Syntheses of (S)-Bicalutamide and Somatostatin analogs, and development of Green procedures for Peptide synthesis
[eng] Peptides are defined as compounds that contain between two and fifty amino acids connected together by amide bonds. Inside our body, peptides are natural biological messengers that play critical roles in human physiology as hormones, neurotransmitters, growth factors or antibacterial agents. S...
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| Tipo de documento: | tese |
| Estado: | Versão publicada |
| Data de publicação: | 2021 |
| País: | España |
| Recursos: | Universidad de Barcelona |
| Repositório: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/181970 |
| Acesso em linha: | https://hdl.handle.net/2445/181970 http://hdl.handle.net/10803/673027 |
| Access Level: | Acceso aberto |
| Palavra-chave: | Química farmacèutica Síntesi de pèptids Pharmaceutical chemistry Peptide synthesis |
| Resumo: | [eng] Peptides are defined as compounds that contain between two and fifty amino acids connected together by amide bonds. Inside our body, peptides are natural biological messengers that play critical roles in human physiology as hormones, neurotransmitters, growth factors or antibacterial agents. Since the first efforts on peptide synthesis circa 1900 and the introduction of cleavable protecting groups (PGs), the real breakthrough in the field was the concept of solid-phase peptide synthesis (SPPS) reported by B. Merrifield in 1963. This strategy conceived the use of a polymeric insoluble resin to make the peptide chain grow without having to isolate synthetic intermediates as in previous solution-phase methods. To date, Fmoc/tBu SPPS has gained almost optimal efficiency in terms of coupling efficiency and duration in detriment of solvent consumption, which has been recognized as environmental issue under a Green Chemistry point of view. The first objective (Chapter 2) of this doctoral thesis was to chemically explore new green SPPS methodologies that permit: i) the reduction of hazardous organic solvents using water as the main one; and ii) the minimization of PGs using N-α-unprotected amino acids. The use of orthogonal PGs such as Fmoc (base labile) for the α-amino group or the acid-labile PGs for the sidechains (e.g. Boc, tBu, Trt, Pbf) permitted to use trifluoroacetic acid (TFA) only once, specifically, in the last cleavage/deprotection step of the synthesis. Once the acidic peptide solution is separated from the polymeric resin, the peptide must be precipitated with great volumes of cold diethyl ether (DEE). Under the perspective of Green Chemistry, both TFA and DEE are considered as high concern substances. Therefore, the reduction of these substances is very desirable in industrial acidolysis processes. The second objective (Chapter 3) of this doctoral thesis was to study the possible use of green solvents in peptide cleavage and deprotection procedures. Somatostatin (SST14) is a 14-amino acid cyclopeptide hormone discovered in 1973 that in our body acts as a neuromodulator, a neurotransmitter and a potent inhibitor of various secretory processes and cell proliferation. Because of its broad modulatory activity, SST14 was conceived as an interesting peptide for clinical applications. However, its full therapeutic potential could not be exploited because of its short plasma half-life (t1/2 < 3 min). Therefore, since the 1980s great efforts on finding shorter somatostatin analogs (SSAs) have been performed. The strategy of BCN Peptides and Riera Lab consisted in modifying the original SST14 sequence with unnatural aromatic amino acids maintaining the 14-amino acid structure. By doing this, both the conformation of the synthesized analogs and 1 their biological activity could be effectively modulated. The third objective (Chapter 4) of this doctoral thesis was to design and develop new stable analogs maintaining the 14-amino acid structure of the parent peptide. Unnatural aromatic and D-amino acids were used for the design of these new analogs. Bicalutamide is an oral non-steroidal anti-androgenic drug that has been used in the treatment of prostate cancer since 1995. Bicalutamide is clinically administered in its racemic form, though the anti- androgenic activity is exclusively found in the (R)-enantiomer, being (S)-bicalutamide inactive and non-toxic. Recently, Farrera and co-workers at BCN Peptides demonstrated in vitro the potential use of (S)-bicalutamide as an exocytosis activating compound that could be used as a universal treatment for Lysosomal Storage Diseases (LSDs), which involve the accumulation of macromolecules inside the lysosomes. This abnormal accumulation might initiate a cascade of secondary effects, ultimately leading to irreversible cellular damage or cell death. Despite the in vitro results, the effectiveness of (S)-bicaluamide must be confirmed in vivo in preclinical and clinical studies. The fourth objective (Chapter 5) of this doctoral thesis was to design and develop a synthetic route to obtain (S)-bicalutamide, as well as its precursors using large-scale procedures and methodologies. In addition, this synthetic route was adapted to follow Good Manufacturing Practices (GMP) to produce (S)-bicalutamide according to the required quality standards to use it in preclinical studies. |
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