Synthesis and exploration of multiple synthetic vectors in \"future heteroaromatic\" fragments

Um dos desafios remanescentes para a química de fragmentos é a funcionalização regiosseletiva de moléculas polares, como os fragmentos hidroxi-naftiridina e pirazolo-hidroxipiridina. Assim, neste projeto foram estudados métodos sintéticos para obtenção e funcionalização de fragmentos baseados na estrutura de anéis conhecidos como \"heterociclos do futuro\", para desenvolvimento de uma pequena biblioteca de compostos e estudos de química medicinal. Foram desenvolvidos métodos de síntese, em escala multigramas de hidroxi-naftiridina e pirazolo-hidroxipiridina, assim como obtidos derivados por estudos de modificação e substituição dos materiais de partida nas estratégias de heterociclização. Um estudo de reatividade foi realizado com intuito de identificar vetores sinteticamente acessíveis para construção de uma série de compostos. Foram estudados dois métodos de arilação radicalar, livres de metais de transição, da porção hidroxipiridina dos fragmentos. O primeiro método envolveu aril-hidrazinas, como fonte de radical arila, que levou à formação de derivados arilados em rendimentos moderados, sem a necessidade de proteção de grupos polares. O segundo método, envolveu um reator de fluxo solar e arilazo sulfonas como fonte de radicais arila, do qual foi possível obter uma série de derivados arilados. A funcionalização da porção pirazolo do heterociclo pirazolo-hidroxipiridina envolveu a migração N-C de grupo sulfonila, mediada por base, que resultou na obtenção de uma série de derivados biarilsulfonas. Os compostos obtidos foram estudados para desenvolvimento de compostos antivirais e antipsicóticos. As biarilsulfonas foram submetidas a ensaios frente o vírus da leucemia de células T humanas tipo 1 (HTLV-1), e mostraram atividade semelhante aos padrões. Em outra abordagem, foi desenvolvido um análogo de aripiprazol, por meio de \"scaffold hopping\", que apresentou resultados promissores in vivo para atividade antipsicótica. Por fim, combinando métodos simples e inovadores, este projeto fornece ferramentas aos praticantes de química medicinal de fragmentos, assim como comprova a utilidade dos fragmentos estudados para aplicação em processo de descoberta de fármacos.One of the remaining challenges for synthetic chemistry is the regioselective functionalization of structurally complex polar molecules, such as hydroxy-naphthyridine and pyrazole-hydroxypyridine fragments. Thus, in this project synthetic methods were studied to obtain and functionalize fragments based on the structure of \"heterocycles of the future\", for development of a small library of compounds and medicinal chemistry studies. Methods of synthesis on multigrams scale of hydroxy-naphthyridine and pyrazole-hydroxypyridine have been developed, as well as derivatives obtained by modification and substitution of starting materials. A reactivity study was carried out in order to identify synthetically accessible vectors for obtaining of a compounds collection. There were applied two transition metal free methods for arylation of the hydroxypyridine moiety of the fragments. The first method involved aryl hydrazines as the source of the aryl radical which led to the formation of aryl derivatives in moderate yields without the need for polar groups protection. The second method involved a solar flux reactor and arylazo sulfones as source of aryl radicals, from which it was possible to obtain a series of aryl derivatives. Functionalization of the pyrazole moiety of the pyrazole-hydroxypyridine heterocycle involved the base-mediated sulfonyl N-C migration which resulted in the production of a series of biarylsulfone derivatives. The obtained compounds were studied for the development of antiviral and antipsychotic activities. Biarylsulfones were tested against the human T-cell leukemia virus type 1 (HTLV-1), and showed similar activity to standards. In another approach, an analog of aripiprazole was developed by scaffold hopping, which presented promising results in vivo for antipsychotic activity. Finally, combining simple and innovative methods, this project provides tools to practitioners of medicinal chemistry of fragments, as well as proves the usefulness of the studied fragments for application in the process of drug discover

Heterocyclization strategies applied to synthetic and natural products underexplored by medicinal chemistry

O presente trabalho divide-se em três capítulos: Capítulo I - Nova síntese de ?-xiloidona: rearranjo de Claisen em hidroxinaftoquinonas; Capítulo II - Síntese e estudo de reatividade de promissores núcleos heteroaromáticos subexplorados pela química medicinal; Capítulo III - Análise computacional de similaridade e propriedades físico-químicas dos núcleos heterocíclicos do capítulo II. O capítulo I descreve uma nova rota para a síntese de ?-xiloidona, um produto natural relacionado ao lapachol, subexplorado pela química medicinal. Esta rota é baseada no rearranjo propargílico de Claisen, a partir da reação de lausona com 3-cloro-3- metilbutino sob catálise de CuCl2/I2.Este capítulo também descreveu a síntese de um derivado furano naftoquinoidal, o qual pode ser utilizado como precursor de ?- duniona, via rearranjo de Claisen aril-alílico. Além da realização desta metodologia substituindo o 3-cloro-3-metilbutino por cinco diferentes alcinos. Este novo processo ofereceu como vantagens principais o menor custo dos catalisadores empregados, os rendimentos melhorados e o reduzido número de etapas reacionais em relação as rotas descritas na literatura para obtenção de?-xiloidona. O Capítulo II apresenta o desenvolvimento de métodos sintéticos novos e eficazes para 3 núcleos heterocíclicos (naftiridinona, pirazolopiridinona e dihidropirrolopirazinona) pouco explorados pela química medicinal porém com potencial para descoberta de fármacos. Buscando abranger metodologias orientadas pela diversidade, neste capítulo foi realizado um estudo preliminar de reatividade destes núcleos frente diferentes abordagens, tanto frente métodos diretos de arilação quanto metodologias clássicas de modificação de anéis aromáticos. Além disso, no capítulo III foram realizados estudos de similaridade para a obtenção de padrões estruturais que possam ser aplicados em programas de descoberta de fármacos assim como o estudo de propriedades físico-químicas dos núcleos do capítulo II. Todo este trabalho permitiu desenvolver 10 moléculas inéditas na literatura, bem como novas metodologias para a síntese de compostos previamente descritos.The present work is divided in two chapters: Chapter I - New synthesis of ? - xiloidone: Claisen rearrangement of hydroxynaphthoquinones; Chapter II - Synthesis and reactivity study of promising heteroaromatic coresunderstudied by medicinal chemistry; Chapter III - Similarity and physic-chemical properties analysis of the heterocyclic cores from chapter II. Chapter I describes a newsynthetic route to?- xiloidona, which isa natural product related to lapachol and understudied by medicinal chemistry. This route is based on propargyl Claisen rearrangement from the reaction of lawsone and 3-chloro-3- methylbutynemediated by CuCl2/I2. This chapter also describes the synthesis of a furan derivative which can be used as?- dunnione precursor. Also this methodology had been applied replacing the 3-chloro- 3-methyllbutynefor five different alkynes. This new process is associated with lower cost, improved yields and reduced number of reaction steps when compared to the literature. The chapter II aimed at the development of synthetic methods to obtain 3 heterocyclic cores(naphthyridinone, pyrazolopyridinoneand dihydropyrrolopyrazinone)with drug discovery potential but also understudied by medicinal chemistry. Diversity-oriented methodologies had been performedresulting in a reactivity study of these cores across severalsynthetic approaches. Furthermore, the chapter III described the similarity studies that were conducted aiming to obtain structural patterns that can be applied in drug discovery programs. This work describes the development of 10 non-published molecules as well as new methodologies for the synthesis of these previously described compounds

Rectangular mesh contour generation algorithm for finite differences calculus

In this work, a 2D contour generation algorithm is proposed for irregular regions. The contour of the physical domain is approximated by mesh segments using the known coordinates of the contour. For this purpose, the algorithm uses a repeating structure that analyzes the known irregular contour coordinates to approximate the physical domain contour by mesh segments. To this end, the algorithm calculates the slope of the line defined by the known point of the irregular contours and the neighboring vertices. In this way, the algorithm calculates the points of the line and its distance to the closest known nodes of the mesh, allowing to obtain the points of the approximate contour. This process is repeated until the approximate contour is obtained. Therefore, this approximate contour generation algorithm, from known nodes of a mesh, is suitable for describing meshes involving geometries with irregular contours and for calculating finite differences in numerical simulations. The contour is evaluated through three geometries, the difference between the areas delimited by the given contour and the approximate contour, the number of nodes and the number of internal points. It can be seen that the increase in geometry complexity implies the need for a greater number of nodes in the contour, generating more refined meshes that allow reaching differences in areas below 2%.Comment: In Portuguese languag

Treatment With a Growth Factor–Protein Mixture Inhibits Formation of Mineralized Nodules in Osteogenic Cell Cultures Grown on Titanium

Despite wide clinical application, the efficacy of platelet-rich plasma (PRP) for repairing bone defects and enhancing osseointegration of metal implants is still subject of debate. This study aimed to evaluate the effects of a well-defined PRP-like mixture containing platelet-derived growth factor-BB, transforming growth factor (TGF)-β1, TGF-β2, albumin, fibronectin, and thrombospondin [growth factors (GFs) + proteins] on the development of the osteogenic phenotype on titanium (Ti) in vitro. Human alveolar bone-derived osteoblastic cells were subcultured on Ti discs and exposed during the first 7 days to osteogenic medium supplemented with GFs + proteins and to osteogenic medium alone thereafter up to 14 days. Control cultures were exposed to only osteogenic medium. Dose–response experiments were carried out using rat primary calvarial cells exposed to GFs + proteins and 1:10 or 1:100 dilutions of the mixture. Treated human-derived cell cultures exhibited a significantly higher number of cycling cells at days 1 and 4 and of total cells at days 4 and 7, significantly reduced alkaline phosphatase (ALP) activity at days 4, 7, and 10, and no Alizarin red–stained areas (calcium deposits) at day 14, indicating an impairment in osteoblast differentiation. Although the 1:10 and 1:100 dilutions of the mixture restored the proliferative activity of rat-derived osteogenic cells to control levels and promoted a significant increase in ALP activity at day 10 compared with GFs + proteins, mineralized nodule formation was only observed with the 1:100 dilution (∼50% of the control). These results showed that a PRP-like protein mixture inhibits development of the osteogenic phenotype in both human and rat osteoblastic cell cultures grown on Ti. (J Histochem Cytochem 57:265–276, 2009