Avaliação do efeito anticancer de compostos sinteticos derivados do núcleo tetraidropirano

Abstract

Despite the investments in the search for more effective cancer therapies, the high incidence and mortality produced by this disease continue to increase, which has provoked public health problems to the population. In parallel to the progress of this situation, it has been found a breakthrough in the medicinal chemistry allowing synthesis of a variety of compounds, encouraging researchers into new structures with rich therapeutic potential. The synthesis of compounds derived from tetrahydropyran nucleus (DNT) has been receiving attention, considering the broad of biological activity from these structures. Therefore, the aim of this study was to analyze the cytotoxic activity of 31 DNT compounds. Cell viability was determined by MTT reduction and neutral red stain (CVN) assays. From such 31 compounds studied, only 42a-c and 43a - c showed potent cytotoxic effect on human cancer lines (K562, HL-60, HT-29 and MCF- 7) and a less significant cytotoxic effect on non-cancerous cells (L929 and PBMC cells) were shown. The leukemic cell lines K562 and HL-60 were the most sensitive ones. Compounds 42b and 43c, with IC50 values which range from 8.97 ± 4.1 to 35.35 ± 5.2 for the lines HL-60 and K562, were considered the most promising molecules in terms of their cytotoxic effect and they also demonstrated in primary cultures of peripheral blood and bone marrow from patients with chronic myeloid leukemia. The ability of 42b and 43c compounds to induce molecular changes related to the type of cell death was assessed by flow cytometry. In K562 cells, the compounds 42b and 43c showed similar effect causing an increase in the concentration of hipodiploide DNA and they arrested in the G1 phase of the cell cycle. From double labeling annexin/IP assay, the compound 43c increased about 20% of PI fluorescence. For HL-60 cell line, the compounds 42b and 43c augmented the concentration of hipodiploide DNA and and depolarization of mitochondrial membrane. The compound 43c stimulated ROS production and double staining to annexina/IP. Compounds 42b and 43c showed a potent cytotoxic effect and antileukemic activity, inducing apoptosis and cell cycle. However, there is a need for structural modifications that increase the selectivity of these compounds for cancer cells.