Synthesis and evaluation of 5-substituted (thio)barbiturates as proteasome inhibitors for cancer therapy

• Autor(a) principal: Hummeid, Sara
• Data de Publicação: 2019
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10400.6/8913
• topic: (Tio)Barbituratos 5-Substituídos; Citotoxicidade; Farmácia Comunitária; Farmácia Hospitalar; Inibidores do Proteassoma:cancro; Domínio/Área Científica::Ciências Médicas::Ciências da Saúde::Ciências Farmacêuticas

The present training report was developed to obtain the integrated master’s degree in pharmaceutical sciences. It is subdivided in three chapters that address the three main activities enclosed in the curricular unit “Internship” of the Integrated Master in Pharmaceutical Sciences. The first chapter detailed the laboratorial research component, developed at the Health Sciences Research Center from University of Beira Interior in the area of pharmaceutical chemistry. The ubiquitin proteasome system has been defined as potential target in the treatment of a range of clinical conditions, such as inflammation, neurodegenerative diseases and cancer, particularly, haematological malignancies. A variety of chemical synthesized and natural products have exhibited proteasome inhibitory activity from which three were approved for use in multiple myeloma treatment. 2-Thioxoimidazolidin-4-one arylaldehyde derivatives were described as novel noncovalent proteasome inhibitors in a recent study. Considering the structural similarity of thiobarbituric acid and 2-thioxoimidazolidin-4-one systems, 5-substituted (thio)barbiturate derivatives where designed and efficiently synthesized in this work as a potential novel class of proteasome inhibitors with anticancer interest. In this context, several barbiturate derivatives demonstrated promising antiproliferative effects in different cancer cell lines. Stability study of the 5-benzilidene(thio)barbiturates derivatives in solution was performed and led to the exclusion of 5-benzilidene thiobarbiturates due to their instability. Then, a xanthine oxidase and proteasome inhibition assay were performed. None of the compounds showed relevant inhibition of xanthine oxidase enzyme. However, 5-[1-[2-(4-nitrophenyl)hydrazinyl]ethylidene]barbiturate, 9b, showed interesting inhibitory activity in the proteasome inhibition assay. Cytotoxicity of the assayed compounds was evaluated by the MTT assay in healthy (NHDF) and antiproliferative effect of 9b in cancer cell lines (Caco-2 and PC-3) was assessed and compared with the effect of bortezomib, an approved proteasome inhibitor. Although 9b showed cytotoxicity against healthy and cancer cell lines, it was less potent than bortezomib. The second chapter describes the activities accomplished during the internship in Community Pharmacy that took place in the Pharmacy Holon Covilhã under the supervision of Dr. Patrícia Pais. It is divided to present generally the operations performed at the pharmacy, the legislation that regulates the sector, and the tasks and activities perform. The third chapter describes the hospital pharmacy internship at The Barts Heart Centre in St Bartholomew's Hospital in London, UK that was guided by my main supervisor and contact person, Paul Wright, the Lead Cardiac Pharmacist at Barts. It is organized based on the activity I observed or performed myself. It is divided into four main subchapters, The Barts Heart Centre, Oncology, Clinical trials, and Dispensary.