The sea conceals a mermaid’s grotto of useful chemicals-marine natural products of therapeutic potential. Marine sponges in particular are a rich source of natural products with structural diversity and novel biological activity. In recent times, there has been a growing interest in the synthesis of marine natural products. The present thesis entitled, “Synthesis of bioactive marine meroterpenoids: frondosins and liphagal” is an endeavor along the same lines and is organized under two parts –Part A and Part B. Part A: Studies towards the total synthesis of (±) frondosins A and B Frondosins A-E are IL-8 inhibiting marine meroterpenoids, with novel bicyclo[5.4.0]undecane framework, exhibiting anti-inflammatory and anti HIV-1 activities. A relatively simple and inherently flexible ring-closing metathesis (RCM) based strategy was employed to achieve the total synthesis of frondosins A (formal) and B in only 17 linear steps (total 13 operations) and 5% overall yield. A concise route, based on RCM, to the core structure of bioactive frondosins is amenable to ready appendage diversification and enables implementation of functionalization manoeuvres on all positions in the seven-membered ring of the bicyclic framework was also developed. A Diels-Alder strategy that led to the synthesis of 8-des-methyl norfrondosin A dimethyl ether is also delineated in Part A of the thesis. Part B: A concise synthesis of (±) liphagal Liphagal is a marine meroterpenoid displaying an unprecedented “liphagane” skeleton. It is a selective inhibitor of PI3K  and significantly toxic against a small panel of human tumor cell lines (LoVo, CaCo-human colon and MDA-468-human breast). A concise and straightforward biomimetic strategy towards liphagal and its 14-des-formyl analogue that awarded liphagal dimethyl ether in only eight steps from commercially available building blocks is described in Part B of the thesis.

El siguiente proyecto de investigación tiene como finalidad determinar si es rentable la implementación de una planta de elaboración de crema corporal hidratante a base de camu camu y de jalea real. Hoy en día el mercado del cuidado personal ya no es sólo cuestión de cuidar la imagen sino también la salud, es por eso que en el presente es uno de los negocios más rentables. / The main objective of the following research is to determine the successful of installing a factory of a hydrating body lotion of Camu camu and Royal jelly. Nowadays, the hygiene and personal care market is one of the most rentable business because the more someone invest in this topic the better personal image in a healthy body they will have. / Trabajo de investigación

Bacterial infections remain a significant threat to human health. Due to the emergence of widespread antibiotic resistance, development of novel antibiotics is required in order to ensure that effective treatment remains available. The aim of this study was to isolate and identify the fraction responsible for the antimicrobial activity in Tabernaemontana elegans (Stapf.) root extracts. The active fraction was characterised by thin layer chromatography (TLC) and gas chromatography – mass spectrometry (GC-MS). Antibacterial activity was determined using the broth micro-dilution assay and antimycobacterial activity using the BACTEC radiometric assay. Cytotoxicity of the crude extract and fractions was assessed against primary cell cultures; lymphocytes and fibroblasts; as well as a hepatocarcinoma (HepG2) and macrophage (THP-1) cell line using the Neutral Red uptake and MTT assays. The crude root extracts were found to contain a high concentration of alkaloids (1.2% w/w). GC-MS analysis identified the indole alkaloids, voacangine and dregamine, as major components. Antibacterial activity was limited to the Gram-positive bacteria and Mycobacterium species, with MIC values in the range of 64 – 256 ìg/ml. When combined with antibiotics, additive antibacterial effects were observed. Marked cytotoxicity to all cell lines tested was evident in the MTT and Neutral Red uptake assays, with IC50 values ranging between 1.11 – 9.81 ìg/ml. This study confirms the antibacterial activity of T. elegans and supports its potential for being investigated further for the development of a novel antibacterial compound. / Dissertation (MSc)--University of Pretoria, 2011. / Pharmacology / unrestricted

This study aimed to evaluate the antiretroviral activity of natural products. Initially implemented the cell culture for cytotoxicity tests and some tests of antiviral activity. Were selected based on pre-existing data in the literature of antiviral activity in the genus or family under study and also in a chemotaxonomic approach, 39 extracts (from 12 plant families and four families of Brazilian algae) and 11 pure compounds from the group of quinones and terpenes. All were evaluated for cytotoxicity in order to find a concentration with low cytotoxicity for testing antivirals ( 50%). Cytotoxicity was evaluated by the methods of Trypan Blue exclusion and MTT reduction. The evaluation of antiviral activity was done by two methods: research on the inhibition of cytopathic effects (ECPs) characteristic of retroviruses (syncytium and lysis) using maedi visna virus which is a model in vitro and in vivo of the HIV, and inhibition of activity of reverse transcriptase (RT) of HIV-1. The activity of RT HIV-1 was measured by a colorimetric method quantitative immunoassay (Reverse Transcriptase Assay, Roche , Germany). Was first tested an extract of each plant species on the potential antiviral activity, and when it showed some activity other extracts of the same species were tested. Efavirenz was used as control and showed antiviral inhibition of CPE and TR of 75 and 98%, respectively, at a concentration of 1 μg/mL. Among the pure compounds the best results were those of emotinas D and F, which also inhibit the ECPs in 37.5 and 25% were 24.4 and 20.5% inhibition of TR, respectively, 1 μg/mL. Among the tested plants found seven with inhibitory activity of HIV-1 RT. Among these we find a plant whose activity was very high in the crude extract when compared with control efavirenz and has been even greater in isolated fractions. The crude extracts of leaves (50 μg/mL) and stem bark (100 μg/mL) showed 98 and 67% inhibition of TR, respectively. The acetate (50 μg/mL) and chloroform (100 μg/mL) fractions of the latter, showed 95 and 89% of inhibition, respectively. Our results suggest that we have strong candidates for to combat the HIV that may present as a rich source of inhibitors of RT. / Este trabalho objetivou avaliar a atividade antirretroviral de produtos naturais. Inicialmente implementamos o cultivo celular para realização de testes de citotoxicidade e alguns dos testes de atividade antiviral. Foram selecionados, baseados em dados pré-existentes na literatura de atividade antiviral no gênero ou família em estudo e ainda em uma abordagem quimiotaxonômica, 39 extratos (de 12 famílias de plantas e quatro famílias de algas brasileiras) e 11 substâncias puras do grupo das quinonas e dos terpenos. Todos foram avaliados quanto à citotoxicidade a fim de encontrarmos uma dose com baixa citotoxicidade para os testes antivirais (50%). A citotoxicidade foi avaliada pelos métodos de exclusão do Azul de Tripan e redução do MTT. A avaliação da atividade antiviral foi feita por duas metodologias: pesquisa da inibição de efeitos citopáticos (ECPs) característicos de retrovírus (sincício e lise) utilizando-se o vírus maedi visna que é um modelo in vitro e in vivo do HIV e inibição da transcriptase reversa (TR) do HIV-1. A atividade da TR do HIV-1 foi medida por um método colorimétrico quantitativo imunoenzimático (Reverse Transcriptase Assay, Roche , Germany). Foi inicialmente testado um extrato de cada espécie de planta quanto à potencial atividade antiviral e quando o mesmo mostrava alguma atividade os outros extratos da mesma espécie eram testados. O efavirenz foi utilizado como controle antiviral e apresentou 75 e 98% de inibição do ECP e da TR, respectivamente, em uma concentração de 1 μg/mL. Dentre as substâncias puras os melhores resultados encontrados foram os das emotinas D e F que além de inibirem os ECPs em 37,5 e 25%, apresentaram 24,4 e 20,5% de inibição da TR, respectivamente, a 1 μg/mL. Entre as plantas testadas encontramos sete com atividade inibidora da TR do HIV-1. Entre estas encontramos uma planta cuja atividade foi muito elevada no extrato bruto quando comparada ao controle efavirenz e tem se mostrado ainda maior nas frações isoladas. Os extratos brutos das folhas (50 μg/mL) e da casca do caule (100 μg/mL) apresentaram 98 e 67% de inibição da TR, respectivamente. E as frações acetato (50 μg/mL) e clorofórmio (100 μg/mL) deste último, 95 e 89% de inibição, respectivamente. Nossos resultados sugerem que temos fortes candidatos para o combate ao HIV que podem se apresentar como uma rica fonte de substâncias inibidoras da TR.

Orientador: Ronaldo Aloise Pilli / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Química / Made available in DSpace on 2018-08-26T20:06:35Z (GMT). No. of bitstreams: 1 Sant'Ana_CarolinaMartinsAvilade_D.pdf: 25003165 bytes, checksum: deb5835cc499985cdc35e9f74c89025a (MD5) Previous issue date: 2014 / Resumo: No capítulo 1 estudou-se uma rota sintética inédita para a obtenção da fostriecina e seus análogos, a qual possui como etapa chave a adição aldólica 1,4-anti, mediada por enolato de boro, para instalar o centro estereogênico em C11. Neste contexto, foi avaliada a influência do substituinte em ? nas reações aldólicas envolvendo enolatos de boro de metilcetonas quirais, que contêm em sua estrutura um centro estereogênico quaternário em C-8. Explorou-se seu escopo reacional, utilizando aldeídos que diferem entre si no que se refere aos aspectos estéreo e eletrônico. Obteve-se adutos com excelente diastereoseletividade (rd 1,4-anti versus 1,4-syn > 90:10). Esta metodologia foi aplicada na síntese do fragmento C5-C13 da fostriecina sendo obtido em 10 etapas e 8,4% de rendimento global a partir do (2E)-2-metil-2-buten-1-ol, disponível comercialmente. Este fragmento foi utilizado por G. A. O¿Doherty e colaboradores na síntese total mais recente da fostriecina, sendo preparado em 15 etapas a partir do (2E)-pent-2-en-4-in-1-ol (Org. Lett., 12, 3752, 2010). No capítulo 2, foi desenvolvida uma rota sintética flexível utilizando-se uma abordagem modular que permitiu a preparação de quatro estereoisômeros do produto natural coibacina A a fim de determinar a configuração absoluta do produto natural. Esta rota sintética possui como etapas chave olefinações de Wittig e Julia e ciclopropanação assimétrica de Charette. Após comparação por HPLC, utilizando coluna quiral, dos tempos de retenção destes quatro estereoisômeros com uma amostra da coibacina A de origem natural, foi possível estabelecer inequivocamente a configuração absoluta deste policetídeo como sendo 5R,16S,18S. A estereoquímica do centro estereogênico em C-5 da lactona ?-? insaturada, previamente assinalada como S, foi corrigida para R e a estereoquímica dos centros em C-16 e C-18 foi estabelecida como sendo S e S, respectivamente. Dessa forma concluímos a primeira síntese total do policetídeo insaturado coibacina A em 13 etapas (etapa linear mais longa) e 3,4% de rendimento global a partir do (S)-glicidol, obtido comercialmente. Adicionalmente, sintetizamos o isômero 5R,14S,16S da coibacina B em 13 etapas (etapa linear mais longa) e 5,7% de rendimento global / Abstract: In chapter 1, a new synthetic route for fostriecin and analogues was studied with the 1,4-anti boron-mediated aldol reaction as the key step in the formation of the stereogenic center at C11. In this context, the influence of the ?-alkoxy substituent in the aldol reaction involving the boron enolate of the chiral methyl ketones with a quaternary stereogenic center at C-8 was evaluated. The reaction scope was explored by using aldehydes with different steric and electronic patterns. Products were obtained in excellent diastereoselectivity (rd 1,4-anti versus 1,4-syn > 90:10). This methodology was applied to the synthesis of C5-C13 fragment of fostriecin in 10 steps and 8.4% overall yield from commercially available (2E)-2-methyl-2-buten-1-ol. This intermediate was used by G. A. O¿Doherty and co-workers in the most recent total synthesis of fostriecin and it was prepared in 15 steps from (2E)-pent-2-en-4-yn-1-ol (Org. Lett., 12, 3752, 2010). In chapter 2, a flexible synthetic route for four stereoisomers of the natural product coibacin A was developed based on a modular approach in order to establish the absolute configuration of this natural product. This synthetic strategy possesses as key steps the Wittig and Julia olefination reactions and Charette asymmetric cyclopropanation reaction. After comparison by chiral HPLC chromatography of the retention time of the four synthetic stereoisomers with a sample of coibacin A obtained from natural sources, the absolute configuration of the natural product was unequivocally established as 5R,16S,18S. The stereochemistry of the stereogenic center at C-5 of the ?,?-unsaturated ?-lactone, that had been previously assigned as S, was corrected to R and the absolute configurations at C-16 and C-18 were assigned as S and S, respectively. Therefore, we accomplished the first total synthesis of the unsaturated polyketide coibacin A in 13 steps (longest linear sequence) and 3.4% overall yield from commercially available (S)-glycidol. Additionally, we synthesized the 5R,14S,16S isomer of coibacin B in 13 steps (longest linear sequence) and 5.7% overall yield / Doutorado / Quimica Organica / Doutor em Ciências

Orientador: Luiz Carlos Dias / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Química / Made available in DSpace on 2018-08-27T15:23:27Z (GMT). No. of bitstreams: 1 Polo_EllenChristine_D.pdf: 34484354 bytes, checksum: 4caa49b48c6b6c122794cf9e1e497292 (MD5) Previous issue date: 2015 / Resumo: A nhatrangina A foi isolada em 2010, por Orjala e colaboradores, a partir de uma coleção vietnamita da cianobactéria marinha Lyngbya majuscula. Este policetídeo apresenta seis centros estereogênicos e sua determinação estrutural foi realizada através da análise conjunta dos espectros de RMN 1D e 2D. O objetivo principal deste trabalho foi investigar uma rota sintética convergente e flexível para a obtenção deste produto natural e checar o assinalamento estrutural proposto pelos autores do isolamento. A estrutura proposta para a nhatrangina A foi sintetizada em 19 etapas, considerando a rota linear mais longa, e rendimento global de 6,7%. As etapas chave envolveram reação aldólica, reação de Corey-Fuchs, acoplamento entre alcino e amida de Weinreb mediado por lítio, redução estereosseltiva de Noyori e reação de esterificação de Yamaguchi. Além disso, sintetizamos seis diastereoisômeros da estrutura proposta para o produto natural, utilizando a mesma estratégia sintética empregada na síntese da estrutura proposta para a nhatrangina A, no entanto nenhum destes isômeros corresponderam ao produto natural / Abstract: The nhatrangin A was isolated in 2010 by Orjala and co-workers, from a Vietnamese collection of marine cyanobacterium Lyngbya majuscula. This polyketide containing six stereogenic centers and its structure was assigned based on spectrometric and spectroscopic methods including 1D and 2D NMR experiments. The aim of this work was to investigate the convergent and flexible synthetic route for obtaining this natural product and check the structural assignment proposed by the authors of isolation. The proposed structure of nhatrangin A was synthesized in 19 steps, considering the longest linear route, and overall yield of 6.7%. The key steps involved aldol reaction, Corey-Fuchs reaction, lithium-mediated coupling between alkyne and Weinreb amide, Noyori stereoselective reduction and Yamaguchi esterification. In addition, we synthesized six diastereoisomers of the proposed structure for the natural product, using the same synthetic strategy employed in the synthesis of the proposed structure of nhatrangin A, however none of these isomers correspond to the natural product / Doutorado / Quimica Organica / Doutora em Química

El presente trabajo de investigación expone una propuesta de negocio innovadora y económicamente viable. Dentro del mercado de Lima Metropolitana se ha detectado la necesidad por el consumo de avena 100% pura, si bien en la actualidad existen productos alternativos, en el canal moderno no existe un producto de avena 100% grano entero disponible. Por parte de la población existe desconocimiento acerca de la composición del producto y los aportes nutricionales que benefician su pureza. Por ello, el objetivo de la empresa es crear conciencia en el consumidor. El 80% del mercado peruano en promedio consume avena y esto varía dependiendo el NSE al que pertenezca, en el caso NSE AB muestra 70% de consumo de avena para lo cual se busca captar mercado con un producto de mayor calidad y pureza, ya que este segmento estaría dispuesto a pagar hasta 123% más por un producto de mayor valor nutricional en comparación del resto. Bajo esa perspectiva, la empresa distribuirá y comercializará avena 100% pura desarrollando una nueva línea de productos. Para el posicionamiento y expansión de marca se plantean estrategias de gestión comercial. El modelo de negocio asegura la viabilidad de este, debido al incremento en la tendencia del consumo. Se han realizado diversos análisis cualitativos y cuantitativos, y se ha llegado a la conclusión que la demanda del segmento es inelástica, lo que es una oportunidad para la empresa y el desarrollo de la marca. / This research paper presents an innovative and economically viable business proposal. Within the Metropolitan Lima market, the need for the consumption of 100% pure oats has been detected, although there are currently alternative products, there is no 100% whole grain oat product available in the modern channel. On the part of the population there is ignorance about the composition of the product and the nutritional contributions that benefit its purity. Therefore, the objective of the company is to create awareness in the consumer. 80% of the Peruvian market on average consumes oats and this varies depending on the NSE to which it belongs, in the case NSE AB shows 70% consumption of oats for which it seeks to capture market with a product of higher quality and purity, since This segment would be willing to pay up to 123% more for a product of higher nutritional value compared to the rest. Under that perspective, the company will distribute and market 100% pure oats by developing a new product line. For the positioning and expansion of the brand, commercial management strategies are proposed. The business model ensures its viability, due to the increase in the consumption trend. Various qualitative and quantitative analyzes have been carried out, and it has been concluded that the segment's demand is inelastic, which is an opportunity for the company and the development of the brand. / Trabajo de investigación

El presente proyecto se realiza con la finalidad de lanzar al mercado una empresa que se encarga de la elaboración de una crema para bebes y niños a bases de productos naturales, tal y como lo es IGTBE Perú o MamaKhuyay el nombre de nuestro principal producto. Esto surge a través de un trabajo de investigación, en el cual se ha identificado como problemática principal que los padres de familia carecían de productos naturales para el cuidado de la piel de sus pequeños. MamaKhuyay tiene como objetivo apoyar a los padres de familia a prevenir que sus hijos sufran de escaldaduras o enfermedades posteriores, causado por la irritación química producida en la piel a causa de la orina y las heces de los pequeños. Nuestro producto actúa como un antiinflamatorio gracias a su componente principal el cual es el extracto de manzanilla. Esta planta brinda diferentes beneficios para la piel debido a las propiedades antiinflamatorias que posee, por lo contribuye con la restauración del equilibrio de la piel inflamada de los niños. Así mismo, nuestra crema también sirve como un hidratante para la piel de los pequeños, además de mantenerla relajada por la esencia de manzanilla que también trae como componente. El presente informe se encargará de presentar todos los experimentos realizados con la finalidad de validar que nuestra propuesta es un negocio escalable e innovador. Así como, mostrar la aceptación del público objetivo a través de las interacciones en redes sociales y realización de ventas en frío. / This project is carried out with the purpose of launching a company that is in charge of developing a cream for babies and children based on natural products, such as IGTBE Peru or MamaKhuyay, the name of our main product. This arises through a research project, in which it has been identified as the main problem that parents lacked natural products for the care of their children's skin. MamaKhuyay aims to support parents to prevent their children from suffering from scalds or subsequent illnesses, caused by chemical irritation caused by the urine and feces of the little ones. Our product acts as an anti-inflammatory thanks to its main component, which is chamomile extract. This plant offers different benefits for the skin due to the anti-inflammatory properties it possesses, thus contributing to the restoration of the balance of the inflamed skin of children. Likewise, our cream also serves as a moisturizer for the skin of the little ones, in addition to keeping it relaxed by the essence of chamomile that it also brings as a component. This report will be in charge of presenting all the experiments carried out in order to validate that our proposal is a scalable and innovative business. As well as, show the acceptance of the target audience through interactions in social networks and realization of cold sales. / Trabajo de investigación

Hoy en día, no solo las mujeres se preocupan por el cuidado de la piel sino también los hombres. Sumado a esta nueva tendencia, se puede observar el ascenso de la preferencia en productos de origen natural que contribuyen al aporte de beneficios a la piel y a la reducción del daño ocasionado por los químicos. En este sentido, se ha encontrado un mercado potencial, los hombres específicamente del estilo de vida sofisticado, una parte de la población, definida por Arellano Marketing, como preocupados por el status, la moda y la imagen. Partiendo de la imagen, es sabido que en la actualidad el mercado de productos estéticos para hombres se encuentra en crecimiento desde hace algunos años habiendo generado hasta S/1,000 millones en el año 2018. Es por ello que “Spartan Man Care” busca abordar el negocio de los productos naturales especializados en hombres que se preocupan por su aspecto físico. Además, es importante resaltar que hoy en día a pesar del mercado potencial existente en los hombres, no existe una variedad de productos dirigidos a ellos, por lo que hay una oportunidad de negocio latente para trabajar. Actualmente, el total de hombres considerados sofisticados en Lima dentro del rango de 25 a 39 años es de 121, 392. De este total el 14% compra productos de higiene con regularidad, representado por 16,995 habitantes y S/3, 976,830 en soles. Finalmente, se determinó que la ganancia del proyecto, calculada a través del VAN, será de S/126, 316 de retorno sobre la inversión. / Today, not only women care about skin care but also men. In addition to this new trend, you can see the rise in preference in products of natural origin that contribute to providing benefits to the skin and reducing the damage caused by chemicals. In this sense, a potential market has been found, men specifically for the sophisticated lifestyle, a part of the population, defined by Arellano Marketing, as concerned about status, fashion and image. Based on the image, it is known that currently the market for men's cosmetic products has been growing for some years, having generated up to S / 1,000 million in 2018. That is why "Spartan Man Care" seeks to address the business of natural products specialized in men who care about their physical appearance. Furthermore, it is important to note that today despite the potential market for men, there is no variety of products for them, so there is a latent business opportunity to work. Currently, the total of men considered sophisticated in Lima within the range of 25 to 39 years is 121, 392. Of this total, 14% purchase hygiene products regularly, represented by 16,995 inhabitants and S / 3,976,830 in soles. Finally, it was determined that the project's profit, calculated through the NPV, will be S / 126, 316 of return on investment. / Trabajo de investigación

<div> Carbon monoxide is a useful carbon linchpin to construct complex molecules of natural products by stitching different pieces of target molecules together. Recently, our group reported a novel and efficient palladium-catalyzed spirolactonization by Dr. Dexter Davis to construct oxaspirolacones from esters or lactones. As an essential motif, oxaspirolactone structures in natural products exhibit diverse and exciting structures and biological activities. The first part of this thesis mainly describes the total synthesis of stemoamide alkaloids in the stemona family and the application of our palladium-catalyzed spirolactonization, which was developed by our group to complete total synthesis of bisdehydroneostemoninine and bisdehydrostemoninine with Prof. Kaiqing Ma. The total synthesis features a one-pot ring-closing cross-metathesis, Lewis acid-mediated Friedel-Crafts reaction and lactonization, and accomplished bisdehydrostemonine in 15 steps. The total synthesis of stemoamide, tuberostemoamide, and sessilifoliamide A were finished, and the critical step features an mCPBA oxidation to convert pyrrole to lactam in one step without destructing other functional groups. </div><div> In the second part of this thesis, we developed a novel and efficient palladium-catalyzed cascade amino-carbonylative lactonization to streamline the synthesis of dihydropyrrole-fused furanones in collaboration with Prof. Seleem’s lab for biological activities. Using this method, we quickly expanded this method to construct different ring structures, such as β-lactone and dihydropyrrole-fused pyrrolone. This method was applied to the total synthesis study towards stemofoline alkaloids. Our palladium-catalyzed spirolactonizaiton was also used in this total synthesis study for target molecules. </div><div><br></div>