Design, synthesis and biological evaluation of new organoseleno compounds as cytotoxic and leishmanicidal agents

Résumé

A series of thirty-three novel selenium-containing compounds with potential antitumoral and/or leishmanicidal activity have been synthesized and evaluated in this work. Numerous preclinical studies have proven the strong dependency between chemical form of Se and its biological activity. Taking into account the experience of our research group in this field, we selected two leader compounds bis(4- aminopheny)diselenide and 4-aminophenyselenocyanate to design second generation derivatives. The structural modifications performed on these core structures had the aim of improving their activity and selectivity. The novel derivatives containing the functionalities diselenide and selenocyanate have been tested against a panel of several human cancer cell lines and two cell lines derived for non-malignant tissue. Once obtained their cytotoxic profiles and selectivity, derivatives were ranked to stablish the hit compounds. The most promising molecules have been selected to preform further biological studies relative to cell death and cell cycle status in order to elucidate their mechanism of action. Moreover, the development of new methodologies that enable the possibility to study the glutathione peroxidase mimetic ability of new derivatives has been explored. The leishmanicidal activity of the synthesized Se-containing compounds was analyzed against Leishmania Infantum axenic amastigotes. In order to assess selectivity cytotoxicity against THP-1 cells was tested. According to potency and selectivity six derivatives were selected to further study the mechanism of action by which they cause their effect. Also, we decided to explore the ability of these compounds to inhibit Trypanothione Reductase, enzyme that plays a crucial role in the survival of the parasite. In addition, their stability under formulation conditions such as temperature, acid or alkaline conditions have been evaluated. The objective was to predict the non- desired transitions or degradation processes that may occur along the pharmaceutical manufacturing processing.