Regulation of nucleic acids biosynthesis : design and study of metabolic effectors

Les analogues de nucléoside représentent une famille d'agents thérapeutiques très largement utilisée en chimiothérapie anticancéreuse. Cependant des phénomènes de résistance d'origine multifactorielle apparaissent chez les patients atteints de leucémie et il semble que la surexpression d'une enzyme, la 5'-nucléotidase cytosolique de type II (cN-II) soit un des facteurs impliqués. Nous nous sommes donc intéressés à la synthèse et à l'étude d'inhibiteurs potentiels de cN-II du type analogues de nucléoside phosphonate. Ce manuscrit rapporte dans un premier temps le contexte biologique des travaux de thèse, et les découvertes ayant supposés l'implication de la cN-II dans les mécanismes de résistance associés à l'utilisation clinique de nucléosides cytotoxiques. Le deuxième chapitre décrit la synthèse d'analogues phosphonates de l'uridine et de la cytosine modifiés en position 5, ainsi que leur évaluation biologique vis-à-vis de la cN-II purifiée. Enfin, la mise au point d'une stratégie inédite, via l'ouverture d'un époxynucléoside par un phosphite, a permis de synthétiser des béta-hydroxyphosphonates en série purique, et également d'obtenir les prodrogues bis(SATE) correspondantes.Nucleosidic analogs are widely used as therapeutic agents in antitumoral chemotherapy. However, cellular resistance appears in a multifactorial manner in leukemic patient and it seems that the overexpression of a nucleotidase, the 5'-cytosolic nucleotidase (cN-II) is involved in this phenomenon. We focused our interest on the synthesis and the study of potential inhibitors belonging to the family of phosphonate nucleoside analogs. First, we reviewed literature data about the biological context of our research, especially concerning the involvement of cN-II in resistance phenomenon. Then, we described the synthesis of various phosphonate nucleosides bearing 5-modified uracil and cytosine as nucleobase, as well as their evaluation as inhibitors against the purified enzyme. Finally, a novel strategy for the synthesis of beta-hydroxyphosphonate nucleosides in purine series was designed and developed, and then applied to the synthesis of the corresponding bis(SATE) prodrugs

An alternative pathway to ribonucleoside β-hydroxyphosphonate analogues and related prodrugs.

International audienceNucleoside β-(S)-hydroxyphosphonate analogues have recently proven to be interesting bioactive compounds as 5'-nucleotidase inhibitors. These derivatives were obtained in a pyrimidine series through an ex-chiral pool pathway or the stereoselective reduction of a β-ketophosphonate intermediate. Herein, an original synthesis of these compounds using nucleoside epoxide intermediates, containing either a pyrimidine or a purine as nucleobase, was explored and allowed the direct synthesis of the corresponding bis S-acyl-2-thioethyl (SATE) prodrugs

An Alternative Pathway to Ribonucleoside β‑Hydroxyphosphonate Analogues and Related Prodrugs

Nucleoside β-(<i>S</i>)-hydroxyphosphonate analogues have recently proven to be interesting bioactive compounds as 5′-nucleotidase inhibitors. These derivatives were obtained in a pyrimidine series through an ex-chiral pool pathway or the stereoselective reduction of a β-ketophosphonate intermediate. Herein, an original synthesis of these compounds using nucleoside epoxide intermediates, containing either a pyrimidine or a purine as nucleobase, was explored and allowed the direct synthesis of the corresponding bis <i>S</i>-acyl-2-thioethyl (SATE) prodrugs

A water soluble Cu-I-NHC for CuAAC ligation of unprotected peptides under open air conditions.

International audienceA reducing agent-free version of CuAAC able to operate under open air conditions is reported. A readily-synthesizable, hydrophilic and highly stable CuI-NHC allows the clean ligations of unprotected peptides comprising sensitive side chains, at millimolar concentrations

Beta-hydroxyphosphonate ribonucleoside analogues derived from 4-substituted-1,2,3-triazoles as IMP/GMP mimics: synthesis and biological evaluation

International audienceA series of seventeen beta-hydroxyphosphonate ribonucleoside analogues containing 4-substituted-1,2,3-triazoles was synthesized and fully characterized. Such compounds were designed as potential inhibitors of the cytosolic 5'-nucleotidase II (cN-II), an enzyme involved in the regulation of purine nucleotide pools. NMR and molecular modelling studies showed that a few derivatives adopted similar structural features to IMP or GMP. Five derivatives were identified as modest inhibitors with 53 to 64% of cN-II inhibition at 1 m

Access to functionalised silver(I) and gold(I) N-heterocyclic carbenes by [2+3] dipolar cycloadditions.

International audiencenew strategy was developed for the modification of silver(I) and gold(I) N-heterocyclic carbenes. Azido groups were grafted and used either by copper-catalysed azide-alkyne cycloaddition before metallation or by thermal and "strain-promoted" 1,3-dipolar cycloaddition after metallation to functionalise the metal-NHCs

Structure-activity relationships of β-hydroxyphosphonate nucleoside analogues as cytosolic 5′-nucleotidase II potential inhibitors: Synthesis, in vitro evaluation and molecular modeling studies.

International audienceThe cytosolic 5′-nucleotidase II (cN-II) has been proposed as an attractive molecular target for the development of novel drugs circumventing resistance to cytotoxic nucleoside analogues currently used for treating leukemia and other malignant hemopathies. In the present work, synthesis of β-hydroxyphosphonate nucleoside analogues incorporating modifications either on the sugar residue or the nucleobase, and their in vitro evaluation towards the purified enzyme were carried out in order to determine their potency towards the inhibition of cN-II. In addition to the biochemical investigations, molecular modeling studies revealed important structural features for binding affinities towards the target enzyme

European Non-Polio Enterovirus Network: Introduction of Hospital-Based Surveillance Network to Understand the True Disease Burden of Non-Polio Enterovirus and Parechovirus Infections in Europe

International audienceBackground. Non-polio enteroviruses (EVs) and human parechoviruses (PeVs) cause a wide range of human infections. Limited data on their true disease burden exist as standardized European-wide surveillance is lacking. Aims. Our aim is to estimate the disease burden of EV and PeV infections in Europe via establishment of standardized surveillance for hand, foot and mouth disease (HFMD) and respiratory and neurological infections caused by these viruses. We will also assess the sensitivity of assays implemented in the network of participating laboratories so that all EV and PeV types are adequately detected. Plan. The European Non-Polio Enterovirus Network (ENPEN) has developed standardized protocols for a prospective, multi-center and cross-sectional hospital-based pilot study. Protocols include guidance for diagnosis, case definition, detection, characterization and reporting of EV and PeV infections associated with HFMD and respiratory and neurological diseases. Over 30 sites from 17 European countries have already registered to this one pilot study, likely to be commenced in 2022. Benefits. This surveillance will allow European-wide comparison of data on EV and PeV infection. These data will also be used to determine the burden of EV and PeV infections, which is needed to guide the further prevention measures and policies