Síntese, caracterização e avaliação citotóxica de análogos tiossubstituídos do geraniol em células tumorais da linhagem U87MG

Abstract

The cancer is a serious public health problem defined by a set of more than 100 diseases associated with disordered cell growth, which affects various organs and tissues of the body. This disease is responsible for about nine million deaths annually worldw ide and, according to estimates, this number will rise to 11.5 million in 2030. Of this mortality rate, 70% is concentrated in developing countries, such as the Brazil. Therefore, in view of the high number of deaths caused annually by this disease, it bec omes extremely important to develop new alternatives for the treatment of cancer. In this sense, the healing potential of medicinal plants, more specifically the substances found in the essential oils that are extracted from them, have shown to be good pos sibilities in the development of drugs for diseases in general. Among these essential oils, a compound called geraniol showed promising results in recent studies, in vitro and in vivo, evaluating the antineoplastic potential. Among the various types of can cer, glioblastoma multiforme (GBM) is considered one of the rarest and most lethal types, which belongs to the category of central nervous system (CNS) tumors. In general, patients diagnosed with this disease have a very low life expectancy. A significant challenge related to GBM lies in the scarcity of therapeutic options available, since only one drug has been approved by the Food and Drug Administration (FDA) and is used for the treatment of this disease. Considering the demand for new therapeutic altern atives in the treatment of cancer, especially in the case of glioblastoma, and motivated by the promising results obtained with geraniol, an attempt was made to develop derivatives with better properties, aiming at their improved effectiveness in inhibitin g neoplastic cells. Therefore, this work describes the synthesis, characterization and evaluation of the cytotoxic activity of 11 thiosubstituted analogues of this monoterpene against glioblastoma tumor cells of the U87MG cell line. Of the 11 derivatives s ynthesized so far, only 9 were evaluated for cytotoxicity. The compounds were obtained in low to moderate yields ranging from 10 to 69%. The derivatives were characterized by Infrared (FT IR), 13 C and 1 H NMR, DEPT 135 and high resolution mass spectrometry ESI HRMS (ElectroSpray Ionization High Resolution Mass Spectrometry). The evaluation of the cytotoxic activity of the 9 analogues was carried out in relation to cells of the U87MG lineage. IC 50 values were compared to geraniol and Temozolomide, the standard drug used in the treatment of GBM. Notably, compound 3e stood out as the most active among all evaluated compounds, demonstrating an IC 50 of 25 μ M, being at least four times more effective th an the monoterpenoid geraniol and approximately twenty times more potent than the reference drug used in the treatment of Glioblastoma U87MG. Conversely, compounds 3c, 3d, 3dsub, 3esub, and 5c yielded IC 50 values ranging from 57,8 to 86,6 μ M, whereas the r emaining compounds exhibited values exceeding 100 μ M.