Natural products offer many possibilities for the treatment of disease. More than 70% of the Earth’s surface is ocean, and recent exploration and access has allowed for new additions to this catalog of natural treasures. The Central Red Sea off the coast of Saudi Arabia serves as a newly accessible location, which provides the opportunity to bioprospect marine sponges with the purpose of identifying novel antiviral scaffolds. Antivirals are underrepresented in present day clinical trials, as well as in the academic screens of marine natural product libraries. Here a high-throughput pipeline was initiated by prefacing the antiviral screen with an Image-based High-Content Screening (HCS) technique in order to identify candidates with antiviral potential. Prospective candidates were tested in a biochemical or cell-based assay for the ability to inhibit the NS3 protease of the West Nile Virus (WNV NS protease) as well as replication and reverse transcription of the Human Immunodeficiency Virus 1 (HIV-1). The analytical chemistry techniques of High-Performance Liquid Chromatograpy (HPLC), Liquid Chromatography-Mass Spectrometry (LC-MS), and Nuclear Magnetic Resonance (NMR) where used in order to identify the compounds responsible for the characteristic antiviral activity of the selected sponge fractions. We have identified a 3-alkyl pyridinium from Amphimedon chloros as the causative agent of the observed WNV NS3 protease inhibition in vitro. Additionally, we identified debromohymenialdisine, hymenialdisine, and oroidin from Stylissa carteri as prospective scaffolds capable of HIV-1 inhibition.

Pashoo es una empresa que se creó gracias a la idea de cinco estudiantes que se encuentran cursando el décimo ciclo en la Universidad Peruana de Ciencias Aplicadas (UPC), la cual está orientada a la industria de cuidado de belleza y salud mediante la fabricación y comercialización de shampoo en barra 100% naturales a base de ingredientes seleccionados de acuerdo con sus valores nutricionales que estos le brindan al cabello. Contamos con shampoos de distintos olores y para todo tipo de cabellos como por ejemplo shampoo a base de aceite de jojoba, coco, almendras, argán y palta combinados con esencias naturales que le brindan al cliente una sensación de relajación. Por otro lado, hemos segmentado a nuestros clientes de manera que nuestro producto pueda solucionar sus problemas. Para este proyecto, nos estamos fijando en las mujeres que tienen problemas de caída de cabello e irritación en el cuero cabelludo y que estén buscando productos orgánicos y naturales que tengan conciencia sobre el cuidado del medio ambiente. Vamos a distribuir nuestros productos mediante ferias y por delivery utilizando como canales de comunicación las redes sociales y nuestra página web en donde los clientes podrán encontrar información necesaria sobre nosotros y nuestros productos. De la misma forma, mostrar las validaciones del modelo de negocio, el desarrollo del negocio, el plan financiero y de marketing, así como las operaciones que se realizaron a lo largo de este proyecto dejando por último nuestras conclusiones y recomendaciones por la realización del proyecto de negocio. / Pashoo is a company that was created thanks to the idea of five students who are studying the tenth cycle at the Universidad Peruana de Ciencias Aplicadas (UPC), which is oriented to the beauty and health care industry through manufacturing and marketing 100% natural bar shampoo based on selected ingredients according to their nutritional values that they provide to the hair. We have shampoos of different scents and for all types of hair such as jojoba oil, coconut, almond, argan and avocado shampoo combined with natural essences that give the client a feeling of relaxation. On the other hand, we have segmented our customers so that our product can solve their problems. For this project, we are looking at women who have problems with hair loss and irritation on the scalp and who are looking for organic and natural products that are aware of the care of the environment. We will distribute our products through fairs and by delivery using social media and our webpage as communication channels where customers can find necessary information about us and our products. In the same way, show the validations of the business model, the development of the business, the financial and marketing plan, as well as the operations that were carried out throughout this project, finally leaving our conclusions and recommendations for the completion of the project of business. / Trabajo de investigación

This work consists of four consecutive parts, each dealing with syntheses of structurally diverse compounds. The syntheses were based on the methods within the domain of transition-metal catalyzed and/or mediated reactions with particular emaphasis on the application of organozirconium chemistry. 1. A method for synthesis of tricyclic condensed hydrocarbons possessing 5(6)-7-6(aryl) framework was developed. It is based on reaction of bicyclic zirconacyclopentenes, prepared by oxidative dimerization of enynes on a low-valent zirconocene species (Negishi's reagent), with ortho-halobenzaldehydes in the presence of various additives. The presence of two different centers of reactivity - the sp2 C-Zr and sp3 C-Zr bond - allowed sequential functionalization of each bond. Thanks to its higher nucleophilicity, the sp3 C-Zr bond reacted preferentially with the carbonyl carbon of the aldehyde yielding an oxazirconacycloheptene. The subsequent transmetallation of the remaining sp2 C-Zr bond with CuCl in the presence of other additives (catalysts) enabled an intramolecular cross-coupling reaction with the aryl halide moiety furnishing the desired tricyclic products in reasonable yields. The scope of the reaction with respect to differently functionalized reactants was assessed, as well as its mechanistic...

Marine ascidian metabolite perophoramidine has since its isolation in 2002 attracted the interest of several research groups. The complex polycyclic structure with vicinal quaternary carbon stereocenters and two amidine functionalities constitutes a formidable synthetic challenge. In this project a new synthetic approach to dehalogenated perophoramidine has been investigated. The vicinal quaternary carbon stereocenters were introduced via a samarium mediated reductive dialkylation, in which the stereochemistry was determined by the metal chelate that formed, as outlined below. Several of the steps suggested in the synthetic approach have been successfully evaluated. Future work is needed to assess the remaining steps of the suggested route to dehalogenated perophoramidine.

>Magister Scientiae - MSc / The growing resistance of Methicillin-Resistant Staphylococcus aureus (MRSA) to currently prescribed drugs has resulted in the failure of prevention and treatment of different infections caused by the superbug. Therefore, to keep pace with the resistance, there is a pressing need for novel antimicrobial agents, especially from non-conventional sources. Several natural products (NPs) have displayed varying in vitro activities against the pathogen but few of these natural compounds have been studied for their prospects to be potential antimicrobial drug candidates. This may be due to the high cost, tedious, and time-consuming process of conducting the important preclinical tests on these compounds. Hence, there is a need for cost-effective strategies for mining the available data on these natural compounds. This would help to get the knowledge that may guide rational prioritization of “likely to succeed” natural compounds to be developed into potential antimicrobial drug candidates. Cheminformatic approaches in drug discovery enable chemical data mining, in conjunction with unsupervised and supervised learning from available bioactivity data that may unlock the full potential of NPs in antimicrobial drug discovery. Therefore, taking advantage of the available NPs with their known in vitro activity against MRSA, this study conducted cheminformatic and data mining analysis towards hit profiling, hit-prioritization, hit-optimization, and target prediction of anti-MRSA NPs. Cheminformatic profiling was conducted on the 111 anti-MRSA NPs (AMNPs) retrieved from literature. About 20 current drugs for MRSA (CDs) were used as a reference to identify AMNPs with promising prospects to become drug candidates.

<p>The hamigeran diterpenoid is a family of natural products with diverse structures and biological activities. Most of the syntheses focus on hamigerans with [6–6–5] tricyclic core, but synthetic efforts toward the more challenging [6–7–5] tricyclic hamigerans are very limited. Herein, our studies in synthesizing the [6–7–5] tricyclic hamigerans are disclosed.  Through a benzyne-β-ketoester annulative ring expansion and a Nazarov reaction, an approach toward the [6–7–5] tricyclic carbon skeleton of the hamigeran natural products was developed. A Ni-catalyzed conjugate methyl addition or a Corey–Chaykovsky reaction installed the all-carbon quaternary center, and a Suzuki cross coupling followed by reduction introduced the isopropyl group. However, the reduction of challenging tetra-substituted double bond or the regio-selective cyclopropane opening was not successful despite multiple conditions were tried. A revised synthetic strategy was proposed and resulted in a convergent total synthesis of (±)-hamigeran M, enabled by five C–H functionalization reactions and proceeding in 11 steps in 3.9% overall yield. The C–H functionalizations include a hydroxy-directed C–H borylation, one C–H metalation-1,2-addition, one C–H metalation-Negishi coupling, a late-stage oxazole-directed C–H borylation-oxidation, and one electrophilic bromination. Further elaboration of the intermediates obtained here has delivered an advanced polysubstrituted precursor towards multiple other hamigerans.</p>

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Hematologic malignancies account for a substantial percentage of cancers worldwide, and the heterogeneity and biological characteristics of leukemias and lymphomas present unique therapeutic challenges. Although treatment options exist for most of these diseases, many types remain incurable and the emergence of drug resistance is pervasive. Thus, novel treatment approaches are essential to improve outcome. Nearly half of the agents used in cancer therapy today are either natural products or derivatives of natural products. The e l,normous chemical diversity in nature, coupled with millennia of biological selection, has generated a vast and underexplored reservoir of unique chemical structures with biologic activity. This review will describe the investigation and application of natural products derived from higher plants in the treatment of leukemia and lymphoma and the rationale behind these efforts. In addition to the approved vinca alkaloids and the epipodophyllotoxin derivatives, a number of other plant compounds have shown promise in clinical trials and in preclinical investigations. In particular, we will focus on the discovery and biological evaluation of the plant- derived agent silvestrol, which shows potential for additional development as a new therapeutic agent for B-cell malignancies including chronic lymphocytic leukemia.

Cette thèse décrit une nouvelle approche pour la synthèse des kingianines, une famille d'inhibiteurs de la protéine anti-apoptotique Bcl-xL, isolés à partir de l'écorce d'Endiandra kingiana. Nous avons proposé des solutions pour éviter les problèmes de réactivité et de sélectivité rencontrés lors des études précédentes. Une stratégie reposant sur une réaction de cycloaddition [2+2] a été appliquée pour former le système bicyclique intermédiaire, au lieu d’une cascade biomimétique de réactions d’électrocyclisation. Ce choix a été efficace et un seul diastéréoisomère a été obtenu. L’utilisation d’un diénophile appauvri en électrons et d’un diène riche en électrons dans l’étape clé a permis la réalisation d’une réaction de Diels-Alder dans des conditions classiques, avec une bonne régiosélectivité. Nous avons réussi à synthétiser plusieurs analogues simplifiés des kingianines. Leur activité biologique sur les protéines Bcl-2, Bcl-xL et Mcl-1 sera évaluée dans un futur proche. / This dissertation describes a new approach for the synthesis of kingianins, a family of inhibitors of the anti-apoptotic protein BclxL, which were isolated from the bark of Endiandra kingiana. We have proposed solutions to address the problems of reactivity and selectivity that had been met in previous studies. A strategy involving a [2+2] cycloaddition reaction was applied for the formation of the intermediate bicyclic system, instead of a biomimetic electrocyclisation cascade. This choice was efficient and a single diastereoisomer was obtained. The use of an electron-poor dienophile and an electron-rich diene in the key step allowed for a Diels-Alder reaction to proceed under classic conditions, with good regioselectivity. We have succeeded in synthesising several simplified kingianin analogues. Their biological activities on the Bcl-2, Bcl-xL and Mcl-1 proteins will be evaluated in the near future.

Actualmente en Lima Metropolitana, 7 de cada 10 personas consumen bebidas alcohólicas como la cerveza y el trago corto. Este hecho origina que casi el 90% de estas personas padezcan resaca por alcohol, producto de la ingesta excesiva y/o la mezcla de estas bebidas, originando malestar general acompañado de dolor de cabeza, náuseas, mareos y dolor estomacal. Los momentos más frecuentes de consumo que se presentan son los fines de semana, festividades, feriados y fines de mes. Los consumos de las bebidas alcohólicas se presentan en su mayoría en reuniones, fiestas, integraciones familiares, amicales y de trabajo. Para solucionar esta problemática identificada hemos creado R-BORN, una Bebida hecha a base de insumos naturales, teniendo como propuesta de valor principal aliviar el malestar y mitigar los síntomas de la resaca con productos naturales. Esta bebida está hecha a base de tres frutas, las cuales son la tuna, piña y coco, debido a sus componentes y propiedades que permiten contrarrestar los efectos del alcohol. Nuestro producto va dirigido para hombres y mujeres mayores de 18 años hasta los 39 años de edad, que pertenezcan a un nivel socioeconómico A y B, que padezcan el malestar de resaca producto de la ingesta excesiva de bebidas alcohólicas y prefieran combatirla con un producto hecho a base de insumos naturales. Nuestro tamaño de mercado estimado es de 390,378 personas. Asimismo, este producto será comercializado a través de los siguientes canales de ventas: bodegas, ferias saludables, sitio web, redes sociales y venta directa. / Currently in Lima Metropolitan 7 out of 10 people, consume alcoholic beverages such as beer and short drink. This fact results in almost 90% of these people developing alcohol hangover caused by an excessive intake and/or the mixture of these drinks, producing general discomfort accompanied by headache, nausea, dizziness and stomach pain. The most frequent times of consumption that occur are weekends, holidays and weekends. Consumption of alcoholic beverages are the mostly presented in meetings, parties, and family, amical and work integrations. To solve this identified problem we have created R-BORN, a drink made from natural inputs having as its main value proposition to alleviate the discomfort and mitigate hangover symptoms with natural products. This drink is made from three fruits, which are tuna, pineapple and coconut because of its components, and properties that counteract the effects of alcohol. Our product is aimed at men and women over the age of 18 up to the age of 39 who belong to a socioeconomic level A and B who suffer from hangover discomfort resulting from excessive alcoholic beverages and preferring to fight it with a product made from natural supplies. Our estimated market size is 390,378 people. In addition, this product will be marketed through the following sale’s channels: grocery stores, healthy food fairs, website, social networks and direct selling. / Trabajo de investigación