Búsqueda de nuevos selenoderivados con potencial antitumoral y leishmanicida: Diseño, síntesis y desarrollo preclínico

Abstract

This work, entitled New selenoderivatives with dual activity. Synthesis and preclinical development of their antitumor and leishmanicidal potential, describes the design, synthesis and preliminary biological evaluation of new active molecules containing selenium (Se) in their structure as a treatment and prevention of cancer, as well as for the fight against human leishmaniasis. Numerous preclinical studies have demonstrated the relevance of the chemical form of Se and its biological activity. Based on the literature and the experience of our research group, we have studied molecules with Se in different chemical forms and different substituents. For this purpose, 48 new compounds have been synthesized, where Se is introduced in the form of Se-acylsoselenourea and acylselenourea (Part 1), or in the form of selenoester, selenocyanate and selenol (Part 2). In Part 1, 22 new derivatives of Se-acylisoselenourea and acylselenourea have been studied as antitumor agents (Chapter 1). To the best of our knowledge, this is the first time that carbodiimides have been used as a substituent in the design of new antitumor agents. These new selenoderivatives were evaluated in vitro in 3 tumor cell lines of breast, prostate, and lung. Compound 4 highlighted for its potential activity, showing the lowest IC50 despite being poorly selective. This hit compound has demonstrated its ability to induce cell death by apoptosis and increase the generation of reactive oxygen species (ROS). The 22 new derivatives were evaluated in Chapter 2 as potential leishaminicidal agents in promastigotes of two Leishmania species, L. major and L. infantum. Compounds 8 and 21 showed potent leishmanicidal activity, especially on L. infantum, with EC50 below 10 µM. Moreover, compound 8 showed a synergistic effect with the reference drug miltefosine in L. major species. Finally, these structures have shown potent antioxidant, presenting similar values of activity when compared with the positive controls ascorbic acid and Trolox. Part 2 also contains two chapters as in the previous Part. The first of them (Chapter 3) provides a bibliographic review of a structure used as a nucleus in the design of new antitumor agents, 1,4-naphthoquinone. This chapter includes the different natural and synthetic derivatives that have been designed and evaluated as antitumor agents in the last 10 years. This review also describes the main mechanisms of action of these 1,4-naphthoquinone-derived compounds. In the next chapter, chapter 4, based on the antitumor potential of 1,4-naphthoquinone and its derivatives described in chapter 3, 26 novel naphthoquinone derivatives containing Se in their structure in different chemical forms were designed. The selenoesters showed potent antitumor activity, especially compounds B2 and B8, which are selective against breast cancer. Currently, their mechanism of action in being elucidated among the most typical mechanisms known for naphthoquinones: induction of apoptosis, generation of ROS and inhibition of topoisomerase II. Related to Part 3, the advances made in recent years in the design and synthesis of chemical molecules as inhibitors or modulators of four enzymes involved in glucose metabolism (hexokinase, pyruvate kinase, pyruvate dehydrogenase kinase and lactate dehydrogenase), which are overexpressed in cancer and have become potential therapeutic targets, have been discussed. The results obtained in this PhD dissertation reinforce the hypothesis that the incorporation of Se into organic molecules is a valid approach for the design of potential antitumor and leishmanicidal agents.