the substrate. Fourteen peptido‐carbapenems were efficiently synthesized. They were more effective than the reference drug, meropenem, owing to the positive impact of a phenethylthio substituent introduced at position C2 but the peptidomimetics added at position C8 did not further improve the activity. Thus, position C8 can be modified to modulate the pharmacokinetic properties of highly efficient carbapenems

Synthesis of tRNA analogues containing a terminal ribose locked in the South conformation to study tRNA-dependent enzymes

International audienceSynthesis and biological evaluation of tRNA analogues containing a terminal ribose locked in the South conformation