Natural inspired small organic molecules for targeting aquaporins as a novel therapeutic approach to pancreatic cancer

• Autor(a) principal: Jesus, Rita Rodrigues Fernandes de
• Data de Publicação: 2021
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10362/117540
• topic: aquaporins; modulators; electrochemistry; quinolizidine alkaloid; flow chemistry; Domínio/Área Científica::Engenharia e Tecnologia::Engenharia Química

Exploration of natural products for potential therapeutic use and asymmetric organic synthesis is an interesting approach for natural product valorisation. Therefore, in the present work, two projects were investigated: discovery of novel pharmacological agents for cancer treatment and development of a new series of asymmetric catalysts. Aquaporins (AQPs) are transmembrane proteins involved in metastatic and tumour growth processes. Thus, their potential as a novel druggable cancer target prompted the study of AQPs modulators, from natural sources. In this first project, two labdane diterpenes present in Cistus Ladaniferus — Labdanolic acid (LA) and 6-oxocativic acid (OA) — were isolated and their biological activity was studied in three different AQPs (AQP1, AQP3, AQP5), aiming to unleash a new therapeutic application for cancer treatment. Through AQPs permeability assays using the stopped flow technique, results indicated that both compounds were not promising for cancer treatment, since a decrease in permeability is not depicted in any of the AQPs under study. In addition, a linear total synthesis of OA from LA was investigated but without promising results. Using another natural source —Lupinus albus L. — another family of natural products is encountered: quinolizidine alkaloids. Lupanine and Sparteine are members of this family with known pharmacological activity. Sparteine is mostly known for its use in asymmetric catalysis as a chiral base. Considering the possibility of developing a new series of asymmetric catalysts with increased enantioselectivity comparing to the already known chiral base sparteine, and based on studies previously developed in our group, in this second project we envisioned the development of a new series of asymmetric catalysts via functionalization of lupanine with a nitrile functional group, through a yet unreported C-H activation electrochemical approach. In batch, 17-cyano rac-lupanine was obtained in high yield and selectivity, whereas in flow, further studies need to be performed to improve reaction selectivity. Additionally, derivatizations of 17-cyano-rac lupanine and 17-cyano-rac-sparteine were investigated, yielding new synthetically useful products. In the context of finding novel AQPs inhibitors, 17-cyano-rac-lupanine, 17-cyano-rac sparteine and the derivatives synthetized throughout this work were studied in three different AQPs (AQP1, AQP3, AQP5) using the stopped flow technique. No promising results in regard to cancer treatment were obtained. Both projects will add insight to natural product utility.