One-pot two-step catalytic synthesis of 6-amino-2-pyridone-3,5-dicarbonitriles enabling anti-cancer bioactivity

We report a one-pot two-step synthesis of a bioactive 6-amino-2-pyridone-3,5-dicarbonitrile derivative using natural product catalysts betaine and guanidine carbonate. Anti-cancer bioactivity was observed in specific molecules within the library of 16 derivatives. Out of the compounds, 5o had the most potent anti-cancer activity against glioblastoma cells and was selected for further study. Compound 5o showed anti-cancer properties against liver, breast, lung cancers as well as primary patient-derived glioblastoma cell lines. Furthermore, 5o in combination with specific clinically relevant small molecule inhibitors induced enhanced cytotoxicity in glioblastoma cells. Through our current work, we establish a promising 6-amino-2-pyridone-3,5-dicarbonitrile based lead compound with anti-cancer activity either on its own or in combination with specific clinically relevant small molecule kinase and proteasome inhibitors

Transcriptome profiling of a Sinorhizobium meliloti fadD mutant reveals the role of rhizobactin 1021 biosynthesis and regulation genes in the control of swarming

58 pages, 7 figures, 3 tables, 3 additional files.-- Provisional PDF.[Background] Swarming is a multicellular phenomenom characterized by the coordinated and rapid movement of bacteria across semisolid surfaces. In Sinorhizobium meliloti this type of motility has been described in a fadD mutant. To gain insights into the mechanisms underlying the process of swarming in rhizobia, we compared the transcriptome of a S. meliloti fadD mutant grown under swarming inducing conditions (semisolid medium) to those of cells grown under non-swarming conditions (broth and solid medium).[Results] More than a thousand genes were identified as differentially expressed in response to growth on agar surfaces including genes for several metabolic activities, iron uptake, chemotaxis, motility and stress-related genes. Under swarming-specific conditions, the most remarkable response was the up-regulation of iron-related genes. We demonstrate that the pSymA plasmid and specifically genes required for the biosynthesis of the siderophore rhizobactin 1021 are essential for swarming of a S. meliloti wild-type strain but not in a fadD mutant. Moreover, high iron conditions inhibit swarming of the wild-type strain but not in mutants lacking either the iron limitation response regulator RirA or FadD.[Conclusions] The present work represents the first transcriptomic study of rhizobium growth on surfaces including swarming inducing conditions. The results have revealed major changes in the physiology of S. meliloti cells grown on a surface relative to liquid cultures. Moreover, analysis of genes responding to swarming inducing conditions led to the demonstration that iron and genes involved in rhizobactin 1021 synthesis play a role in the surface motility shown by S. meliloti which can be circumvented in a fadD mutant. This work opens a way to the identification of new traits and regulatory networks involved in swarming by rhizobia.JN was supported by a postdoctoral contract (Consejería de Innovación, Ciencia y Empresa, Junta de Andalucía). This work was supported by a FPI fellowship from MICINN to CVA-G, and by grants BIO2007-62988 and CVI 03541 to MJS.Peer reviewe

Development and optimisation of in vitro sonodynamic therapy for glioblastoma

Sonodynamic therapy (SDT) is currently on critical path for glioblastoma therapeutics. SDT is a non-invasive approach utilising focused ultrasound to activate photosensitisers like 5-ALA to impede tumour growth. Unfortunately, the molecular mechanisms underlying the therapeutic functions of SDT remain enigmatic. This is primarily due to the lack of intricately optimised instrumentation capable of modulating SDT delivery to glioma cells in vitro. Consequently, very little information is available on the effects of SDT on glioma stem cells which are key drivers of gliomagenesis and recurrence. To address this, the current study has developed and validated an automated in vitro SDT system to allow the application and mapping of focused ultrasound fields under varied exposure conditions and setup configurations. The study optimizes ultrasound frequency, intensity, plate base material, thermal effect, and the integration of live cells. Indeed, in the presence of 5-ALA, focused ultrasound induces apoptotic cell death in primary patient-derived glioma cells with concurrent upregulation of intracellular reactive oxygen species. Intriguingly, primary glioma stem neurospheres also exhibit remarkably reduced 3D growth upon SDT exposure. Taken together, the study reports an in vitro system for SDT applications on tissue culture-based disease models to potentially benchmark the novel approach to the current standard-of-care.</p

2-Tridecanone impacts surface-associated bacterial behaviours and hinders plant-bacteria interactions

Surface motility and biofilm formation are behaviours which enable bacteria to infect their hosts and are controlled by different chemical signals. In the plant symbiotic alpha‐proteobacterium Sinorhizobium meliloti, the lack of long‐chain fatty acyl‐coenzyme A synthetase activity (FadD) leads to increased surface motility, defects in biofilm development, and impaired root colonization. In this study, analyses of lipid extracts and volatiles revealed that a fadD mutant accumulates 2‐tridecanone (2‐TDC), a methylketone known as a natural insecticide. Application of pure 2‐TDC to the wild‐type strain phenocopies the free‐living and symbiotic behaviours of the fadD mutant. Structural features of the methylketone determine its ability to promote S. meliloti surface translocation, which is mainly mediated by a flagella‐independent motility. Transcriptomic analyses showed that 2‐TDC induces differential expression of iron uptake, redox, and stress‐related genes. Interestingly, this methylketone also influences surface motility and impairs biofilm formation in plant and animal pathogenic bacteria. Moreover, 2‐TDC not only hampers alfalfa nodulation but also the development of tomato bacterial speck disease. This work assigns a new role to 2‐TDC as an infochemical that affects important bacterial traits and hampers plant‐bacteria interactions by interfering with microbial colonization of plant tissues

Caracterización genética de sistemas de transporte de péptidos en Sinorhizobium meliloti

Universidad de Granada, Facultad de Ciencias. Leída en 200

Método para prevenir y/o controlar infecciones bacterianas

La presente invención se refiere a un método para prevenir y/o controlar infecciones bacterianas en una planta y/o cultivo, así como en productos (alimentos crudos, soluciones de lavado, material de uso hospitalario) e instalaciones susceptibles de contaminación por bacterias, mediante aplicación de metilcetonas alifáticas de cadena larga, fundamentalmente 2-tridecanona pero también 2- undecanona, 2-dodecanona, y 2-pentadecanona, en formas y concentraciones del orden micromolar no tóxicas tales que permiten evitar dicha infección sin producir un efecto bactericida (destrucción de bacterias). Asimismo, la presente invención se refiere a estas metilcetonas citadas para uso en medicina, mediante administración de dicho compuesto a un animal o un ser humanoPeer reviewedConsejo Superior de Investigaciones CientíficasA1 Solicitud de patente con informe sobre el estado de la técnic

ExpR Is Not Required for Swarming but Promotes Sliding in Sinorhizobium meliloti

Swarming is a mode of translocation dependent on flagellar activity that allows bacteria to move rapidly across surfaces. In several bacteria, swarming is a phenotype regulated by quorum sensing. It has been reported that the swarming ability of the soil bacterium Sinorhizobium meliloti Rm2011 requires a functional ExpR/Sin quorum-sensing system. However, our previous published results demonstrate that strains Rm1021 and Rm2011, both known to have a disrupted copy of expR, are able to swarm on semisolid minimal medium. In order to clarify these contradictory results, the role played by the LuxR-type regulator ExpR has been reexamined. Results obtained in this work revealed that S. meliloti can move over semisolid surfaces using at least two different types of motility. One type is flagellum-independent surface spreading or sliding, which is positively influenced by a functional expR gene mainly through the production of exopolysaccharide II (EPS II). To a lesser extent, EPS II-deficient strains can also slide on surfaces by a mechanism that is at least dependent on the siderophore rhizobactin 1021. The second type of surface translocation shown by S. meliloti is swarming, which is greatly dependent on flagella and rhizobactin 1021 but does not require ExpR. We have extended our study to demonstrate that the production of normal amounts of succinoglycan (EPS I) does not play a relevant role in surface translocation but that its overproduction facilitates both swarming and sliding motilities.This work was supported by grants BIO2007-62988 and BIO2010-18005 from the Ministerio de Ciencia e Innovación (Spain), CVI 03541 from the Junta de Andalucía (Spain), and FEDER funds. J.N. and L.B.R. were sup- ported by grants from the Consejería de Innovación, Ciencia y Empresa (Junta de Andalucía, Spain).Peer Reviewe

Método para prevenir y/o controlar infecciones bacterianas

La presente invención se refiere a un método para prevenir y/o controlar infecciones bacterianas en una planta y/o cultivo, así como en productos (alimentos crudos, soluciones de lavado, material de uso hospitalario) e instalaciones susceptibles de contaminación por bacterias, mediante aplicación de metilcetonas alifáticas de cadena larga, fundamentalmente 2-tridecanona pero también 2- undecanona, 2-dodecanona, y 2-pentadecanona, en formas y concentraciones del orden micromolar no tóxicas tales que permiten evitar dicha infección sin producir un efecto bactericida (destrucción de bacterias). Asimismo, la presente invención se refiere a estas metilcetonas citadas para uso en medicina, mediante administración de dicho compuesto a un animal o un ser humanoPeer reviewedConsejo Superior de Investigaciones CientíficasB1 Patente sin examen previ

Análisis de los rasgos del concepto "familia"

Los contenidos representados en la mente se ajustan a los modelos de redes y de atributos. Éstos últimos como componentes del significado de un concepto son esenciales. Las categorías que producen más atributos son las de Nivel Básico, las que primero aprende y nombra el niño, las más útiles en el lenguaje. Observando los dibujos de los niños podemos conocer como aprenden conceptos. En este trabajo presentamos el análisis de los rasgos del concepto familia mediante instrucciones pictóricas, y estudiamos las variables que influyen en la producción de los rasgos pictóricos que conforman este concepto. Examinamos como los rasgos diseñables de la forma, se corresponden con atributos lingüísticamente enumerables.The contents represented in the mind are adjusted to the network and attributes models. The latter are essential as components of concept meaning. The Basic Leve! categories are those which produce more attributes, they are learned and named the first by children, being the most useful in language. By observing children 's drawings we can know how they learn concepts. In this study we present the analysis of features of the family concept, through drawing instructions and we study the variables that influence the drawing of features belonging to this concept. We examined hozv designable features of the shape, correspond with linguistical y countable attributes.peerReviewe