Potencial citotóxico e predições farmacocinéticas de um derivado de chalcona tipo terpenóide

Abstract

Cancer is a serious public health problem and has a considerable impact on the morbidity and mortality rate worldwide. Anticancer therapy faces several challenges, including drug resistance and serious side effects that compromise patients' quality of life, making it necessary to search for new therapeutic strategies. Medicinal chemistry is emerging as a leading area in the synthesis of new compounds, mainly seeking to optimize efficacy and safety properties, aiming to improve quality of life in the fight against cancer. In this context, the aim of this study was to evaluate the in vitro cytotoxic profile and in silico pharmacokinetic predictions of a terpenoid-type chalcone derivative (BR4Cl) containing chlorine as a halogen substituent. Initially, the cytotoxicity of BR4Cl was evaluated in nine cell lines (seven cancerous and two non-cancerous). The MTT test showed that the HCT-116 strain was more sensitive to the effects of the molecule, with a CI50 of 8.58μM after 72h of treatment. BR4CL was more selective for cancer cells after 72 hours of treatment. In the hemolytic test, using O+ human erythrocytes, there was no lysis at the concentrations tested, demonstrating good biocompatibility. When checking the minimum exposure time for the molecule to start acting on the cells, it was observed that a 3-hour exposure was enough to show changes in cell proliferation. Based on the 24-hour CI50 for HCT-116, trypan blue exclusion assays and morphological analysis by staining with the rapid panoptic kit were carried out at concentrations of 7.5, 15 and 30 μM. A significant decrease in cell viability was observed at concentrations of 15 and 30 μM, when compared to the negative control. Morphological analysis revealed cellular characteristics suggestive of cell death, especially intense vacuolization, especially at the highest concentration tested. As a result, a 72-hour MTT test was carried out with a co-treatment of BR4Cl and Chloroquine, a late autophagic inhibitor, to ascertain the effects of this inhibitor on the cytotoxic activity of the molecule. The results suggest the participation of the autophagic pathway in the cell death process induced by BR4Cl. In addition to the in vitro tests, in silico tests were carried out to verify its absorption, distribution, metabolism, excretion and toxicity parameters in the body, which showed promising potential for oral administration, with good absorption from the gastrointestinal tract. However, distribution, metabolism and excretion parameters suggest possible drug interactions, adverse effects and challenges in the clearance of the compound as well as its excretion. In addition, BR4Cl presented a moderate risk of cardiotoxicity, due to inhibition of the hERG gene, and was shown to be mutagenic, with carcinogenic potential in mice, although not in rats. Structural modifications can improve the pharmacokinetic properties of the sample and reduce adverse effects, while maintaining its anticancer potential. Additional studies will therefore be carried out to elucidate the mechanisms of action of BR4Cl involved in its cytotoxic effect, mitigate the risks of toxicity and drug interactions, and thus exploit the therapeutic potential of this molecule.