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Here, molecular dynamics simulations have been carried out on phosphate glasses to clarify the previously debated influence of fluoride on the bioactivity of these glasses. We developed a computationally advanced inter-atomic force field including polarisation effects of the fluorine and oxygen atoms. Structural characterisations of the simulated systems showed that fluoride ions exclusively bond to the calcium modifier cations creating clusters within the glass structure and therefore decreasing the bioactivity of fluoridated phosphate glasses, making them less suitable for biomedical applications.

Three-dimensional (3D) printing has been combined with electrospinning to manufacture multi-layered polymer/glass scaffolds that possess multi-scale porosity, are mechanically robust, release bioactive compounds, degrade at a controlled rate and are biocompatible. Fibrous mats of poly (caprolactone) (PCL) and poly (glycerol sebacate) (PGS) have been directly electrospun on one side of 3D-printed grids of PCL-PGS blends containing bioactive glasses (BGs). The excellent adhesion between layers has resulted in composite scaffolds with a Young&rsquo, s modulus of 240&ndash, 310 MPa, higher than that of 3D-printed grids (125&ndash, 280 MPa, without the electrospun layer). The scaffolds degraded in vitro by releasing PGS and BGs, reaching a weight loss of ~14% after 56 days of incubation. Although the hydrolysis of PGS resulted in the acidification of the buffer medium (to a pH of 5.3&ndash, 5.4), the release of alkaline ions from the BGs balanced that out and brought the pH back to 6.0. Cytotoxicity tests performed on fibroblasts showed that the PCL-PGS-BGs constructs were biocompatible, with cell viability of above 125% at day 2. This study demonstrates the fabrication of systems with engineered properties by the synergy of diverse technologies and materials (organic and inorganic) for potential applications in tendon and ligament tissue engineering.

Les tumeurs stromales gastro-intestinales (GIST, gastro-intestinal stromal tumor) sont des tumeurs rares dont l’individualisation a ete possible grâce aux techniques d’immunomarquage, et dont le pronostic a ete considerablement ameliore grâce aux antityrosines-kinases. Leurs caracteristiques sont peu etudiees en Afrique subsaharienne. Notre etude decrit les caracteristiques cliniques et pronostiques de 15 cas de GIST dans un service d’oncologie medicale subsaharien a l’ere des antityrosines-kinases. Ces cas representaient 4,3 % des tumeurs digestives et affectaient 11 hommes et quatre femmes, dont l’âge moyen etait de 62 ± 9,9 ans. Leurs circonstances de diagnostic etaient dominees par la douleur epigastrique (67 %) et le syndrome occlusif (13 %), refletant leurs localisations surtout gastriques (53 %) et greliques (20 %). Les types histologiques frequents etaient la forme fusiforme (80 %) et la forme epithelioide (13 %). Toutes les tumeurs exprimaient le CD117 et avaient un index mitotique superieur a 5/50 CFG (Champs a Fort Grossissement), trois exprimaient en plus le DOG1. La tumeur etait metastatique et non operable chez sept patients, operee chez les huit autres. Un traitement par imatinib mesylate a permis d’obtenir une remission complete chez les huit patients operes, une stabilisation des lesions chez deux patients non operes avec un recul de suivi de 2 a 96 mois. Cinq cas metastatiques avaient progresse avec une issue fatale pour quatre patients. En conclusion, les GIST ont, dans notre contexte, des localisations le plus souvent gastriques ou greliques, sans specificite clinique. Leur sensibilite a l’imatinib mesylate incite a les evoquer devant toute symptomatologie digestive chez le sujet âge de plus de 40 ans.

While adding the structural features that are more favored by on-target activity is the more common strategy in selectivity optimization, the opposite strategy of subtracting the structural features that contribute more to off-target activity can also be very effective. Reported here is our successful effort of improving the kinase selectivity of type II maternal embryonic leucine zipper kinase inhibitors by applying these two complementary approaches together, which clearly demonstrates the powerful synergy between them.

Konnen klassische und moderne C-H-Oxidationsreaktionen Biotransformationen bei der Synthese von Wirkstoffmetaboliten erganzen? Wir haben versucht, bei einer Durchsicht der Literatur eine Antwort auf diese wichtige Frage fur die Praxis der pharmazeutischen Industrie zu finden. Solche Metaboliten werden wahrend aller Phasen der Wirkstoffsuche und -entwicklung benotigt; ihre Synthese ist jedoch noch immer ein ungelostes Problem. Dieser Aufsatz stellt relevante Anwendungen von chemischen C-H-Oxidationen, Elektrochemie und Mikrofluidiktechniken auf Wirkstoff-Grundgeruste vor, mit denen Metaboliten zuganglich gemacht werden sollen, und fasst vielversprechende Reaktionen fur diesen Zweck zusammen. Wo es moglich oder passend ist, wird der Vergleich zur Biotransformation gezogen. So haben wir versucht, bestehende Lucken zu finden, um weitere Aktivitaten auf diesem wichtigen Forschungsfeld anzuspornen.

MELK kinase has been implicated in playing an important role in tumorigenesis. Our previous studies suggested that MELK is involved in the regulation of cell cycle and its genetic depletion leads to growth inhibition in a subset of high MELK-expressing basal-like breast cancer cell lines. Herein we describe the discovery and optimization of novel MELK inhibitors 8a and 8b that recapitulate the cellular effects observed by short hairpin ribonucleic acid (shRNA)-mediated MELK knockdown in cellular models. We also discovered a novel fluorine-induced hydrophobic collapse that locked the ligand in its bioactive conformation and led to a 20-fold gain in potency. These novel pharmacological inhibitors achieved high exposure in vivo and were well tolerated, which may allow further in vivo evaluation.

We aim the power of C–H bond functionalization at a problem of major practical consequence—namely, scalable access to drug metabolites and their analogs. In this context, we pursue the development of simple C–H oxidation methods that tolerate a wide range of functional groups and structural features found in pharmaceuticals (‘chemotransformations’). In this Letter, we focus on N,N-dimethylamines as they are frequently found in pharmaceuticals and undergo CYP-mediated N-demethylation reactions in vivo. The direct access to these in vivo metabolites, from the parent drugs, has remained a significant synthetic challenge for which a broad solution had not previously been found. We here show that a simple copper–oxygen catalytic system provides a scalable route to complex N-demethylated drug metabolites.

Can classical and modern chemical C-H oxidation reactions complement biotransformation in the synthesis of drug metabolites? We have surveyed the literature in an effort to try to answer this important question of major practical significance in the pharmaceutical industry. Drug metabolites are required throughout all phases of the drug discovery and development process; however, their synthesis is still an unsolved problem. This Review, not intended to be comprehensive or historical, highlights relevant applications of chemical C-H oxidation reactions, electrochemistry and microfluidic technologies to drug templates in order to access drug metabolites, and also highlights promising reactions to this end. Where possible or appropriate, the contrast with biotransformation is drawn. In doing so, we have tried to identify gaps where they exist in the hope to spur further activity in this very important research area.

The isolation, quantitation, and characterization of drug metabolites in biological fluids remain challenging. Rapid access to oxidized drugs could facilitate metabolite identification and enable early pharmacology and toxicity studies. Herein, we compared biotransformations to classical and new chemical C-H oxidation methods using oxcarbazepine, naproxen, and an early compound hit (phthalazine 1). These studies illustrated the low preparative efficacy of biotransformations and the inability of chemical methods to oxidize complex pharmaceuticals. We also disclose an aerobic catalytic protocole (CuI/air) to oxidize tertiary amines and benzylic CH's in drugs. The reaction tolerates a broad range of functionalities and displays a high level of chemoselectivity, which is not generally explained by the strength of the C-H bonds but by the individual structural chemotype. This study represents a first step toward establishing a chemical toolkit (chemotransformations) that can selectively oxidize C-H bonds in complex pharmaceuticals and rapidly deliver drug metabolites.

Les sarcomes de la tete et du cou sont des cancers otorhinolaryngologiques (ORL) rares et histologiquement tres heterogenes. Nous rapportons une observation de sarcomes de l’enfant a localisation ORL au centre hospitalo-universitaire de Conakry. L’etude a concerne une enfant de quatre ans, sans antecedents particuliers, qui presentait depuis huit mois une tumeur parotidienne droite d’installation progressive. Apres une biopsie et une cytoponction qui n’ont pas permis de poser le diagnostic, nous avons realise une exerese chirurgicale complete, en monobloc de la tumeur. L’etude anatomopathologique couplee a l’immunohistochimie ont permis de poser le diagnostic de sarcome fusocellulaire de bas grade. En l’absence de traitement complementaire, la patiente est decedee dans un tableau de metastases pulmonaires. Les sarcomes de la tete et du cou sont tres agressifs et de mauvais pronostic etant donne leur potentiel important d’extension locoregionale, de metastases a distance et de recidive tumorale.

Le lymphangiome kystique est une tumeur vasculaire, benigne, rare, d’origine lymphatique. La forme principale est representee par le lymphangiome cervico-facial congenital de l’enfant. Sa pathogenese est inconnue. Cette malformation congenitale du systeme lymphatique est composee de formations kystiques developpees a partir d’endothelium lymphatique et remplies de lymphe et de sang. L’atteinte des voies aerodigestives superieures (VaDS) peut conduire a des complications graves, mettant en jeu le pronostic vital. nous presentons trois observations de lymphangiomes kystiques de diagnostic post natal. Le traitement etait chirurgical dans tous les cas consistant en exerese complete de la tumeur et le diagnostic confirme par l’examen histopathologique de la piece operatoire. apres un recul d’au moins 12 mois, aucune recidive locale n’a ete observee cependant la surveillance reste de mise. Mots cles : Lymphangiomes kystique, malformation, cervico-faciale Cystic lymphangioma is a vascular tumor, rare benign lymphatic origin. The main form is represented by the cervicofacial congenital lymphangioma of the child. Its pathogenesis is unknown. This congenital malformation of the lymphatic system is composed of cystic formations developed from lymphatic endothelium and filled with lymph and blood. Involvement of the upper aero digestive tract (UaDT) can lead to serious complications, involving life-threatening. We present three cases of cystic lymphangiomas of postnatal diagnosis. Treatment was surgical in all cases consisting of complete resection of the tumor and the diagnosis confirmed by histopathological examination of the surgical specimen. after a decline of at least 12 months, no local recurrence was observed; however, monitoring is still required. Keywords : cystic lymphangioma malformation, cervicofacial

Oncogenic IDH1 and IDH2 mutations contribute to cancer via production of R-2-hydroxyglutarate (2-HG). Here, we characterize two structurally distinct mutant- and isoform-selective IDH1 inhibitors that inhibit 2-HG production. Both bind to an allosteric pocket on IDH1, yet shape it differently, highlighting the plasticity of this site. Oncogenic IDH1R132H mutation destabilizes an IDH1 “regulatory segment,” which otherwise restricts compound access to the allosteric pocket. Regulatory segment destabilization in wild-type IDH1 promotes inhibitor binding, suggesting that destabilization is critical for mutant selectivity. We also report crystal structures of oncogenic IDH2 mutant isoforms, highlighting the fact that the analogous segment of IDH2 is not similarly destabilized. This intrinsic stability of IDH2 may contribute to observed inhibitor IDH1 isoform selectivity. Moreover, discrete residues in the IDH1 allosteric pocket that differ from IDH2 may also guide IDH1 isoform selectivity. These data provide a deeper understanding of how IDH1 inhibitors achieve mutant and isoform selectivity.

High throughput screening and subsequent hit validation identified 4-isopropyl-3-(2-((1-phenylethyl)amino)pyrimidin-4-yl)oxazolidin-2-one as a potent inhibitor of IDH1R132H. Synthesis of the four separate stereoisomers identified the (S,S)-diastereomer (IDH125, 1f) as the most potent isomer. This also showed reasonable cellular activity and excellent selectivity vs IDH1wt. Initial structure–activity relationship exploration identified the key tolerances and potential for optimization. X-ray crystallography identified a functionally relevant allosteric binding site amenable to inhibitors, which can penetrate the blood–brain barrier, and aided rational optimization. Potency improvement and modulation of the physicochemical properties identified (S,S)-oxazolidinone IDH889 (5x) with good exposure and 2-HG inhibitory activity in a mutant IDH1 xenograft mouse model.

Can classical and modern chemical C-H oxidation reactions complement biotransformation in the synthesis of drug metabolites? We have surveyed the literature in an effort to try to answer this important question of major practical significance in the pharmaceutical industry. Drug metabolites are required throughout all phases of the drug discovery and development process; however, their synthesis is still an unsolved problem. This Review, not intended to be comprehensive or historical, highlights relevant applications of chemical C-H oxidation reactions, electrochemistry and microfluidic technologies to drug templates in order to access drug metabolites, and also highlights promising reactions to this end. Where possible or appropriate, the contrast with biotransformation is drawn. In doing so, we have tried to identify gaps where they exist in the hope to spur further activity in this very important research area.

We describe the coupling of primary sulfonamides and various halogenated heterocyclic cores, with an emphasis on 2-heteroaryl halides, via copper catalysis. These studies enabled the synthesis of many new mono-N-heteroaryl sulfonamides. The electronic factors that influence the course of the reaction have also been investigated.

The practical, cost-effective and operationally simple two-step transformation is applied to a range of dimethylamine-containing pharmaceuticals including clomipramine (I) and diltiazem (IV).

Cerebral vasculopathy exposes patients to a high risk of stroke, a major complication of sickle cell disease (SCD) associated with a high risk of death and disability. Transcranial doppler (TCD) ultrasonography used to identify SCD patients at risk of stroke may contribute to significantly reducing morbidity and mortality in these patients by indicating appropriate treatment. From March 2008 to February 2013, we conducted systematic screening for cerebral vasculopathy using TCD in 572 SCD patients (including 375 SS, 144 SC, 26 S/β(0), and 27 S/β(+) thalassemia patients) aged 1-17 years in a comprehensive center for follow-up and research on sickle cell disease in Bamako, Mali. After exclusion of 30 inadequate results and one case of abnormal TCD observed in a multiple organ failure patient, we found an abnormal or conditional TCD in 18% of 541 children examined in a steady state. The highest prevalence of abnormal cases concerned homozygous SS patients (8.1%). No case of abnormal or conditional TCD was observed in children with S/β(+) thalassemia. Hemoglobin concentrations were significantly lower in patients with conditional or abnormal TCD (P0.01). In a subgroup of 68 patients with conditional TCD, nine (13%) converted to abnormal TCD over 1 year. In this subgroup of 68 conditional TCD patients, a decrease or increase in baseline hemoglobin concentration was predictive of conditional or abnormal TCD at the follow-up visit. Progression towards conditional TCD was observed in four patients (0.9%) who initially had normal TCD. Children with abnormal TCD had, whenever possible, a monthly exchange transfusion program. One case of transient stroke in the context of P. falciparum malaria with low hemoglobin concentration and one death were observed. These findings highlight the need for systematic TCD in sickle cell disease monitoring and implementing regular blood transfusion programs in the context of limited access to regular and secure blood transfusions.

It has long been admitted that male and female cultivars of Dioscorea cayenensis-rotundata complex do not flower at the same period and consequently natural outcrossing rarely occurs. Flowering in thirteen (7 males and 6 females) traditional cultivars were studied. Four main results were obtained: i) the first bud emergence occurred 25 days earlier in males; ii) the male and female first flower opening overlapped for 10 days (85 to 95 days after sprouting); iii) for both sexes, highest frequency of flower opening occurred at mid-day; and iv) the female cultivar 1800 could flower for 8 consecutive days, with a peak between day 4 and day 8. These results are discussed in relation to intercrossing success.

Tankyrase 1 and 2 have been shown to be redundant, druggable nodes in the Wnt pathway. As such, there has been intense interest in developing agents suitable for modulating the Wnt pathway in vivo by targeting this enzyme pair. By utilizing a combination of structure-based design and LipE-based structure efficiency relationships, the core of XAV939 was optimized into a more stable, more efficient, but less potent dihydropyran motif 7. This core was combined with elements of screening hits 2, 19, and 33 and resulted in highly potent, selective tankyrase inhibitors that are novel three pocket binders. NVP-TNKS656 (43) was identified as an orally active antagonist of Wnt pathway activity in the MMTV-Wnt1 mouse xenograft model. With an enthalpy-driven thermodynamic signature of binding, highly favorable physicochemical properties, and high lipophilic efficiency, NVP-TNKS656 is a novel tankyrase inhibitor that is well suited for further in vivo validation studies.

Red cell transfusion is one of the main treatments in sickle cell disease. However there are potential risks of blood transfusions. In order to propose strategies to improve blood safety in sickle cell disease in Mali, we conducted a prospective study of 133 patients with sickle cell anemia recruited at the sickle cell disease research and control center of Bamako, November 2010 to October 2011. The study aimed to determine the prevalence of human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) infections by serum screening and the frequency of red cell alloimmunization before and after blood transfusion. The diagnosis of sickle cell syndrome was made by HPLC, the detection of markers of viral infection was performed by ELISA, and the diagnosis of alloimmunization was conducted by the Indirect Coombs test. Prevalence of viral infections observed at the time of enrolment of patients in the study was 1%, 3% and 1% respectively for HIV, HBV and HCV. Three cases of seroconversion after blood transfusion were detected, including one for HIV, one for HBV and one another for HCV in sickle cell anemia patients. All these patients had received blood from occasional donors. The red cell alloimmunization was observed in 4.4% of patients. All antibodies belonged to Rh system only. Blood transfusion safety in sickle cell anemia patients in Mali should be improved by the introduction of at least the technique for detecting the viral genome in the panel of screening tests and a policy of transfusions of blood units only from regular blood donors.

Overexpression of the antiapoptotic members of the Bcl-2 family of proteins is commonly associated with cancer cell survival and resistance to chemotherapeutics. Here, we describe the structure-based optimization of a series of N-heteroaryl sulfonamides that demonstrate potent mechanism-based cell death. The role of the acidic nature of the sulfonamide moiety as it relates to potency, solubility, and clearance is examined. This has led to the discovery of novel heterocyclic replacements for the acylsulfonamide core of ABT-737 and ABT-263.

The first TiCl(4)-mediated condensation of secondary amides with aldehydes and ketones has been achieved. The reaction proceeds at room temperature and is complete within 5 h in most cases. The optimized procedure used 5 equiv of an amine base hinting that the in situ activation of both the amide and the Lewis acid is required. The reaction affords polysubstituted (E)-enamides.

The discovery of new Bcl-2 protein–protein interaction antagonists is described. We replaced the northern fragment of ABT737 (π–π stacking interactions) with structurally simplified hydrophobic cage structures with much reduced conformational flexibility and rotational freedom. The binding mode of the compounds was elucidated by X-ray crystallography, and the compounds showed excellent oral bioavailability and clearance in rat PK studies.

We describe the coupling of primary sulfonamides and various halogenated heterocyclic cores, with an emphasis on 2-heteroaryl halides, via copper catalysis. These studies enabled the synthesis of many new mono-N-heteroaryl sulfonamides. The electronic factors that influence the course of the reaction have also been investigated.

The first TiCl(4)-mediated condensation of secondary amides with aldehydes and ketones has been achieved. The reaction proceeds at room temperature and is complete within 5 h in most cases. The optimized procedure used 5 equiv of an amine base hinting that the in situ activation of both the amide and the Lewis acid is required. The reaction affords polysubstituted (E)-enamides.

Les études concernant les descendances d'hybridations contrôlées sont rares chez les ignames africaines relevant de l'espèce D. cayenensis-rotundata. Une telle étude a pu être réalisée en Côte d'Ivoire en combinant l'utilisation de géniteurs génétiquement bien caractérisés, la maîtrise des conditions d'hybridation et le recours aux isoenzymes pour contrôler la légitimité des descendances. L'utilisation de 6 systèmes enzymatiques a permis de détecter les fécondations illégitimes et de fournir des informations sur la génétique de l'igname. L'hétérozygotie observée au niveau des géniteurs est apparue inférieure à ce qui doit normalement être attendu chez des plantes dioïques. Ceci laisse supposer que les descendances "demi-frères" pourraient ne pas être rares