Chemical engineered extracts of Portuguese biorenewable resources to the synthesis of diverse natural products hybrids towards new bioactive entities

• Autor(a) principal: Nunes, Gonçalo Bernardo Fidalgo
• Data de Publicação: 2022
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10362/158350
• topic: Natural products; Thiol-ene; Cistus ladanifer; labdanolic Acid; Domínio/Área Científica::Engenharia e Tecnologia::Engenharia Química

Natural products (NPs) with biologically active pharmacophores are biologically validated starting points for the development of new drugs. Between 1981 and 2019, NPs and their derivatives represented 24% of all newly approved drugs. Cistus ladanifer is an aromatic plant from Mediterranean climates that exist in high quantity in Portugal. Cistus ladanifer essential oils have shown antimicrobial and antitumoral biological activities. An interesting methodology to access NPs derivatives is the preparation of chemically engineered extracts (CEEs). This approach focuses on the transformation of selected chemical functionalities, highly common in natural products extracts, into new chemical entities. This work aims to develop a new and efficient methodology to prepare CEEs from Cistus ladanifer. To this end, light-mediated thiol-ene reaction, was applied to natural extracts of Cistus ladanifer, to took advantage of alkene functional groups and form thioether-CEEs. The optimization of the reaction conditions was executed using limonene as model substrate (3 equiv. of N-acetylcysteine, 0.1 equiv. of DMPA, dry MeOH, 2.2 M limonene, for 1h at 365 nm in a FEP Tube). The optimized reaction conditions were applied to a basic fraction of the natural extract of Cistus ladanifer, however further optimization was needed. Cistus ladanifer profile was studied through UPLC/ESI-HR-MS and two approaches were used for the purification of the new CEEs. (i) Flash chromatography, where the best protocol was based in an initial MTBE acid/basic workup followed by 2 consecutives normal phase column chromatography’s (ii) semi-preparative HPLC that allowed the identification of 3 Peaks at 254 nm. The m/z identified correspond to 33 possible compounds in peak 1, 19 in peak 2, and 37 in peak 3. The main compound of the acid fraction of Cistus ladanifer, labdanolic acid, was also studied. A methylation reaction followed by a dehydration allowed the introduction of alkenes in the molecule making it susceptible to thiol-ene reaction. Unfortunately, no conversion was obtained.