Síntese, caracterização e avaliação da atividade citotóxica de análogos ao Geraniol contra a linhagem celular tumoral de Glioblastoma U87MG

Abstract

Cancer has long been a major public health problem and affects all countries around the world. By 2020, it is estimated that there will be approximately 19.3 million new cases and 10 million deaths from the disease. Cancer encompasses a wide variety of diseases, which differ in the regions of the body that are affected. One of the rarest and most lethal cancers is Glioblastoma multiforme (GBM), included in the class of central nervous system (CNS) cancers. Generally, patients with the disease live only 12 to 18 months after diagnosis. One problem with GBM is the lack of variety in the treatment of the disease: Only four drugs are approved by the FDA (Food and drug administration) and used in the treatment of the disease. Thus, the need arises for the development of new compounds that offer an effective and at the same time less aggressive treatment to healthy cells. In this context, products of natural origin have shown promise in fighting these cancerous cells. Among these products, some classes, such as terpenes, stand out. One of the most well-reported monoterpenes by the scientific community is Geraniol. Geraniol has shown interesting characteristics in the pharmacological field, especially when it comes to its anti-cancer activity. In this context, this research reports a proposal for the synthesis, characterization, and evaluation of the cytotoxic activity against glioblastoma tumor cells (U87MG strain) of 24 geraniol analogues, 16 of which are novel derivatives. The analogs consist of eight terpenic 1(a-h) amino alcohol derivatives and their four N,N-dialkenylated by-products (2a, 2c, 2e, and 2f), three acetylated 3a, 3b, and 3f

derivatives, two mesylate intermediates 4a/4b, six derivatives from different nucleophiles 5(a- c) and 6(a-c) and two diamine derivatives 7a and 7b. The terpene amino alcohols 1a-h and their

N,N-dialkenylated by-products 2a, 2c, 2e, and 2f were obtained with yields of 18-85%; the acetylated derivatives 3a, 3b, and 3f, 66-95%; the mesylate intermediates 4a and 4b, 90 and 96%, respectively; the derivatives 5b, 5c, and 5c(sub), 45-78%; the compounds 6a, 6b(sub) and 6c, 43-86% and the derivative 7a obtained with a yield of 81%. All products, except intermediates 4a and 4b (characterized by FT-IR only), were characterized by FT-IR and NMR (1H, 13C, and DEPT-135). The novel derivatives were characterized by ESI-HRMS. The cytotoxic activity of 16 of the 24 analogues was evaluated against U87MG lineage cells, and IC50 values were calculated in comparison to Geraniol and the standard drug used in the treatment of GBM, Temozolomide (IC50 = 1mM or 1000 μM). The activity presented by the compound N,N-dialkenylated 2a with IC50 = 2.71 μM stands out, a value about 369 times higher than Temozolomide. Other derivatives (1e, 2e, 2f, 2c, 1a, and 7a) showed IC50 values ranging from 6.47 to 56.5 μM, also showing promise. The rest of the analogs evaluated presented IC50 >100 μM, the highest concentration value evaluated. Based on the results, it was possible to perform a structure-activity relation of the synthesized analogues.