Design, synthesis, biological evaluation and nanoformulation of novel selenocyanate and diselenide derivatives as leishmanicidal and cytotoxic agents
- Autores: Mikel Etxebeste Mitxeltorena
- Directores de la Tesis: María del Carmen Sanmartín Grijalba (dir. tes.), Socorro Espuelas Millán (codir. tes.)
- Lectura: En la Universidad de Navarra ( España ) en 2020
- Idioma: inglés
- Tribunal Calificador de la Tesis: Antonio Jiménez Ruiz (presid.), Daniel Plano Amatriain (secret.), Esther Moreno Amatria (voc.), Ignacio José Encio Martínez (voc.), Manuela Carvalheiro (voc.)
- Programa de doctorado: Programa de Doctorado en Medicamentos y Salud por la Universidad de Navarra
- Materias:
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- Resumen
Two series of 41 novel Se-containing compounds with potential leishmanicidal and/or antitumoral activity have been synthesized and evaluated in this thesis. Numerous studies have demonstrated the interesting activity of this element in the treatment on both diseases. Taking into account the experience of our research group in this field, 4-aminophenylselenocyanate and bis(4-aminophenyl)diselenide moieties have been selected as core for the design of novel amide and phosphoramidate derivatives.
The newly synthesized compounds have been tested against Leishmania infantum axenic amastigotes. In order to assess their selectivity, cytotoxicity against THP-1 cells was tested. According to their leishmanicidal activity and selectivity, three derivatives were selected for its activity evaluation against infected macrophages. Compounds ability to alter the redox system of the parasite was also studied in order to stablish their possible mechanism of action.
Moreover, their stability under formulation conditions such as temperature, acid, alkaline or oxidative conditions have been evaluated, with such interesting results.
Considering all the obtained data, two compounds (2h and 2m) were selected for further ex vivo and in vivo studies. Compounds, with potent leishmanicidal acitivity and high values of selectivity, were formulated in nanostructured lipid carriers in order to achieve the oral route. Obtained microsomal stability, ex vivo permeation, pharmacokinetics, low in vivo toxicity and interesting in vivo oral antileishmanial activity results, lead 2m-NLC as a promising formulation for the development of a novel leishmanicidal drug in VL cases.
Otherwise, compounds have been tested against a panel of five human cancer cell lines and two non-malignant cell lines. According to their cytotoxicity and selectivity values, derivatives were ranked to stablish the lead compounds. The most promising molecules were selected for further biological and mechanistic studies. Cell cycle status and cell death studies were perform in order to elucidate their possible mechanism of action.
