Design and synthesis of new selenoderivatives with biomedical applications

Abstract

The purpose of this Ph.D. project is the development of novel therapeutic agents incorporating the selenium (Se) atom into the structure of small molecules, thus expanding further knowledge about the design and molecular biology of Se-containing drugs. Se is an essential trace element that exerts multiple and complex effects on human health. This element is crucial for human well-being largely due to its involvement in several physiological functions such as protection against oxidative stress or immune response through its incorporation into selenoproteins. Additionally, Se supplementation and adequate maintenance levels of this micronutrient in the organism have been generally related to the prevention of certain pathologies such as cancer, diabetes, neurological disorders, and infections, among others. Accordingly, a plethora of natural and synthetic Se-containing compounds have been recently studied and explored for their therapeutic potential in the treatment of cancer, leishmaniasis, and other diseases. In this context, we designed four series of compounds in which Se was included in a variety of chemical entities, including acylselenourea, selenocyanate, diselenide, and selenide. Different organic nuclei, ferrocene, and NSAIDs as parent molecules that are suitable to be chemically modified by the incorporation of Se into their structures were also considered in our design. Thus, a total of eighty-three novel selenoderivatives were synthesized and purified. Additionally, their preliminary assessment as therapeutic agents were studied in both in vitro and in vivo assays. The results compiled in this Ph.D. project confirm our initial hypothesis of designing selenoderivatives that may confer biomedical properties and provide new strategies and insights for further developing new small molecules containing Se with therapeutic activity. Our results also reinforce the importance of the chemical form of this chalcogen atom in the structure of the organic scaffold, since it is directly linked to the metabolism process and therefore the biological effect of the resulting selenoderivative. The combination of Se entities with other relevant structural features including the incorporation of biologically active frameworks led to the discovery of potent anticancer or even multitarget drugs with additional antileishmanial and antibacterial activities. This Ph.D. memory is expected to provide a basis for future drug development and stimulate further research of new Se-containing compounds with biomedical applications.