Longer telomere length in peripheral white blood cells is associated with risk of lung cancer and the rs2736100 (CLPTM1L-TERT) polymorphism in a prospective cohort study among women in China.

A recent genome-wide association study of lung cancer among never-smoking females in Asia demonstrated that the rs2736100 polymorphism in the TERT-CLPTM1L locus on chromosome 5p15.33 was strongly and significantly associated with risk of adenocarcinoma of the lung. The telomerase gene TERT is a reverse transcriptase that is critical for telomere replication and stabilization by controlling telomere length. We previously found that longer telomere length measured in peripheral white blood cell DNA was associated with increased risk of lung cancer in a prospective cohort study of smoking males in Finland. To follow up on this finding, we carried out a nested case-control study of 215 female lung cancer cases and 215 female controls, 94% of whom were never-smokers, in the prospective Shanghai Women's Health Study cohort. There was a dose-response relationship between tertiles of telomere length and risk of lung cancer (odds ratio (OR), 95% confidence interval [CI]: 1.0, 1.4 [0.8-2.5], and 2.2 [1.2-4.0], respectively; P trend = 0.003). Further, the association was unchanged by the length of time from blood collection to case diagnosis. In addition, the rs2736100 G allele, which we previously have shown to be associated with risk of lung cancer in this cohort, was significantly associated with longer telomere length in these same study subjects (P trend = 0.030). Our findings suggest that individuals with longer telomere length in peripheral white blood cells may have an increased risk of lung cancer, but require replication in additional prospective cohorts and populations

Loss of STOP Protein Impairs Peripheral Olfactory Neurogenesis

International audienceIn conclusion, STOP protein seems to be involved in the establishment of synapses in the olfactory glomerulus. Our results indicate that the olfactory system of STOP null mice is a well-suited experimental model (1) for the study of the mechanism of action of STOP protein in synaptic function/plasticity and (2) for pathophysiological studies of the mechanisms of altered neuronal connections in schizophrenia

Nouvelle approche de la synthèse du FR-900482 (Synthèse totale du FR-6679)

Les FR-900482 et FR-66979 sont des produits naturels isolés de la même souche de champignons et qui possèdent d'intéressantes propriétés anti-tumorales. Leur structure inhabituelle, proche de celle des mitomycines, constitue un important challenge synthétique. Dans le but de réaliser la synthèse totale de ces substances, nous avons développé une nouvelle méthodologie pour obtenir des composés de type benzazocènes qui sont d'importants intermédiaires dans la synthèse du FR-900482 et du FR-66979. Cette méthode, mise au point sur un composé modèle et dont nous avons élucidé le mécanisme, consiste à provoquer une transposition dite de " homo-Brook " d'un béta-hydroxysilane qui induit une expansion de cycle par ouverture d'une aziridine. Cette transformation conduit directement à un benzazocène correctement fonctionnalisé pour la synthèse des FR-900482 et FR-66979. Grâce à cette méthodologie, nous avons pu achever la synthèse totale du FR-66979. Cette thèse comporte une partie bibliographique qui traite de l'activité biologique de ces produits naturels ainsi que des différentes approches rapportées dans la littérature visant à leur synthèse. Le deuxième chapitre de la thèse porte sur la mise au point de l'étape clé de notre synthèse grâce à l'étude d'un composé modèle. Le troisième et dernier chapitre décrit la synthèse totale du FR-66979.LYON1-BU.Sciences (692662101) / SudocLYON-ENS Sciences (693872304) / SudocSudocFranceF

Homo-Brook route to benzazocenols and congeners via allylsilane-derived aziridines

We describe a concise entry to benzazocenols intermediates, e.g. I, for mitomycinoids via a homo-Brook rearrangement-ring opening sequence of a silylated aziridine, e.g. II. The latter is obtained by intramol. 1,3-dipolar cycloaddn. of an azide with an allylsilane, followed by irradn. of the resulting triazoline

Discovery of a Potent, Selective, Orally Bioavailable, and Efficacious Novel 2‑(Pyrazol-4-ylamino)-pyrimidine Inhibitor of the Insulin-like Growth Factor‑1 Receptor (IGF-1R)

Optimization of cellular lipophilic ligand efficiency (LLE) in a series of 2-anilino-pyrimidine IGF-1R kinase inhibitors led to the identification of novel 2-(pyrazol-4-ylamino)-pyrimidines with improved physicochemical properties. Replacement of the imidazo­[1,2-<i>a</i>]­pyridine group of the previously reported inhibitor <b>3</b> with the related pyrazolo­[1,5-<i>a</i>]­pyridine improved IGF-1R cellular potency. Substitution of the amino-pyrazole group was key to obtaining excellent kinase selectivity and pharmacokinetic parameters suitable for oral dosing, which led to the discovery of (2<i>R</i>)-1-[4-(4-{[5-chloro-4-(pyrazolo­[1,5-<i>a</i>]­pyridin-3-yl)-2-pyrimidinyl]­amino}-3,5-dimethyl-1<i>H</i>-pyrazol-1-yl)-1-piperidinyl]-2-hydroxy-1-propanone (AZD9362, <b>28</b>), a novel, efficacious inhibitor of IGF-1R

Discovery of Novel 3‑Quinoline Carboxamides as Potent, Selective, and Orally Bioavailable Inhibitors of Ataxia Telangiectasia Mutated (ATM) Kinase

A novel series of 3-quinoline carboxamides has been discovered and optimized as selective inhibitors of the ataxia telangiectasia mutated (ATM) kinase. From a modestly potent HTS hit (<b>4</b>), we identified molecules such as 6-[6-(methoxymethyl)-3-pyridinyl]-4-{[(1<i>R</i>)-1-(tetrahydro-2<i>H</i>-pyran-4-yl)­ethyl]­amino}-3-quinolinecarboxamide (<b>72</b>) and 7-fluoro-6-[6-(methoxymethyl)­pyridin-3-yl]-4-{[(1<i>S</i>)-1-(1-methyl-1<i>H</i>-pyrazol-3-yl)­ethyl]­amino}­quinoline-3-carboxamide (<b>74</b>) as potent and highly selective ATM inhibitors with overall ADME properties suitable for oral administration. <b>72</b> and <b>74</b> constitute excellent oral tools to probe ATM inhibition in vivo. Efficacy in combination with the DSB-inducing agent irinotecan was observed in a disease relevant model