Browsing by Author "Baptista, Maria Gomes de Pinho"
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- Synthesis of novel potentially bioactive Pseudo-C-Nucleosides for the treatment or control of Bipolar DisorderPublication . Baptista, Maria Gomes de Pinho; Ismael, Maria Isabel Guerreiro da Costa; Silvestre, Samuel MartinsCarbohydrates are natural aliphatic polyhydroxy aldehydes and ketones with an empirical formula of Cn(H2O)n that are distributed throughout our planet. This class of compounds have a central role in numerous physiological events, such as in cellular communication, and are part of the basic structure of some endogenous biomolecules. It also presents several chiral carbons that confers them stereogenic centres, which is an advantage for the selective interaction with the biological targets. In fact, carbohydrates are considered privileged scaffolds and can be linked to several pharmacophores, such as heterocycles, forming pseudo-C-nucleosides, which are composed by a heterocyclic ring attached to the carbon 4 of the furanose ring by a carbon-carbon bond. Therefore, they are largely used at the therapeutic level in the treatment of several illnesses. As an important example the association between carbohydrates and the treatment of bipolar disorder occurred through the discovery of an anticonvulsive compound, topiramate. Bipolar Disorder (BD), also known as manic-depressive illness, affects between 1 to 4% of the world's population and is characterised by recurrent mood changes, named manic or depressive episodes. In a manic episode, the patient is extremely euphoric, while in depressive episodes the patient feels depressed and may present suicidal tendencies. Currently, the most effective drug on the market for the treatment of this disorder is Lithium Carbonate. However, this inorganic compound has very significant adverse effects. Despite a large group of studies that have been developed in this context, it has not yet been possible to clearly identify the pathological basis of this disease as well as the mechanism of action of Lithium Carbonate. Thus, as presently there is a clear lack of available pharmacological alternatives for the treatment of this disease, the objective of this dissertation was to synthesise pseudo-C-nucleosides with potential interest for the treatment of BD and subsequent evaluation of cytotoxicity. For this purpose, three different techniques to synthesise the pseudo-C-nucleosides were performed, the Click Chemistry, the cyclization to form pyrazolidin-3-ones and the cyclization to form 5-hydroxypyrazoles. From these three strategies seven different compounds, six of which are pyrazolidin-3-one derivatives and one 5-hydroxypyrazole, have been obtained. Finally, MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide] assays were performed to evaluate the cytotoxicity of the final compounds synthesised in two different cell lines, NHDF (Normal Human Dermal Fibroblasts) and N27 (Rat Mesencephalic Dopaminergic Neural Cells). In both cell lines, the compounds under study did not show relevant cytotoxicity. Thus, even if it was not possible to infer their potential for the treatment of BD, the results obtained for cytotoxicity are positive indicators to continue to develop tests to evaluate the activity of this compound for the treatment of this disorder.