Rational design and synthesis of novel selective PI3K inhibitors for cancer therapy

Dissertação de mestrado em Química MedicinalA via da fosfatidilinositol-3 quinase (PI3K) é uma das cascatas de sinalização patogénica mais frequentemente ativada numa grande variedade de cancros. Nos últimos 15 anos tem havido um crescimento na procura de inibidores seletivos das 4 isoformas da classe I da PI3K, uma vez que demonstram melhor especificidade e reduzida toxicidade em relação aos inibidores existentes. Dada a similaridade estrutural entre alguns compostos reportados como inibidores seletivos de PI3K, e compostos sintetizados e testados pelo grupo de investigação, a possibilidade destes últimos poderem ser ativos nestes tipos de recetores foi considerada. Foi construída uma biblioteca virtual contendo 661 ligandos que se submeteu a um screening virtual nas 4 isoformas da classe I da PI3K. No screening foram identificados 68 ligandos selectivos, 60 para PI3Kα e 8 para PI3Kγ. A análise estatística dos resultados permitiu estabelecer correlações entre os dados de afinidade e algumas propriedades físico-químicos dos ligandos. Também foram investigados os locais de ligação estabelecidos pelos ligandos seletivos no centro ativo das isoformas alfa e gama da PI3K. Com o objetivo de sintetizar uma amostra dos ligandos submetidos ao screening virtual, foi estabelecida uma via sintética extensa a partir de reagentes comerciais, que se dividiu em duas partes: síntese de reagentes de partida e síntese de produtos finais. A síntese de reagentes de partida contemplou a preparação de derivados de 2-(3-aminofenil)-purina (1-23) através de uma abordagem sintética já reportada. A síntese de produtos finais ocorreu por reação dos compostos 1-23 com agentes acilantes seguida de reação com nucleófilos. Foram sintetizados uma série de diferentes amidas, ureias e carbamatos usando diferentes metodologias. De um modo geral, as abordagens sintéticas seguidas foram eficientes, contudo, em alguns casos há necessidade de algum trabalho futuro, para otimizar algumas das vias sintéticas.The phosphatidylinositol-3 kinase (PI3K) pathway is one of the most frequently activated pathogenic signalling cascades in a wide variety of cancers. In the last 15 years there has been an increase in the search for selective inhibitors of the 4 class I isoforms of PI3K, as they demonstrate better specificity and reduced toxicity in comparison to existing inhibitors. Given the structural similarity between some compounds reported as selective PI3K inhibitors, and those synthesised and tested by the research group, the possibility that these may be active on these receptors was considered. A virtual library containing 661 ligands was constructed and subjected to a virtual screening on the 4 class I isoforms of PI3K. In the screening, 68 selective ligands were identified, 60 for PI3Kα and 8 for PI3Kγ. Statistical analysis of the results allowed the establishment of correlations between the affinity data and some of the physicochemical properties of the ligands. The binding sites established by the selective ligands in the active centre of the alpha and gamma isoforms of PI3K were also investigated. In order to synthesize a sample of the ligands submitted to virtual screening, an extensive synthetic route was established from commercial reagents and was divided into two parts: synthesis of starting reagents and synthesis of final products. The synthesis of starting reagents contemplated the preparation of 2-(3-aminophenyl)-purine derivatives (1-23) through an already reported synthetic approach. The synthesis of final products occurred by reaction of compounds 1-23 with acylation agents, followed by reaction with nucleophiles. A new series of different amides, ureas and carbamates were synthesised using different methodologies. Overall, the synthetic approaches followed were efficient, however, in some cases there is a need for some future work to optimise some of the synthetic routes.I want to take the opportunity to thank the Centre of Chemistry from University of Minho. Also, the access to computing resources funded by the Project “Search-ON2: Revitalization of HPC infrastructure of UMinho” (NORTE-07-0162-FEDER-000086), co-founded by the North Portugal Regional Operational Programme (ON.2–O Novo Norte), under the National Strategic Reference Framework (NSRF), through the European Regional Development Fund (ERDF), is gratefully acknowledge

Evolution of form and function in a model of differentiated multicellular organisms with gene regulatory networks

The emergence of novelties, as a generator of diversity, in the form and function of the organisms have long puzzled biologists. The study of the developmental process and the anatomical properties of an organism provides scarce information into the means by which its morphology evolved. Some have argued that the very nature of novelty is believed to be linked to the evolution of gene regulation, rather than to the emergence of new structural genes. In order to gain further insight into the evolution of novelty and diversity, we describe a simple computational model of gene regulation that controls the development of locomotive multicellular organisms through a fixed set of simple structural genes. Organisms, modeled as two-dimensional spring networks, are simulated in a virtual environment to evaluate their steering skills for path-following. Proposed as a behavior-finding problem, this fitness function guides an evolutionary algorithm that produces structures whose function is well-adapted to the environment (i.e., good path-followers). We show that, despite the fixed simple set of structural genes, the evolution of gene regulation yields a rich variety of body plans, including symmetries, body segments, and modularity, resulting in a diversity of original behaviors to follow a simple path. These results suggest that the sole variation in the regulation of gene expression is a sufficient condition for the emergence of novelty and diversity.This work has been partially funded by the Sixth European Union Framework Program for Research and Technological Development, contract #028892

Diversidad genética usando marcadores de pelaje en gatos domésticos (Felis catus) en la asociación defensora de animales - ADA - Cartago, Valle del Cauca

El gato doméstico presenta diferentes características asociadas al pelaje, algunas de estas características por su herencia codominante o de dominancia incompleta pueden ser determinadas a partir del fenotipo. En la ciudad de Cartago existe un albergue con un gran número de felinos de los cuales no se conoce su procedencia, sus relaciones y su diversidad genética, esto genera un problema sobre los factores asociados a la pérdida de diversidad y al cruce de individuos. El objetivo de éste estudio fue caracterizar la población de gatos domésticos (Feliscatus) de la asociación defensora de animales – A.D.A de Cartago y estimar la diversidad genética mediante marcadores de pelaje. Se utilizó el cálculo en el software Arlequín usando los genes O y S, para esto se realizó el cálculo de desequilibrio de ligamiento con 10.000 literaciones y el cálculo del equilibrio de Hardy Weinberg por máximo de similitud con 1.000.000 de pasos, realizado por medio de la Cadena de Montecarlo. En el desequilibrio de ligamiento para el gen Orange (O) se hicieron 10.000 permutaciones dando como resultado la no combinación de los 2 genes (O y S). No hay ligamiento significativo entre estos con una correlación cercana a 0, la heterocigosidad observada para este gen fue aproximadamente del 50% y la heterocigosidad esperada del 43%, con pi value de 0.25, no siendo significativo, con respecto al equilibrio de Hardy Weinberg la población con este gen (O) está en equilibrio, la heterocigosidad observada fue de 0.5 y la heterocigosidad esperada fue de 0.37

Analog Simulation of Weyl Particles with Cold Atoms

We study theoretically, numerically, and experimentally the relaxation of a collisionless gas in a quadrupole trap after a momentum kick. The non-separability of the potential enables a quasi thermalization of the single particle distribution function even in the absence of interactions. Suprinsingly, the dynamics features an effective decoupling between the strong trapping axis and the weak trapping plane. The energy delivered during the kick is redistributed according to the symmetries of the system and satisfies the Virial theorem, allowing for the prediction of the final temperatures. We show that this behaviour is formally equivalent to the relaxation of massless relativistic Weyl fermions after a sudden displacement from the center of a harmonic trap

R&D Tax Incentives: How Do They Impact Portuguese Start-ups?

In this work, a comparison between start-up companies’ performance is made based on the way they use the Portuguese R&D tax credit program. From the analysis of the results, it is possible to verify that companies that benefit from this program have a distinct behavior from those that do not, either in what regards financial performance, the weight of the intangible assets in the company or in what regards the quality and value added of the jobs created. It is also possible to find that beneficiary companies mix the tax credits with the use of European, national and regional grants, thus mixing the funding available to support their Research, Development and Innovation activities

Evolutionary Development based on Genetic Regulatory Models for Behavior-Finding

This thesis investigates the role, implications, and applications of a genetic-regulated developmental process in evolution. A novel formalism of string-regulated graph grammar, as an abstraction of biological development, is presented and studied. Founded on this formalism, evolutionary developmental models are introduced and tested. The results demonstrate the benefits of the models, compared to traditional direct encoding approaches, for the problems of form-finding and behavior-finding

Caracterización del comportamiento y las señales vibratorias en Euthyrhynchus floridanus (Hemiptera: Pentatomidae) durante el cortejo y la cópula

artículo (arbitrado) -- Universidad de Costa Rica. Escuela de Biología, 2014Euthyrhynchus floridanus (Linnaeus) (Hemiptera: Pentatomidae) es una especie neotropical perteneciente a la familia Pentatomidae con más de 4 000 especies descritas, y se distribuye desde la Florida hasta Brasil. Este estudio describe el comportamiento sexual y reporta por primera vez la producción de vibraciones de sustrato por machos y hembras durante el comportamiento precopulatorio y la cópula. Se grabó tanto el comportamiento de cortejo y de cópula como las diversas señales producidas utilizando un cartucho fonográfico, conectado a una cámara de video. 106 Rev. Biol. Trop. (Int. J. Trop. Biol. ISSN-0034-7744) Vol. 62 (1): 95-107 March 2014 Posteriormente se reprodujo las vibraciones de las hem- bras en ausencia de estas y se registró las respuestas de los machos. Se distinguieron al menos tres vibraciones de sustrato distintas para los machos y una para las hembras, y se caracterizaron por ser señales de baja frecuencia que van desde los 127 hasta 180Hz. Las sonidos de los machos en E. floridianus fueron significativamente diferentes en la frecuencia, duración y número de pulsos tanto en el cortejo como en la cópula para los sonidos de ronroneo y tamborileo. La producción de sonidos en esta especie se asoció principalmente con comportamientos estimulatorios- mecánicos durante el cortejo y copula. Patrones de comportamiento y su relación con las vibraciones del sustrato sugiere que estas señales pueden ser importantes para los machos en el contexto de la localización de su compañera y la selección sexual.Characterization of the behavioral and vibrational signals in Euthyrhynchus floridanus (Hemiptera: Pentatomidae) during courtship and copulation. Euthyrhynchus floridanus (Linnaeus) (Hemiptera: Pentatomidae) is a neotropical species belonging to the family Pentatomidae with over 4 000 species described, and is distributed from Florida to Brazil. This study describes the sexual behavior and reported for the first time the production of substrate vibrations by males and females during copulatory behavior and mating. Courtship and copulatory behavior, as well as the diverse signals, were recorded with a phonographic cartridge connected to a video camera. Female vibrations were reproduced in the absence of females and the responses by males were recorded. At least three types of substrate vibrations were distinguished in males and one in females, and these signals were characterized by their low frequency, varying from 127 to 180Hz. The sounds of E. floridianus males were significantly different in frequency, duration and number of pulses, both in courtship and in copulation, for the purring and drumming sounds. The production of sounds in this species is associated principally with mechanical, stimulatory behavior during courtship and copulation. Patterns of behavior and their relation to substrate vibrations suggest that these signals are important for the males in the context of mate location and sexual selection.Universidad de Costa RicaUCR::Vicerrectoría de Docencia::Ciencias Básicas::Facultad de Ciencias::Escuela de Biologí

Work and Inmate Resocialization: An Ambiguous Solution

This article evaluates the efficiency of an agreement between the SEAP-Secretariat of Penitentiary Administration of Pará state, Brazil and a metallurgical company located in the metropolitan region of Belém, Pará, Brazil, which sought to provide jobs to prisoners during their sentences. We used qualitative and quantitative research methods and included data on the 240 inmates who participated in the above-mentioned initiative while serving in a semi-open prison regime, after being accepted into the program. Results show a blatant mismatch between the rhetoric that supports resocialization strategies and the reality of the situation, in which such initiatives are minor accessories in the context of the responsibilities involved in managing prison institutions

Behavior finding: Morphogenetic Designs Shaped by Function

Evolution has shaped an incredible diversity of multicellular living organisms, whose complex forms are self-made through a robust developmental process. This fundamental combination of biological evolution and development has served as an inspiration for novel engineering design methodologies, with the goal to overcome the scalability problems suffered by classical top-down approaches. Top-down methodologies are based on the manual decomposition of the design into modular, independent subunits. In contrast, recent computational morphogenetic techniques have shown that they were able to automatically generate truly complex innovative designs. Algorithms based on evolutionary computation and artificial development have been proposed to automatically design both the structures, within certain constraints, and the controllers that optimize their function. However, the driving force of biological evolution does not resemble an enumeration of design requirements, but much rather relies on the interaction of organisms within the environment. Similarly, controllers do not evolve nor develop separately, but are woven into the organism’s morphology. In this chapter, we discuss evolutionary morphogenetic algorithms inspired by these important aspects of biological evolution. The proposed methodologies could contribute to the automation of processes that design “organic” structures, whose morphologies and controllers are intended to solve a functional problem. The performance of the algorithms is tested on a class of optimization problems that we call behavior-finding. These challenges are not explicitly based on morphology or controller constraints, but only on the solving abilities and efficacy of the design. Our results show that morphogenetic algorithms are well suited to behavior-finding